Action and Clinical
Triavil exerts the actions of its components. Perphenazine is a potent tranquilizer and also a potent antiemetic. Perphenazine has a nonhypnotic depressant activity on the CNS and is capable of relieving anxiety, tension, psychomotor excitement and other psychotic symptoms. Perphenazine has also widespread effects which include central and peripheral adrenergic blocking effects, anticholinergic action and loss of inhibitory control of the basal ganglia, which may result in extrapyramidal symptoms.:
In addition, perphenazine has endocrine, antihistaminic, antiserotonin, metabolic and other effects. Its central adrenergic blocking action is believed to result from interference with norepinephrine uptake at the nerve cell endings, and appears to act principally in the subcortical area.
Amitriptyline is an antidepressant with sedative properties. Its mechanism of action in man is not known. It is not a MAO inhibitor and it does not act primarily by stimulation of the CNS.
Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since re-uptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the re-uptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline. It has also anticholinergic properties.
Indications And Clinical Uses:
In patients with agitated depression. It is particularly indicated in patients with depression associated with marked psychomotor unrest.
It has also been found useful in some schizophrenic patients who have associated symptoms of depression.
Triavil has been used in depressed patients, suffering from marked agitation, anxiety and tension, who may respond to the combination of a phenothiazine with amitriptyline.
In depression of the CNS caused by drugs (barbiturates, alcohol, narcotics, analgesics, antihistamines); in the presence of evidence of bone marrow depression; and in patients known to be hypersensitive to phenothiazines or amitriptyline.
This drug is not recommended for use during the acute recovery phase following myocardial infarction, and in the presence of acute congestive heart failure.
Triavil should not be given concomitantly with guanethidine or similarly acting compounds, since amitriptyline, like other tricyclic antidepressants, is capable of blocking the antihypertensive effect of these compounds.
Monoamine oxidase (MAO) inhibitor drugs may potentiate other drug effects and such potentiation may even cause death. Accordingly, Triavil should not be given to patients who have been receiving an MAO inhibitor, for at least 2 weeks after stopping the MAO inhibitor. In such patients, it is recommended that therapy with Triavil be initiated cautiously with gradual increase in the dosage required to obtain a satisfactory response.
Warnings in Clinical States:
Tricyclic antidepressant drugs, including amitriptyline, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia and prolongation of conduction time. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, these drugs should be used with caution in patients with a history of cardiovascular disease, such as myocardial infarction and congestive heart failure.
Because of the anticholinergic activity of amitriptyline, Triavil should be used with caution in patients with glaucoma and in those who may be expected to experience problems of urinary retention.
Occupational Hazards: The drug may impair alertness in some patients; operation of automobiles and other activities made hazardous by diminished alertness should be avoided.
Perphenazine can lower the convulsive threshold in susceptible individuals. It should be given with caution to patients with convulsive disorders. Dosage of the anticonvulsive agent may have to be increased.
Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements may develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome.
If signs and symptoms of tardive dyskinesia appear in a patient on Triavil, drug discontinuation should be considered, as the syndrome may remit, partially or completely. However, some patients may require treatment despite the presence of the syndrome.
Neuroleptic Malignant Syndrome: A potentially fatal syndrome complex, sometimes referred to as neuroleptic malignant syndrome (NMS), has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are muscle rigidity, altered mental status, and evidence of autonomic instability (labile pulse and blood pressure, hyperpyrexia, diaphoresis and cardiac dysrhythmias).
If a patient manifests evidence of NMS, therapy with Triavil should be discontinued immediately. If a patient requires antipsychotic therapy after recovery from NMS, the potential re-introduction of Triavil should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
General: The possibility of suicide in seriously depressed patients is inherent in the illness and may remain until significant remission occurs. Patients should be closely supervised during the early phase of therapy with Triavil in case they may require hospitalization or concomitant electroshock therapy in addition to therapy with Triavil.
As with any psychotherapeutic agent, patients should be cautioned by the physician against errors of judgment attributable to change in mood.
As with all phenothiazine compounds, perphenazine should not be used indiscriminantly. Caution should be observed in giving it to patients who have previously exhibited severe adverse reactions to other phenothiazines.
Some of the untoward actions of perphenazine tend to appear more frequently when high doses are used. However, as with other phenothiazine compounds, patients receiving perphenazine in any dosage should be kept under close supervision.
The antiemetic effect of perphenazine may obscure signs of toxicity due to overdosage of other drugs, or render more difficult the diagnosis of disorders such as brain tumors or intestinal obstruction.
A significant, not otherwise explained, rise in body temperature may suggest individual intolerance to perphenazine, in which case Triavil should be discontinued.
