Side Effects of Etrafon (perphenazine/amitriptyline)

Does Etrafon (perphenazine/amitriptyline) cause side effects?

Etrafon (perphenazine/amitriptyline) is a combination of an antipsychotic and an antidepressant used to treat depression and other mood or mental disorders.

Perphenazine is an antipsychotic that works in the brain and nervous system. Its exact mechanism of action is unknown. Amitriptyline is a tricyclic antidepressant.

It is believed that in some patients with depression, abnormal levels of neurotransmitters may be related to their depression. Amitriptyline elevates mood by raising the level of neurotransmitters in nerves in the brain. The brand name Etrafon is no longer available in the U.S.

Common side effects of Etrafon include

Serious side effects of Etrafon include

  • difficulty breathing and swallowing,
  • increased risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders, and
  • increased risk of death in elderly patients with dementia related psychosis.

Drug interactions of Etrafon include paroxetine, fluoxetine, and sertraline, because these medications also increase the concentration of neurotransmitters in the body leading to severe and deadly reactions.

Etrafon should be avoided with medications like quinidine, disopyramide, procainamide, propafenone, and flecainide because they may also affect heart rhythm and increase the risk of an irregular heart rate and rhythm.

Etrafon should be used with caution with medications like epinephrine due to increased risk of irregular heart rates and rhythms. Safe use of Etrafon during pregnancy has not been established. Etrafon enters breast milk and is not recommended for use during breastfeeding.

What are the important side effects of Etrafon (perphenazine/amitriptyline)?

Side effects of Perphenazine/amitriptyline are

  • abnormal muscle contractions,
  • difficulty breathing and swallowing,
  • neck spasms, and
  • movement abnormalities on face, arms, and legs.

This medication also causes

  • dizziness,
  • drowsiness,
  • sedation,
  • irregular heart rate and rhythm,
  • increase or decrease in blood pressure, and
  • blurred vision.

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of antidepressants in a child or adolescent must balance this risk of suicide with the clinical need.

Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death.

Etrafon (perphenazine/amitriptyline) side effects list for healthcare professionals

Adverse reactions to Etrafon (perphenazine and amitriptyline) Tablets are the same as those to its components, perphenazine and amitriptyline hydrochloride. There have been no reports of effects peculiar to the combination of these components in Etrafon (perphenazine and amitriptyline) Tablets.


Not all of the following adverse reactions have been reported with perphenazine; however, pharmacological similarities among various phenothiazine derivatives require that each be considered.

With the piperazine group (of which perphenazine is an example), the extrapyramidal symptoms are more common, and others (eg, sedative effects, jaundice, and blood dyscrasias) are less frequently seen.

CNS Effects: Extrapyramidal reactions, including opisthotonus; trismus; torticollis; retrocollis; aching and numbness of the limbs; motor restlessness; oculogyric crisis; hyperreflexia; dystonia, including protrusion, discoloration, aching and rounding of the tongue; tonic spasm of the masticatory muscles; tight feeling in the throat; slurred speech; dysphagia; akathisia; dyskinesia; parkinsonism; and ataxia.

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, however, these extrapyramidal reactions may persist after discontinuation of treatment with perphenazine.

Persistent tardive dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or may appear after drug therapy has been discontinued. Although the risk appears to be greater in elderly patients on high-dose therapy, especially females, it may occur in either sex and in pediatric patients.

The symptoms are persistent and, in some patients, appear to be irreversible. The syndrome is characterized by rhythmical, involuntary movements of the tongue, face, mouth, or jaw (eg, protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.

There is no known effective treatment for tardive dyskinesia; antiparkinsonism agents usually do not alleviate the symptoms of this syndrome. It is suggested that all antipsychotic agents be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked.

It has been reported that fine vermicular movements of the tongue may be an early sign of the syndrome, and if the medication is stopped at that time the syndrome may not develop.

