Perphenazine and Amitriptyline (Systemic)


VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Elavil Plus; Etrafon; Etrafon-A; Etrafon-D; Etrafon-F; Etrafon-Forte; PMS Levazine; Triavil.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipsychotic-antidepressant—

Indications

Accepted

Anxiety associated with mental depression (treatment)—Perphenazine and amitriptyline combination is indicated in the treatment of patients with moderate to severe anxiety and/or agitation and depression, anxiety and depression associated with chronic physical disease, anxiety and depression that cannot be differentiated, and symptoms of depression in schizophrenia {03} {04}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Perphenazine: 403.97 {01}
    Amitriptyline hydrochloride: 313.87 {02}

Mechanism of action/Effect:

Perphenazine—Perphenazine is thought to improve psychotic conditions by blocking postsynaptic mesolimbic dopaminergic receptors in the brain. Phenothiazines also produce an alpha-adrenergic blocking effect and depress the release of hypothalamic and hypophyseal hormones. However, blockade of dopamine receptors increases prolactin release by the pituitary. {01}

Amitriptyline—Although the exact mechanism of action in the treatment of depression is unclear, tricyclic antidepressants, such as amitriptyline, are thought to increase the synaptic concentration of norepinephrine (levarterenol; NE) and/or serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS). One theory suggests that these neurotransmitters are increased through inhibition of their reuptake by the presynaptic neuronal membrane. Amitriptyline appears to be more potent in blocking serotonin, although, through its metabolites, it also becomes a powerful inhibitor of norepinephrine reuptake. {02}


Other actions/effects:

Perphenazine—Perphenazine also has strong antiemetic and extrapyramidal effects, weak to moderate anticholinergic and sedative effects, and weak hypotensive effects {01}.

Amitriptyline—Tricyclic antidepressants also produce prominent peripheral and central anticholinergic effects due to their potent and high binding affinity for muscarinic receptors; sedative effects due to strong binding affinity for histamine H 1-receptors (although the central actions of histamine are poorly understood, increased cholinoceptive activity in the brain has been associated with clinical depression); an orthostatic hypotensive effect due to alpha blockade; and possible quinidine-like myocardial depressant effects {02}.

Protein binding:

Perphenazine—Very high (90% or more) {01}.

Amitriptyline—Very high (96%) {02}.

Biotransformation:

Perphenazine—Hepatic {01}.

Amitriptyline—Exclusively hepatic, with first-pass effect {02}.

Onset of action:

Perphenazine—Antipsychotic effect: Gradual (up to several weeks) and variable among patients {01}.

Amitriptyline—2 to 3 weeks {02}.

Elimination:
    Perphenazine—Primarily renal; biliary; not successfully dialyzed because of its high protein binding {01}.
    Amitriptyline—As metabolites, primarily renal, over several days; not dialyzable because of high protein binding {02}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other phenothiazines, other tricyclic antidepressants, or possibly maprotiline or trazodone may be sensitive to this medication also {01} {02}.

Tumorigenicity

Antipsychotic medications such as perphenazine produce an elevation in prolactin concentrations, which 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 medications 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 concentrations is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic medications. However, neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these medications and mammary tumorigenesis; the available evidence is considered too limited to be conclusive. {01} {03} {04}

Pregnancy/Reproduction
Fertility—
Phenothiazines have been found to depress spermatogenesis in animals at doses greatly exceeding the human dose {01}.

Pregnancy—

For perphenazine

Although adequate and well-controlled studies in humans have not been done, there have been reports of prolonged jaundice, hypo- or hyperreflexia, and extrapyramidal effects in the neonates of mothers who received phenothiazines near term. Phenothiazines are not recommended for use during pregnancy. {01} {03}



For amitriptyline

Adequate and well-controlled studies have not been done in humans {02}.

Animal studies have shown amitriptyline to cause teratogenic effects when used in doses many times the human dose {02}.

FDA Pregnancy Category C {02}.


Delivery—


For amitriptyline:

There have been reports of infants suffering cardiac problems, muscle spasms, respiratory distress, and urinary retention when their mothers received tricyclic antidepressants immediately prior to delivery {02}.


