ETRAFON Tablets contain perphenazine, USP and amitriptyline hydrochloride, USP. Perphenazine is a piperazinyl phenothiazine having the chemical formula, C ₂₁ H ₂₆ CIN ₃ OS. Amitriptyline hydrochloride is a dibenzocycloheptadiene derivative having the chemical formula, C ₂₀ H ₂₃ N.HCl.

ETRAFON Tablets are available in multiple strengths to afford dosage flexibility for optimum management. They are available as ETRAFON 2-10 Tablets, 2 mg perphenazine and 10 mg amitriptyline hydrochloride; ETRAFON Tablets, 2 mg perphenazine and 25 mg amitriptyline hydrochloride; ETRAFON-Forte Tablets, 4 mg perphenazine and 25 mg amitriptyline hydrochloride.

The inactive ingredients for ETRAFON 2-10 Tablets (2-10) include: acacia, butylparaben, calcium phosphate, calcium sulfate, carnauba wax, corn starch, D&C Yellow No. 10 Al Lake, FD&C Yellow No. 6 Al Lake, gelatin, lactose, magnesium stearate, potato starch, sugar, and white wax. May also contain talc.

The inactive ingredients for ETRAFON-Forte Tablets (4-25) include: acacia, butylparaben, calcium phosphate, calcium sulfate, carnauba wax, corn starch, FD&C Red No. 40 Al Lake, FD&C Yellow No. 6 Al Lake, gelatin, lactose, magnesium stearate, potato starch, sugar, and white wax. May also contain talc.

Last updated on RxList: 12/8/2004

ETRAFON Tablets are indicated for the treatment of patients with moderate to severe anxiety and/or agitation and depressed mood; patients with depression in whom anxiety and/or agitation are moderate or severe; patients with anxiety and depression associated with chronic physical disease; patients in whom depression and anxiety cannot be clearly differentiated.

Schizophrenic patients who have associated symptoms of depression should be considered for therapy with ETRAFON.

Initial Dosage

In psychoneurotic patients whose anxiety and depression warrant combined therapy, one ETRAFON Tablet (2-25) or one ETRAFON-Forte Tablet (4-25) three or four times a day is recommended.

In elderly patients and adolescents, a lower initial dosage may be needed. The dosage may then be adjusted cautiously to produce an adequate response.

In more severely ill patients with schizophrenia, two ETRAFON-Forte Tablets (4-25) three times a day are recommended as the initial dosage. If necessary, a fourth dose may be given at bedtime. The total daily dosage should not exceed eight tablets of any strength.

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. After a satisfactory response is noted, dosage should be reduced to the smallest dose which is effective for relief of the symptoms for which ETRAFON Tablets are being administered. A useful maintenance dosage is one ETRAFON Tablet (2-25) or one ETRAFON-Forte Tablet (4-25) two to four times a day. In some patients, maintenance dosage is required for many months.

ETRAFON 2-10 Tablets (2-10) can be used to increase flexibility in adjusting maintenance dosage to the lowest amount consistent with relief of symptoms.

ETRAFON 2-10 Tablets (perphenazine 2 mg and amitriptyline hydrochloride 10 mg): deep yellow, sugar-coated tablets branded in blue-black with the Schering trademark and either product identification letters ANA, or number 287; bottles of 100 (NDC 0085-0287-04) and box of 100 for unit-dose dispensing (10 strips of 10 tablets each) (NDC 0085-0287-08).

ETRAFON Tablets (perphenazine 2 mg and amitriptyline hydrochloride 25 mg): pink, sugar-coated tablets branded in red with the Schering trademark and either product identification letters ANC, or number 598; bottles of 100 (NDC 0085-0598-04) and box of 100 for unit-dose dispensing (10 strips of 10 tablets each) (NDC 0085-0598-08).

ETRAFON-Forte Tablets (perphenazine 4 mg and amitriptyline hydrochloride 25 mg): red, sugar-coated tablets branded in blue with the Schering trademark and either product identification letters ANE, or number 720; bottles of 100 (NDC 0085-0720-04) and box of 100 for unit-dose dispensing (10 strips of 10 tablets each) (NDC 0085-0720-08).

Store ETRAFON 2-10, 2-25, 4-25 Tablets between 2° and 25°C (36° and 77°F). In addition, protect unit-dose packages from excessive moisture.

* Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic. Micromedex Inc. Vol 85.

ETRAFON®

brand of perphenazine and

amitriptyline hydrochloride

ETRAFON 2-10 TABLETS (2-10), USP

ETRAFON TABLETS (2-25), USP

ETRAFON-FORTE TABLETS (4-25), USP

Schering Corporation

Kenilworth, NJ 07033 USA

All rights reserved.

Last updated on RxList: 12/8/2004

Adverse reactions to ETRAFON 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 Tablets.

Perphenazine

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:   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 (see WARNINGSsection for further information).

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 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.

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.

Perphenazine

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 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.

Last updated on RxList: 12/8/2004

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 rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to Information for Patients and ADVERSE REACTIONS.)

NEUROLEPTIC MALIGNANT SYNDROME (NMS) A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include; 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported.

Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with drugs of this class.

ETRAFON Tablets should not be given concomitantly with guanethidine or similarly acting compounds, since amitriptyline, like other tricyclic antidepressants, may block the antihypertensive effect of these compounds. If hypotension develops, epinephrine should not be administered since its action is blocked and partially reversed by perphenazine. If a vasopressor is needed, norepinephrine may be used. Severe, acute hypotension has occurred with the use of phenothiazines and is particularly likely to occur in patients with mitral insufficiency or pheochromocytoma. Rebound hypertension may occur in pheochromocytoma patients.

Perphenazine can lower the convulsive threshold in susceptible individuals; it should be used with caution in alcohol withdrawal and in patients with convulsive disorders. If the patient is being treated with an anticonvulsant agent, increased dosage of that agent may be required when ETRAFON Tablets are used concomitantly.

Because of the anticholinergic activity of amitriptyline hydrochloride, ETRAFON Tablets should be used with caution in patients with glaucoma, increased intraocular pressure, and those in whom urinary retention is present or anticipated. In patients with angle-closure glaucoma, even average doses may precipitate an attack.

Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication.

ETRAFON Tablets may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery; the patient should be warned accordingly.

Use in Pregnancy:   Safe use of ETRAFON Tablets during pregnancy and lactation has not been established; therefore, in administering the drug to pregnant patients, nursing mothers, or women who may become pregnant, the possible benefits must be weighed against the possible hazards to mother and child.

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. This type of patient should not have access to large quantities of this drug.

Pediatric Use:   Safety and effectiveness in pediatric patients have not been established.

Perphenazine

As with all phenothiazine compounds, perphenazine should not be used indiscriminately. 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.

Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

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 ETRAFON Tablets should be discontinued.

Blood counts and hepatic and renal functions should be checked periodically. The appearance of signs of blood dyscrasias requires the discontinuance of the drug and institution of appropriate therapy. If abnormalities in hepatic tests occur, phenothiazine treatment should be discontinued. Renal function in patients on long-term therapy should be monitored; if blood urea nitrogen (BUN) becomes abnormal, treatment with the drug should be discontinued.

The use of phenothiazine derivatives in patients with diminished renal function should be undertaken with caution.

Use with caution in patients suffering from respiratory impairment due to acute pulmonary infections, or in chronic respiratory disorders such as severe asthma or emphysema.

In general, phenothiazines do not produce psychic dependence. Gastritis, nausea and vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high-dose therapy. Reports suggest that these symptoms can be reduced by continuing concomitant antiparkinson agents for several weeks after the phenothiazine is withdrawn.

The possibility of liver damage, corneal and lenticular deposits, and irreversible dyskinesias should be kept in mind when patients are on long-term therapy.

Because photosensitivity has been reported, undue exposure to the sun should be avoided during phenothiazine treatment.

Information for Patients:    This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

Amitriptyline Hydrochloride

In manic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Patients with paranoid symptomatology may have an exaggeration of such symptoms. The tranquilizing effect of ETRAFON Tablets has seemed to reduce the likelihood of this effect.

Both elevation and lowering of blood sugar levels have been reported.

The usefulness of amitriptyline in the treatment of depression has been amply demonstrated; however, it should be realized that abuse of amitriptyline among a narcotic-dependent population is not uncommon.

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.

Perphenazine

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 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.

Last updated on RxList: 12/8/2004

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after overdose; therefore, hospital monitoring is required as soon as possible.