Other CNS effects include cerebral edema; abnormality of cerebrospinal fluid proteins; convulsive seizures, particularly in patients with EEG abnormalities or a history of such disorders; and headaches.

Neuroleptic malignant syndrome has been reported in patients treated with neuroleptic drugs.

Drowsiness may occur, particularly during the first or second week, after which it generally disappears. If troublesome, lower the dosage. Hypnotic effects appear to be minimal, especially in patients who are permitted to remain active.

Adverse behavioral effects include paradoxical exacerbation of psychotic symptoms, catatonic-like states, paranoid reactions, lethargy, paradoxical excitement, restlessness, hyperactivity, nocturnal confusion, bizarre dreams, and insomnia. Hyperreflexia has been reported in the newborn when a phenothiazine was used during pregnancy.

Autonomic Effects: dry mouth or salivation, nausea, vomiting, diarrhea, anorexia, constipation, obstipation, fecal impaction, urinary retention, frequency or incontinence, polyuria, bladder paralysis, nasal congestion, pallor, myosis, mydriasis, blurred vision, glaucoma, perspiration, hypertension, hypotension, and a change in pulse rate occasionally may occur. Significant autonomic effects have been infrequent in patients receiving less than 24 mg perphenazine daily.

Adynamic ileus occasionally occurs with phenothiazine therapy and, if severe, can result in complications and death. It is of particular concern in psychiatric patients, who may fail to seek treatment of the condition.

Allergic Effects: urticaria, erythema, eczema, exfoliative dermatitis, pruritus, photosensitivity, asthma, fever, anaphylactoid reactions, laryngeal edema, and angioneurotic edema; contact dermatitis in nursing personnel administering the drug; and, in extremely rare instances, individual idiosyncrasy or hypersensitivity to phenothiazines has resulted in cerebral edema, circulatory collapse, and death.

Endocrine Effects: lactation, galactorrhea, moderate breast enlargement in females and gynecomastia in males on large doses, disturbances in the menstrual cycle, amenorrhea, changes in libido, inhibition of ejaculation, false-positive pregnancy tests, hyperglycemia, hypoglycemia, glycosuria, syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Cardiovascular Effects: postural hypotension, tachycardia (especially with sudden marked increase in dosage), bradycardia, cardiac arrest, faintness, and dizziness. Occasionally the hypotensive effect may produce a shock-like condition. ECG changes, nonspecific (quinidine-like effect), usually reversible, have been observed in some patients receiving phenothiazine tranquilizers.

Sudden death has occasionally been reported in patients who have received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.

Hematological Effects: agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenic purpura, and pancytopenia. Most cases of agranulocytosis have occurred between the fourth and tenth weeks of therapy. Patients should be watched closely, especially during that period, for the sudden appearance of sore throat or signs of infection. If white blood cell and differential cell counts show significant cellular depression, discontinue the drug and start appropriate therapy. However, a slightly lowered white count is not in itself an indication to discontinue the drug.

Other Effects: Special considerations in long-term therapy include pigmentation of the skin, occurring chiefly in the exposed areas; ocular changes consisting of deposition of fine particulate matter in the cornea and lens, progressing in more severe cases to star-shaped lenticular opacities; epithelial keratopathies; and pigmentary retinopathy. Also noted: peripheral edema, reversed epinephrine effect, increase in PBI not attributable to an increase in thyroxine, parotid swelling (rare), hyperpyrexia, systemic lupus erythematosus-like syndrome, increases in appetite and weight, polyphagia, photophobia, and muscle weakness.

Liver damage (biliary stasis) may occur. Jaundice may occur, usually between the second and fourth weeks of treatment, and is regarded as a hypersensitivity reaction. Incidence is low. The clinical picture resembles infectious hepatitis but with laboratory features of obstructive jaundice. It is usually reversible; however, chronic jaundice has been reported.