Breast-feeding

Perphenazine—Phenothiazines are distributed into breast milk, possibly causing drowsiness and an increased risk of dystonias and tardive dyskinesia in the infant. Most phenothiazines increase prolactin secretion in the mother. {01}

Amitriptyline—Problems in nursing infants have not been documented; however, amitriptyline has been found in breast milk with unknown effects {02}.

Pediatrics

Appropriate studies on the relationship of age to the effects of perphenazine and amitriptyline combination have not been performed in children up to 12 years of age. However, children appear to be prone to develop neuromuscular or extrapyramidal reactions, especially dystonias, and should be closely monitored while receiving therapeutic doses of phenothiazines. {01} Children with acute illnesses, such as chickenpox, CNS infections, measles, gastroenteritis, or dehydration, are especially at risk {01}. In addition, adolescent patients are likely to exhibit dose sensitivity, and may require lower initial doses of tricyclic antidepressants {02}.


Geriatrics


Elderly and debilitated patients usually require lower initial dosage and a more gradual titration of dose {02}. These patients appear to be more prone to orthostatic hypotension {01} and exhibit an increased sensitivity to the anticholinergic and sedative effects of this combination {01} {02}. Close supervision is necessary for patients with cardiac problems {02}, glaucoma, urinary retention, and/or gastrointestinal problems {01} {02}. In addition, elderly patients are more prone to develop extrapyramidal side effects from perphenazine, such as tardive dyskinesia and pseudoparkinsonism {01}. The symptoms of tardive dyskinesia are persistent, difficult to control, and, in some patients, appear to be irreversible {01} {03} {04}. There is no known effective treatment {01} {03} {04}. Careful observation during treatment for early signs of tardive dyskinesia and reduction of dosage or discontinuation of medication may prevent a more severe manifestation of the syndrome {01}.


Dental

The peripheral anticholinergic effects of perphenazine and amitriptyline combination may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort {01} {02}.

Extrapyramidal reactions induced by phenothiazines will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable {01}.

The blood dyscrasia–causing effects of this combination medicine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If agranulocytosis, leukopenia, or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks. {01} {02}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Alcohol{01}{02}{03}{04} or
» CNS depression–producing medications, other{01}{02}{03}{04} (See Appendix II )    (concurrent use with perphenazine and amitriptyline combination may result in increased CNS and respiratory depression and increased hypotensive effects; dosage reductions of either drug may be necessary during concurrent use or when sequence of use enhances CNS effects {01} {02})

    (amitriptyline may enhance the response to alcohol, especially during the first few days of treatment; in patients who use alcohol excessively, amitriptyline may increase the danger inherent in any suicide attempt {02}; in addition, alcohol may increase the risk of heat stroke when taken concurrently with perphenazine {01})


Amantadine{01}{02} or
Anticholinergics or other medications with anticholinergic activity{01}{02}{03}{04} (See Appendix II ) or
Antidyskinetic agents{01}{02} or
Antihistamines{01}{02}{03}{04}    (concurrent use with perphenazine and amitriptyline combination may potentiate the anticholinergic effects, especially confusion, hallucinations, and nightmares {01} {02}; medications with anticholinergic effects may potentiate the hyperpyretic effect of phenothiazines, especially when environmental temperatures are high, by preventing sweating as a cooling mechanism; this effect could lead to heat stroke {01}; also, patients should be advised to report occurrence of gastrointestinal problems since paralytic ileus may occur with concurrent therapy {01} {02} {03})

    (concurrent use may potentiate the CNS depressant effects of either antihistamines or perphenazine or amitriptyline {01} {02})


Amphetamines{01}    (stimulant effects may be decreased when amphetamines are used concurrently with perphenazine since phenothiazines produce alpha-adrenergic blockade; also, the antipsychotic effectiveness of perphenazine may be reduced)


Antacids, aluminum- or magnesium-containing{01} or
Antidiarrheals, adsorbent{01}    (concurrent use of these medications with phenothiazines may inhibit the absorption of the phenothiazine; simultaneous use should be avoided)