Manifestations:   Overdosage of ETRAFON Tablets may cause any of the adverse reactions listed for perphenazine or amitriptyline hydrochloride.

Overdosage of perphenazine usually produces extrapyramidal symptoms such as dyskinesia and dystonia as described under ADVERSE REACTIONS, but this may be masked by the anticholinergic effects of amitriptyline. Other symptoms may include stupor or coma; children may have convulsive seizures.

Critical manifestations of tricyclic antidepressant overdose includes: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.

Management:   General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination:   All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

Cardiovascular:   A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH > 7.60 or a pCO ₂ < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium, or phenytoin. Type 1A and 1C anti-arrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS:   In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (eg, phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up:    Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management:   The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

ETRAFON Tablets are contraindicated in comatose or greatly obtunded patients and in patients receiving large doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in the presence of existing blood dyscrasias, bone marrow depression, or liver damage; and in patients who have shown hypersensitivity to ETRAFON Tablets, its components, or related compounds.

ETRAFON Tablets are also contraindicated in patients with suspected or established subcortical brain damage, with or without hypothalamic damage, since a hyperthermic reaction with temperatures in excess of 104°F may occur in such patients, sometimes not until 14 to 16 hours after drug administration. Total body ice-packing is recommended for such a reaction; antipyretics may also be useful.

ETRAFON Tablets should not be given concomitantly with a monoamine oxidase inhibiting compound. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs simultaneously. In patients who have been receiving a monoamine oxidase inhibitor, it is recommended that 2 weeks or longer elapse before the start of treatment with ETRAFON Tablets to permit recovery from the effects of the MAO inhibitor and to avoid possible potentiation. Treatment with ETRAFON Tablets should be initiated cautiously in such patients, with gradual increase in dosage until a satisfactory response is obtained.

Amitriptyline hydrochloride is not recommended for use during the acute recovery phase following myocardial infarction.

Last updated on RxList: 12/8/2004

ETRAFON Tablets combine the tranquilizing action of perphenazine with the antidepressant properties of amitriptyline hydrochloride. Perphenazine acts on the central nervous system, and has a greater behavioral potency than other phenothiazine derivatives whose side chains do not contain a piperazine moiety. Amitriptyline hydrochloride is a tricyclic antidepressant. While its mechanism of action in man is not known, it does not act primarily by stimulation of the central nervous system, and is not a monoamine oxidase (MAO) inhibitor.

Last updated on RxList: 12/8/2004

Information for Patients:    This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Given the likelihood that a substantial proportion of patients exposed chronically to neuroleptics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.

Amitriptyline Hydrochloride

In manic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Patients with paranoid symptomatology may have an exaggeration of such symptoms. The tranquilizing effect of ETRAFON Tablets has seemed to reduce the likelihood of this effect.

Both elevation and lowering of blood sugar levels have been reported.

The usefulness of amitriptyline in the treatment of depression has been amply demonstrated; however, it should be realized that abuse of amitriptyline among a narcotic-dependent population is not uncommon.

Last updated on RxList: 12/8/2004

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PERPHENAZINE/AMITRIPTYLINE - ORAL

(am-eh-TRIP-teh-leen/per-FEN-uh-zeen)

COMMON BRAND NAME(S): Etrafon, Triavil

WARNING: Antidepressant medications are used to treat a variety of conditions, including depression and other mental/mood disorders. These medications can help prevent suicidal thoughts/attempts and provide other important benefits. However, studies have shown that a small number of people (especially people younger than 25) who take antidepressants for any condition may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. Therefore, it is very important to talk with the doctor about the risks and benefits of antidepressant medication (especially for people younger than 25), even if treatment is not for a mental/mood condition. Tell the doctor immediately if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new antidepressant is started or when the dose is changed.

There may be a slightly increased risk of serious, possibly fatal side effects (e.g., pneumonia, heart failure) when this medication is used in older adults with dementia. This medication is not approved for the treatment of dementia-related behavior problems. Discuss the risks and benefits of this medication, as well as other effective and possibly safer treatments for dementia-related behavior problems, with the doctor.