The tendency for antidepressant medication to provoke mania or hypomania in manic-depressive patients has been reported in the literature. The tranquilizing effect of Triavil has seemed to reduce the likelihood of this effect.
Poor Metabolizers of Debrisoquine/Sparteine: Like other tricyclic antidepressants, Triavil is metabolized by the specific hepatic cytochrome P450Â isozyme (IID6), which is responsible for the metabolism of debrisoquine and sparteine. Poor metabolizers of debrisoquine/sparteine represent approximately 5Â to 10% of the white North American population.
Following usual doses of tricyclic antidepressants, plasma concentrations may be higher than expected in these patients. Cautious dose titration is recommended if Triavil is to be administered to patients known to be poor metabolizers of debrisoquine/sparteine. Monitoring of drug plasma levels should be considered.
Phenothiazines may potentiate the action of CNS depressants (opiates, analgesics, antihistamines, barbiturates, alcohol) and atropine. In concurrent therapy with any of these, Triavil should be given in reduced dosage. Patients should be cautioned that the response to alcohol may be increased. Phenothiazines also may potentiate the action of heat and phosphorus insecticides.
If hypotension develops, epinephrine should not be employed, as its action is blocked and partially reversed by perphenazine.
Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.
When amitriptyline is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosage are required. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.
Delirium has been reported with concurrent administration of amitriptyline and disulfiram.
Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with 1Â g of ethchlorvynol and 75Â to 100Â mg of amitriptyline.
Interactions Mediated through Cytochrome P450 Isozyme IID6: Like other tricyclic antidepressants, Triavil is metabolized by the hepatic cytochrome P450Â isozyme, P450Â IID6, which is responsible for the metabolism of debrisoquine and sparteine. Elevated levels of Triavil may result when the drug is co-administered with agents which compete for metabolism by P450Â IID6 such as selective serotonin reuptake inhibitors (e.g. paroxetine, fluoxetine, sertraline, and fluvoxamine), phenothiazines (e.g. fluphenazine, thioridazine, perphenazine), and TypeÂ 1c antiarrhythmics (e.g. propafenone, flecainide). Agents (e.g. quinidine) which inhibit the isozyme may exert a similar effect. Dosage adjustments and monitoring of drug levels should be considered if Triavil is to be used in combination with these agents.
Children: Since a children’s dosage has not been established, Triavil is not recommended for use in children.
Pregnancy: Triavil is not recommended for use in pregnant patients. Reproduction studies in rats have shown no fetal abnormalities; however, clinical experience and follow-up in pregnancy have been limited, and the possibility of adverse effects on fetal development must be considered.
Lactation: Amitriptyline is detectable in breast milk. Because of the potential for serious adverse reactions in infants from amitriptyline, a decision should be made whether to discontinue nursing or discontinue the drug.
Clinical evaluation of Triavil has not revealed any adverse reactions peculiar to the combination. The adverse reactions that occurred were limited to those that have been reported previously for perphenazine and amitriptyline.
Perphenazine: Behavioral: Oversedation, impaired psychomotor function, paradoxical agitation or excitement and aggravation of psychotic symptoms. Catatonic-like states, lassitude, insomnia, bizarre dreams and toxic confusional states have also been described.
Neurologic: Extrapyramidal symptoms (opisthotonos, oculogyric crisis, hyperreflexia, dystonia, akathisia, dyskinesia, parkinsonism) have been reported. Their incidence and severity usually increase with an increase in dosage, but there is considerable individual variation in the tendency to develop such symptoms. Extrapyramidal symptoms can usually be controlled by the concomitant use of effective antiparkinsonian drugs, such as benztropine mesylate, and/or by reduction in dosage. In some instances, they may persist after discontinuation of the drug. Paresthesias, slowing of the EEG, disturbed body temperature, muscle weakness and convulsions have also been reported.
Autonomic: dry mouth, constipation, urinary frequency, blurred vision, and nasal congestion may occur.
Cardiovascular: Severe, acute hypotension has occurred with phenothiazines, and is of particular concern in patients with mitral insufficiency or pheochromocytoma. ECG abnormalities (quinidine-like effect) have also occurred with phenothiazine compounds. Changes in pulse rate and cutaneous vasodilation have been reported.
Toxic and Allergic: The phenothiazine compounds have produced blood dyscrasias (pancytopenia, thrombocytopenic purpura, leukopenia, agranulocytosis, eosinophilia); and liver damage (jaundice, biliary stasis). These have not been observed with perphenazine.
Skin disorders have occurred with phenothiazine compounds (photosensitivity, itching, contact dermatitis, erythema, urticaria, eczema, up to exfoliative dermatitis), as well as other allergic reactions (asthma, laryngeal edema, angioneurotic edema, anaphylactoid reactions).