Anticoagulants, coumarin- or indandione-derivative{02}    (concurrent use with amitriptyline may cause an increase in anticoagulant activity by inhibiting enzymatic metabolism of the anticoagulant)


Anticonvulsants{01}{02}{03}{04}    (perphenazine and amitriptyline combination may enhance CNS depression, lower the seizure threshold, and decrease the effects of the anticonvulsant medication; dosage adjustments may be necessary to control seizures)

    (in addition, phenothiazines may inhibit phenytoin metabolism, leading to phenytoin toxicity)


» Antithyroid agents{01}{02}    (concurrent use with perphenazine and amitriptyline combination may increase the risk of agranulocytosis)


Appetite suppressants{01}    (concurrent use with phenothiazines may antagonize the anorectic effect of appetite suppressants, with the exception of fenfluramine and phenmetrazine)


Barbiturates{02}{03}{04}    (when barbiturates, especially phenobarbital, are used concurrently with amitriptyline, the effects of amitriptyline may be decreased because of increased metabolism resulting from induction of hepatic microsomal enzymes)


Beta-adrenergic blocking agents{01}    (concurrent use of beta-blockers, possibly including ophthalmics, with phenothiazines may result in an increased plasma concentration of each medication because of inhibition of metabolism; this may result in additive hypotensive effects, irreversible retinopathy, cardiac arrhythmias, and tardive dyskinesia)


Bromocriptine{01}    (concurrent use may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustments may be necessary)


» Cimetidine{01}{02}{03}{04}    (concurrent use may inhibit amitriptyline metabolism and increase plasma concentrations, leading to toxicity)


Contraceptives, oral, estrogen-containing{02} or
Estrogens, including estramustine{02}    (concurrent use may decrease therapeutic effects of amitriptyline; however, these medications may also increase plasma concentrations of amitriptyline, leading to toxicity; dosage reduction of either medication may be necessary)


Disulfiram{02}{04} or
Ethchlorvynol{02}{03}{04}    (concurrent use with amitriptyline may result in transient delirium)


Diuretics, thiazide{01}    (concurrent use may potentiate hyponatremia and water intoxication; alternative methods of hypertension control should be considered)


Dopamine{01}    (concurrent use may antagonize the peripheral vasoconstriction produced by high doses of dopamine, because of the alpha-adrenergic blocking action of perphenazine)


Electroconvulsive therapy{02}{03}{04}    (although electroconvulsive therapy may be used in conjunction with amitriptyline, caution should be used as hazards may be increased)


» Epinephrine{01}{03}{04}    (the use of epinephrine to treat phenothiazine-induced hypotension should be avoided because the alpha-adrenergic effects of epinephrine may be blocked, resulting in beta stimulation only and causing severe hypotension and tachycardia)


» Extrapyramidal reaction–causing medications, other{01}{02} (See Appendix II )    (concurrent use with perphenazine may increase the severity and frequency of extrapyramidal effects)


Fluoxetine{02}    (concurrent use of fluoxetine with tricyclic antidepressants has produced increased plasma concentrations of the tricyclic antidepressant, possibly due to inhibition of tricyclic antidepressant metabolism; in addition, concurrent use may increase the CNS depressant effects of both medications; caution is recommended, and dosage of 1 or both agents should be reduced)


Hepatotoxic medications, other{01} (See Appendix II )    (concurrent use of phenothiazines with medications known to alter hepatic microsomal enzyme activity may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored)


Hypotension-producing medications, other,{01}{02}{03}{04} (See Appendix II )    (concurrent use with phenothiazines may produce severe hypotension with postural syncope)


» Levodopa{01}    (concurrent use with perphenazine may inhibit the therapeutic effects of levodopa, because of the blockade of dopamine receptors in the brain; levodopa has not been shown to be effective in the treatment of phenothiazine-induced parkinsonism)


