Prescription Drugs

CLINICAL PHARMACOLOGY ETRAFON (perphenazine and amitriptyline) 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.

DESCRIPTION ETRAFON (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) Tablets, 2 mg perphenazine and 25 mg amitriptyline hydrochloride; ETRAFON (perphenazine and amitriptyline) -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 (perphenazine and amitriptyline) -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.

INDICATIONS ETRAFON (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) . DOSAGE AND ADMINISTRATIONInitial Dosage In psychoneurotic patients whose anxiety and depression warrant combined therapy, one ETRAFON (perphenazine and amitriptyline) Tablet (2-25) or one ETRAFON (perphenazine and amitriptyline) -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 (perphenazine and amitriptyline) -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 (perphenazine and amitriptyline) Tablets are being administered. A useful maintenance dosage is one ETRAFON (perphenazine and amitriptyline) Tablet (2-25) or one ETRAFON (perphenazine and amitriptyline) -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. HOW SUPPLIED 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) -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 (perphenazine and amitriptyline) ® brand of perphenazine and amitriptyline hydrochloride ETRAFON 2-10 TABLETS (2-10), USP ETRAFON (perphenazine and amitriptyline) TABLETS (2-25), USP ETRAFON (perphenazine and amitriptyline) -FORTE TABLETS (4-25), USP Schering Corporation Kenilworth, NJ 07033 USA All rights reserved.

PATIENT INFORMATION 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 (perphenazine and amitriptyline) 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.

OVERDOSE 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 (perphenazine and amitriptyline) 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. CONTRAINDICATIONS ETRAFON (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) Tablets, its components, or related compounds. ETRAFON (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) Tablets to permit recovery from the effects of the MAO inhibitor and to avoid possible potentiation. Treatment with ETRAFON (perphenazine and amitriptyline) 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.

SIDE EFFECTS 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. 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 (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. DRUG INTERACTIONS 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 (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.

WARNINGS 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) Tablets are used concomitantly. Because of the anticholinergic activity of amitriptyline hydrochloride, ETRAFON (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) 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. PRECAUTIONS 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 (perphenazine and amitriptyline) 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 (perphenazine and amitriptyline) 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 (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.