Endocrine and Metabolic: disturbances in the menstrual cycle, lactation, swollen breasts, failure of ejaculation, reduced sexual urge in the male, increased sexual urge in the female, pseudopregnancy, infertility, and glycosuria, increased appetite, weight gain, hyperglycemia, altered cerebrospinal fluid proteins, peripheral edema.
Ophthalmologic: Centrally located stellate cataracts, corneal opacities, pigmentation of the conjunctiva, cornea or lens, lacrimation, and kerato-conjunctivitis have been reported following the use of phenothiazines. Pigmentary retinopathy has been reported with some phenothiazines with a piperidyl-ethyl side chain.
Miscellaneous: Other adverse reactions reported with various phenothiazine compounds include gastrointestinal effects such as nausea, vomiting and heartburn; potentiation of CNS depressants; headache; and cerebral edema.
Amitriptyline: Behavioral: Confusional states, disturbed concentration, disorientation, delusions, hallucinations, excitement, anxiety, restlessness, drowsiness, insomnia, nightmares.
Neurological: epileptiform seizures, coma, dizziness, tremors, numbness, tingling, paresthesias of the limbs, peripheral neuropathy, headache, ataxia, alteration in EEG patterns, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria, tinnitus, incoordination, and slurred speech.
Anticholinergic: urinary retention, dilatation of the urinary tract, constipation, paralytic ileus, especially in the elderly, hyperpyrexia, dry mouth, blurred vision, disturbance of accommodation, increase intraocular pressure, precipitation of latent glaucoma, aggravation of existing glaucoma, and mydriasis.
Cardiovascular: Quinidine-like effect and other non-specific ECG changes and changes in AV conduction, prolonged conduction time, asystole, hypotension, syncope, hypertension, palpitation, arrhythmias, heart block, ventricular tachycardia, fibrillation, myocardial infarction, stroke, unexpected death in patients with cardiovascular disorders.
Allergic: skin rash, urticaria, photosensitization, edema of face and tongue.
Hematologic: bone marrow depression including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.
Gastrointestinal: nausea, epigastric distress, vomiting, anorexia stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue, rarely hepatitis (including altered liver function and jaundice).
Endocrine: testicular swelling and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, impotence, elevation or lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion.
Miscellaneous: Other adverse reactions that may occur include fainting, weakness, urinary frequency, alopecia and increased perspiration.
Symptoms And Treatment Of Overdose:
OverdoseSymptoms: Deliberate and accidental overdoses with tricyclic antidepressants have been associated with fatalities. Depression of the level of consciousness and marked anticholinergic reactions are the most common manifestations of tricyclic antidepressant overdose. Agitation, confusion, extrapyramidal signs, and hallucinations may also be present. Patients may progress rapidly from lethargy to coma and respiratory failure. Severe hypotension, ventricular arrhythmias, seizures, and respiratory arrest are the major causes of morbidity and mortality. Treatment is essentially supportive.Treatment
Treatment: If overdosage with a tricyclic antidepressant is suspected, the patient should be admitted to the Emergency Department without delay. Gastric lavage should be performed promptly. In the obtunded patient, a cuffed endotracheal tube should be used to secure the airway before beginning lavage. Because the anticholinergic effect of these drugs may delay gastric emptying, lavage is recommended for 12Â hours or more after the overdose. Activated charcoal with a cathartic such as sorbitol should be given after lavage. Repeated doses of activated charcoal every 6Â hours can be given if bowel peristalsis is not suppressed. Persistent unconsciousness (>48Â hours) in the absence of hypoxic brain injury should prompt a search for a pill bezoar. The induction of emesis is not indicated as consciousness can be lost precipitously in tricyclic overdose, and aspiration is a frequent complication.
Maintenance of oxygenation and ventilation is crucial. As seizures, coma, and arrhythmias are exacerbated by acidosis, metabolic or respiratory alkalosis should be induced. Intubation should be undertaken early if there is a decreased level of consciousness. Mechanical ventilation can be used to induce an alkalosis. Arrhythmias and seizures may be abolished when the pH has been titrated to a level within a range of 7.45Â to 7.55; however, a pH of 7.60Â should not be exceeded. An infusion of sodium bicarbonate is often helpful in maintaining the alkalosis.
ICU admission with ECG monitoring is required for all patients with neurological abnormalities, anticholinergic manifestations of overdose, or symptoms of cardiac toxicity (incl. a QRS duration greater than 100Â msec). If overdose is suspected, but these abnormalities are not present at admission to the Emergency Department, the patient should be observed for 6Â hours. If no such abnormalities develop, the likelihood of significant toxicity is low. ECG monitoring should be continued for a period of 24Â hours after full consciousness has been regained and cardiac conduction normalized. Late deaths due to arrhythmias have been reported, but in almost all cases the patients had persistent neurological changes or ECG abnormalities at the time of discharge.