» Lithium{01}    (concurrent use with perphenazine possibly may reduce gastrointestinal absorption of the phenothiazine, thereby decreasing its serum concentrations by as much as 40%; concurrent use may increase rate of renal excretion of lithium; extrapyramidal symptoms may be increased; also, nausea and vomiting, early indications of lithium toxicity, may be masked by the antiemetic effect of some phenothiazines)


Methylphenidate{01}{02}    (serum concentrations of amitriptyline may be increased due to inhibition of metabolism when methylphenidate is used concurrently; also, concurrent use may antagonize the effects of methylphenidate)


» Metrizamide{01}{02}    (concurrent use of perphenazine and amitriptyline combination with intrathecal administration of metrizamide may lower the seizure threshold; it is recommended that this combination medication be discontinued for at least 48 hours before and 24 hours after myelography)


» Monoamine oxidase (MAO) inhibitors{02}{03}{04} , including furazolidone, procarbazine, and selegiline    (in addition to possibly increasing CNS depressant effects with perphenazine and amitriptyline combination, concurrent use of MAO inhibitors with amitriptyline is not recommended, especially on an outpatient basis, because hyperpyretic episodes, severe seizures, hypertensive crises, and death have resulted; at least 2 weeks should elapse between discontinuation of one medication and initiation of the other {02} {03} {04})


Naphazoline, ophthalmic{02} or
Oxymetazoline, nasal{02} or
Phenylephrine, nasal or ophthalmic{02} or
Xylometazoline, nasal{02}    (if significant systemic absorption occurs, concurrent use with amitriptyline may potentiate pressor effects of these medications)


Opioid (narcotic) analgesics{01}{03}{04}    (in addition to increasing CNS and respiratory depression, concurrent use with phenothiazines increases orthostatic hypotension and increases the risk of severe constipation, which may lead to paralytic ileus, and/or urinary retention)


Ototoxic medications, especially ototoxic antibiotics{01} (See Appendix II )    (concurrent use with phenothiazines may mask some symptoms of ototoxicity such as tinnitus, dizziness, or vertigo)


Photosensitizing medications, other{01}    (concurrent use with phenothiazines may cause additive photosensitizing effects)

    (in addition, concurrent use of systemic methoxsalen, trioxsalen, or tetracyclines with phenothiazines may potentiate intraocular photochemical damage to the choroid, retina, or lens)


Pimozide{02}    (concurrent use with amitriptyline may potentiate cardiac arrhythmias)


Probucol{01}{02}{09}    (additive QT interval prolongation may increase the risk of ventricular tachycardia {09})


» Sympathomimetics{01}{02}{03}{04}    (concurrent use with amitriptyline may potentiate cardiovascular effects possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia)

    (significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects of amitriptyline; local anesthetics with epinephrine or levonordefrin should also be avoided)

    (concurrent use of sympathomimetics with perphenazine and amitriptyline combination may decrease the pressor effects of sympathomimetics and the antipsychotic effects of perphenazine and amitriptyline combination)


Thyroid hormones{02}{03}{04}    (concurrent use with amitriptyline may increase the possibility of cardiac arrhythmias and enhance the antidepressant response; also, the onset of action of amitriptyline may be accelerated; dosage adjustments may be necessary, although the problem is reduced in euthyroid patients)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bilirubin tests, urine{01}    (phenothiazine use may produce false-positive results)


Electrocardiogram (ECG) readings{01}{03}{04}    (may cause Q- and T-wave changes, such as increased QT intervals, ST depression, and changes in AV conduction; these are usually reversible)


Gonadorelin test{01}    (phenothiazines may blunt the response to gonadorelin by increasing serum prolactin concentrations)


Metyrapone test{01}{02}    (response to metyrapone may be decreased)


Pregnancy tests, immunologic urine{01}{03}{04}    (phenothiazines may produce false-positive or false-negative results, depending on the test used)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiovascular disease, severe{01}{03}{04} or
» CNS depression, severe{01} or
» Comatose states{01}{03}{04} or
» During the acute recovery period following myocardial infarction{02}{03}{04}    (condition may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active{01}{02}    (CNS depression may be potentiated; risk of heat stroke may be increased; chronic alcohol abusers may be predisposed to hepatotoxic reactions during phenothiazine therapy)