USES: This medication is used to treat depression occurring with anxiety/agitation or with certain mental/mood disorders (e.g., schizophrenia). This medication is a combination of a tricyclic antidepressant (amitriptyline) and an antipsychotic medication (perphenazine). Together, they restore the balance of certain natural chemicals in the brain (neurotransmitters such as dopamine, norepinephrine, and serotonin). This medication helps you to have a better mood and sense of well-being, think more clearly, and feel less nervous, so that you can take part in everyday life.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using this medication and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth as directed by your doctor. When you begin treatment, frequent visits to your doctor may be needed to find the best dose for you. Keep all medical/lab appointments.

Dosage is based on your medical condition and response to treatment. Your doctor may direct you to take a low dose at first, gradually increasing the dose to lower the chance of side effects such as muscle spasms. Follow your doctor's directions carefully. The manufacturer recommends that you do not take more than 16 milligrams of perphenazine or 200 milligrams of amitriptyline per day.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Do not stop taking this medication without consulting your doctor. Your condition may become worse when the drug is suddenly stopped. Muscle aches, headaches, and worsening anxiety may also occur. Your dose may need to be gradually decreased.

Although you may notice some medication effects soon after starting, it may take as much as 4 to 6 weeks of regular use to see the full benefit. Tell your doctor if your condition persists or worsens after this period (e.g., your feelings of sadness get worse, or you have thoughts of suicide).

SIDE EFFECTS: See also Warning section.

Drowsiness, tiredness, dizziness, blurred vision, dry mouth, nausea, vomiting, constipation, change in taste, loss of appetite, or unexplained weight gain/loss may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To relieve dry mouth, suck on hard candy or ice chips, chew gum, drink water, or use a saliva substitute.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

The perphenazine in this medication may cause muscle/nervous system problems (extrapyramidal symptoms-EPS). Your doctor may prescribe another medication to decrease these side effects. Therefore, tell your doctor immediately if you notice any of the following side effects: increased anxiety, drooling/trouble swallowing, restlessness/constant need to move, shaking (tremor), shuffling walk, stiff muscles.

Perphenazine may also cause a condition known as tardive dyskinesia. In some cases, this condition may be permanent. Tell your doctor immediately if you develop any involuntary/repetitive muscle movements such as lip smacking/puckering, tongue thrusting, chewing, or finger/toe movements.

In rare cases, perphenazine may increase your level of a certain chemical made by the body (prolactin). For females, this increase in prolactin may result in unwanted breast milk, missed/stopped periods, or difficulty becoming pregnant. For males, it may result in decreased sexual ability, inability to produce sperm, or enlarged breasts. If you develop any of these symptoms, tell your doctor immediately.

Perphenazine may rarely cause a serious (sometimes fatal) nervous system problem (neuroleptic malignant syndrome-NMS). Seek immediate medical attention if you notice any of the following rare but very serious side effects: fever, stiff muscles, increased sweating, fast heartbeat, mental/mood changes, change in the amount of urine.

Tell your doctor immediately if any of these unlikely but serious side effects occur: numbness/tingling of the hands/feet, ringing in the ears, black tongue, unusual hunger, fainting, persistent heartburn, mental/mood changes (e.g., confusion, restlessness, nervousness), loss of coordination, shaking, sweating, trouble urinating, increased thirst/urination, muscle weakness/spasms.

Tell your doctor immediately if any of these rare but very serious side effects occur: seizures, easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), yellowing eyes/skin, severe stomach/abdominal pain, dark urine, persistent nausea/vomiting, pain/redness/swelling of arms or legs, severe muscle spasm/cramping (e.g., twisting neck, arching back, eyes rolling up), slow/fast/irregular heartbeat.

Seek immediate medical attention if any of these rare but very serious side effects occur: weakness on one side of the body, slurred speech, vision changes, chest pain.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking amitriptyline with perphenazine, tell your doctor or pharmacist if you are allergic to it; or to other tricyclic antidepressants (e.g., nortriptyline); or to other phenothiazines (e.g., chlorpromazine, fluphenazine); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: decreased bone marrow function, recent heart attack, serious head injury, severe liver problems, severe nervous system problems (e.g., coma, drug/alcohol overdose, shock), Parkinson's disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: personal/family history of suicide attempts, personal/family history of bipolar disorder, alcohol/substance abuse, a certain severe reaction to other medications (neuroleptic malignant syndrome), low blood pressure, breast cancer, problems urinating (e.g., due to enlarged prostate, bladder problems), glaucoma (closed-angle), seizures, heart problems (e.g., QT prolongation in the EKG), fast/slow/irregular heartbeat, heart valve problems, a certain adrenal gland tumor (pheochromocytoma), restless legs syndrome, overactive thyroid (hyperthyroidism), breast cancer, liver disease, diabetes, eating disorders (e.g., bulimia), lung disease (e.g., asthma, emphysema, pulmonary insufficiency), conditions that may increase your risk of seizures (e.g., other brain disease, alcohol withdrawal).