Arrhythmias are usually responsive to aggressive alkalinization. Recalcitrant arrhythmias may respond to lidocaine or phenytoin, but these drugs should be given cautiously since they may induce bradyarrhythmias. Class IA anti-arrhythmics (quinidine, procainamide, disopyramide) are contraindicated. Beta-blockers may control tachyarrhythmias, but frequently induce severe hypotension, bradyarrhythmias or third degree atrioventricular block. Overdrive pacing has been used successfully to control tachyarrhythmias. Cardiac pacing is sometimes effective in severe bradycardia or asystole. Potassium replacements should be undertaken cautiously since hyperkalemia may induce or worsen arrhythmias. Because of its effect on cardiac conduction, digitalis should be used only with caution. If rapid digitalization is required for the treatment of congestive heart failure, special care should be exercised in using the drug. Close monitoring of cardiac function of not less than 5Â days is advisable.
Hypotension is usually responsive to i.v. fluids. If hypotension persists after 2Â to 3Â L of normal saline in Ringer’s lactate has been infused, right heart catheterization should be considered since the tricyclic antidepressants can cause direct myocardial depression. Inotropes such as dopamine and dobutamine should be used cautiously, since they may induce, or worsen, arrhythmias. Some authorities suggest norepinephrine as the inotrope of choice.
Seizures must be treated aggressively, as they compromise ventilation and induce acidosis. I.V. benzodiazepines are frequently effective, but the control of seizures is often transient. Early intubation should be undertaken and an alkalosis induced. To prevent the recurrence of convulsions, phenytoin (18Â mg/kg at 25Â to 50Â mg/hr) should be given to all patients who experience seizures. As bradyarrhythmias and atrioventricular block have been reported with phenytoin administration, continuous ECG monitoring should be performed. Barbiturates may be used to control seizures, but they may produce profound hypotension. Refractory seizures are sometimes responsive to physostigmine. However, the use of physostigmine is controversial and should be reserved for life-threatening situations. Physostigmine is not innocuous and carries a risk of inducing seizures, bronchospasm, increased respiratory secretions, muscle weakness, bradycardia, and asystole. Physostigmine is the only drug of this class which may be used. If symptoms of cholinergic toxicity develop, physostigmine should be discontinued. Atropine should be available for the treatment of toxic cholinergic effects such as bronchoconstriction which may be induced by physostigmine.
Severe hyperthermia has been sporadically reported in association with tricyclic antidepressant overdose. Aggressive treatment with cooling blankets and ice packs is recommended in the event of hyperthermia.
As tricyclic antidepressants exhibit high protein binding and rapid tissue fixation, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis have not proved to be effective in the treatment of overdosage with these drugs.
Dosage And Administration:
In prescribing Triavil the recommended indications, management considerations, dosage schedules and attention to tolerance and response that are normal practice in using each one of the combined drugs, perphenazine and amitriptyline, should be borne in mind at all times.
Initial Dosage: In ambulatory depressed patients with anxiety and/or agitation of such degree as to warrant combined therapy rather than amitriptyline HCl alone, 1Â tablet 3Â or 4Â times a day as an initial dosage, depending on the severity of the agitation and anxiety.
The dosage should be individualized according to the need and response of the patient. The total daily dosage should not exceed 10Â tablets. As a dosage for children has not been established, Triavil is not recommended for use in children.
Maintenance Dosage: Depending on the condition being treated, the onset of therapeutic response may vary from a few days to a few weeks or even longer. The sedative effect of Triavil is more rapidly apparent, while the antidepressant effect is usually delayed. After a satisfactory response is noted, dosage should be reduced to the smallest amount necessary to obtain relief from the symptoms for which Triavil is being administered.
A useful maintenance dosage is 1Â tablet 2Â to 4Â times/day. In some patients, maintenance dosage is required for many months.
Availability And Storage:
Each film-coated, capsule shaped, salmon pink tablet, contains: perphenazine 3Â mg and amitriptyline HCl 15Â mg. Nonmedicinal ingredients: calcium phosphate dibasic, cornstarch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, powdered cellulose, red iron oxide, talc and titanium dioxide. Gluten- and tartrazine-free. Bottles ofÂ 100. Keep container tightly closed. Protect from light.
TRIAVILÂ® Merck Frosst Amitriptyline HCl–Perphenazine Antidepressant–Neuroleptic