Amitriptyline Hydrochloride

Although activation of latent schizophrenia has been reported with antidepressant drugs, including amitriptyline hydrochloride, it may be prevented with Etrafon (perphenazine and amitriptyline) Tablets in some cases because of the antipsychotic effect of perphenazine. A few instances of epileptiform seizures have been reported in chronic schizophrenic patients during treatment with amitriptyline hydrochloride.

Note: Included in the listing which follows are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline hydrochloride is administered.

Allergic Effects: rash, pruritus, urticaria, photosensitization, edema of face and tongue.

Anticholinergic Effects: dry mouth, blurred vision, disturbance of accommodation, constipation, paralytic ileus, urinary retention, dilatation of urinary tract.

Cardiovascular Effects: hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke.

CNS and Neuromuscular Effects: confusional states; disturbed concentration; disorientation; delusions; hallucinations; excitement; jitteriness; anxiety; restlessness; insomnia; nightmares; numbness, tingling, and paresthesias of the extremities; peripheral neuropathy; incoordination; ataxia; tremors; seizures; alteration in EEG patterns; extrapyramidal symptoms; tinnitus.

Endocrine Effects: testicular swelling and gynecomastia in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, elevation and lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Gastrointestinal Effects: nausea, epigastric distress, heartburn, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, jaundice, parotid swelling, black tongue. Rarely hepatitis has occurred (including altered liver function and jaundice).

Hematological Effects: bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.

Other Effects: dizziness, weakness, fatigue, headache, weight gain or loss, increased perspiration, urinary frequency, mydriasis, drowsiness, alopecia.

Withdrawal Symptoms: abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. These are not indicative of addiction.

What drugs interact with Etrafon (perphenazine/amitriptyline)?

Drug Interactions: Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7%-10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available.

Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (eight-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy.

The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), eg, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other.

Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.


Patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, reduced amounts of anesthetics or central nervous system depressants may be necessary.

Since phenothiazines and central nervous system depressants (opiates, analgesics, antihistamines, barbiturates) can potentiate each other, less than the usual dosage of the added drug is recommended and caution is advised when they are administered concomitantly.

Use with caution in patients who are receiving atropine or related drugs because of additive anticholinergic effects and also in patients who will be exposed to extreme heat or organic phosphate insecticides.

The use of alcohol should be avoided, since additive effects and hypotension may occur. Patients should be cautioned that their response to alcohol may be increased while they are being treated with Etrafon (perphenazine and amitriptyline) Tablets. The risk of suicide and the danger of overdose may be increased in patients who use alcohol excessively due to its potentiation of the drug's effect.

Amitriptyline Hydrochloride

When amitriptyline hydrochloride is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.

Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.

Concurrent use of large doses of ethchlorvynol should be used with caution, since transient delirium has been reported in patients receiving this drug in combination with amitriptyline hydrochloride.

This drug may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.

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

Discontinue the drug several days before elective surgery, if possible.

Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant.

Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) have been associated with elevations in the serum levels of the tricyclic antidepressant when cimetidine is added to the drug regimen. Additionally, higher than expected steady-state serum concentrations of the tricyclic antidepressant have been observed when therapy is initiated in patients taking cimetidine.

Alternatively, decreases in the steady-state serum concentration of the tricyclic antidepressant have been reported in well-controlled patients on concurrent therapy upon discontinuance of cimetidine. The therapeutic efficacy of the tricyclic antidepressant may be compromised in these patients as the cimetidine is discontinued.


Etrafon (perphenazine/amitriptyline) is a combination of an antipsychotic and an antidepressant used to treat depression and other mood or mental disorders. Common side effects of Etrafon include abnormal muscle contractions, neck spasms, movement abnormalities on face/arms/legs, dizziness, drowsiness, sedation, irregular heart rate and rhythm, changes in blood pressure, and blurred vision. Safe use of Etrafon during pregnancy has not been established. Etrafon enters breast milk and is not recommended for use during breastfeeding.

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