This drug may make you drowsy or dizzy or cause blurred vision. Use caution while driving, using machinery, or doing any activity that requires alertness or clear vision. Avoid alcoholic beverages.

To reduce dizziness, get up slowly when rising from a sitting or lying position.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen (SPF 30 or greater) and wear protective clothing when outdoors.

Before having surgery, tell your doctor or dentist that you are taking this medication.

Caution is advised during hot weather because the perphenazine in this product can reduce sweating, increasing your risk for a severe reaction to too much heat (heatstroke). Drink plenty of fluids. Avoid strenuous exercise in hot weather. If you become overheated, promptly seek cooler shelter and/or stop exercising. Seek immediate medical attention if your body temperature is above normal or if you have mental/mood changes, headache, or dizziness.

Avoid exposure to certain chemicals used in gardening (organic phosphate insecticides). Seek immediate medical attention if you are exposed to garden chemicals and have an unusual headache, heavy sweating, or difficulty breathing.

If you have diabetes, this drug may increase your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms such as increased thirst/urination, shakiness, unusual sweating, or hunger. Your anti-diabetic medication or diet may need to be adjusted.

Depression can lead to thoughts/attempts of suicide. Tell your doctor immediately if you have any suicidal thoughts, worsening depression, or any other mental/mood changes (including new or worsening anxiety, agitation, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, rapid speech). Keep all medical appointments so your doctor can monitor your progress closely and adjust your medication if needed.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially dizziness, drowsiness, confusion, difficulty urinating, and muscle/nervous system problems such as extrapyramidal symptoms and tardive dyskinesia (see also Side Effects).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This drug may pass into breast milk and could have undesirable effects on a nursing infant. Therefore, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: See also How to Use section.

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: drugs with effects on dopamine (e.g., cabergoline, pergolide), lumefantrine, sibutramine, iomeprol, metrizamide.

Avoid taking MAO inhibitors (e.g., furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine) within 2 weeks before, during, and after treatment with this medication. In some cases a serious (possibly fatal) drug interaction may occur.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting amitriptyline.

Other drugs besides amitriptyline that may affect the heart rhythm (QT prolongation in the EKG) include pimozide, cisapride, halofantrine, disopyramide, grepafloxacin and sparfloxacin, among others. Before using this drug, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anticholinergic medications (e.g., dicyclomine, scopolamine), certain antihypertensive medications (clonidine, guanadrel, guanethidine), "blood thinners" (e.g., warfarin), certain anti-HIV drugs (amprenavir, fosamprenavir, ritonavir), barbiturates (e.g., phenobarbital), disulfiram, drugs affecting liver enzymes that remove amitriptyline or perphenazine from your body (e.g., amiodarone, cimetidine, fluconazole, SSRI antidepressants including fluoxetine/paroxetine), drugs for heart rhythm (e.g., flecainide, propafenone, quinidine), drugs that increase the risk for seizures (e.g., alcohol, bupropion, isoniazid, tramadol, other antipsychotic medications such as haloperidol/quetiapine), drugs for Parkinson's disease (e.g., bromocriptine, levodopa), ethchlorvynol, lithium, St John's wort, stimulants (e.g., amphetamines, methylphenidate), certain sympathomimetics (e.g., albuterol, epinephrine, phenylephrine), terbinafine, thyroid supplements, other tricyclic antidepressants (e.g., nortriptyline).

If you have been taking fluoxetine, wait at least 5 weeks after stopping fluoxetine before starting amitriptyline.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., phenytoin, carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., other phenothiazines including chlorpromazine, other antidepressants including trazodone/risperidone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

This medication may interfere with certain laboratory tests (including pregnancy tests), possibly causing false test results. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: fast/irregular heartbeat, severe dizziness, fainting, jerking movements, slow/shallow breathing, seizures, inability to wake up (coma).

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, liver function, eye exams) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.