» Bipolar disorder{02}{03}{04}    (transition to manic or hypomanic phase may be accelerated)


» Blood disorders{01}{03}{04}    (may be potentiated)


Breast cancer{01}    (potentially higher risk of disease progression and possible increased resistance to endocrine and cytotoxic treatment, due to phenothiazine-induced prolactin secretion)


» Cardiovascular disorders{01}{02}{03}{04} , especially in the elderly    (increased risk of hypotension; arrhythmias, heart block, congestive heart failure, cardiomegaly, myocardial infarction, or stroke may be induced)


» Epilepsy or seizure disorders{01}{02}{03}{04}    (seizure threshold may be lowered)


» Gastrointestinal disorders{01}{02}    (risk of paralytic ileus, especially in the elderly)


» Glaucoma, narrow-angle, or predisposition to{01}{02}{03}{04}    (may be aggravated)


» Hepatic function impairment{01}{02}{03}{04}    (metabolism may be decreased; higher serum concentrations may increase sensitivity to CNS effects)


» Hyperthyroidism{02}{03}{04}    (risk of cardiovascular toxicity)


Parkinson's disease{01}    (potentiation of extrapyramidal effects)


» Prostatic hypertrophy{01}{02}    (risk of urinary retention)


» Psychosis, latent{02}{03}{04}    (may be activated)


Respiratory function impairment, due to acute infection or chronic conditions{01}{02}{03}    (may be exacerbated)


» Renal function impairment{02}{03}    (excretion may be decreased; higher serum concentrations may increase sensitivity to CNS effects)


» Reye's syndrome{01}    (increased risk of hepatotoxicity in children and adolescents whose signs and symptoms suggest Reye's syndrome)


Sensitivity to any phenothiazine, tricyclic antidepressant, or possibly maprotiline or trazodone{01}{02}{03}{04}
» Urinary retention{02}{03}{04}    (may be aggravated)


Vomiting{01}{03}{04}    (antiemetic action of phenothiazines may mask vomiting caused by overdose of other medications)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Abnormal-movement determinations{01}    (recommended every 2 months during therapy for institutionalized patients, using the abnormal involuntary movement scale [AIMS], and again at 8 to 12 weeks after therapy has been discontinued)


Blood cell counts{01}{02}{03} and differential{01}{02} in patients with sore throat and fever or infections{01}{02} , or periodically in patients on long-term therapy{02}    (may be required during high-dose or prolonged therapy when symptoms of infection develop; agranulocytosis is more likely to occur between the 4th and 10th weeks of therapy; if significant cellular depression occurs, medication should be discontinued and appropriate therapy initiated; rechallenge in recovered patients will usually cause a recurrence of agranulocytosis)


Blood pressure determinations{01}{02} and
Cardiac function monitoring{02} and
Glaucoma tests{02} and
Hepatic function determinations{01}{02}{03} and
Renal function determinations{02}{03} and
Urine tests for bilirubin and bile{01}    (may be required at periodic intervals during prolonged therapy to detect development of adverse effects that may not be evident to the patient, or if jaundice or grippe-like symptoms occur, to detect liver function impairment; these side effects are more likely to occur between the 2nd and 4th weeks of therapy; phenothiazine should be discontinued if bilirubinemia, bilirubinuria, or icterus occurs)


Careful observation for early signs of tardive dyskinesia{01}{03}{04}    (recommended at periodic intervals, especially in the elderly and other patients on high or extended maintenance dosage; since there is no known effective treatment if syndrome should develop, the phenothiazine should be discontinued at earliest signs, usually fine, worm-like movements of the tongue, to stop further development)


Careful supervision of depressed patients with suicidal tendencies{02}{03}{04}    (recommended especially during early weeks of treatment; hospitalization may be required as a protective measure)


Ophthalmologic examinations{01}    (recommended, if possible, prior to initiation of phenothiazine therapy as a baseline; initial screening should include measurement of visual acuity with and without refraction, a color vision test to detect possible central defects, and, if feasible, a slit-lamp microscopy study of the fundus and examination of the visual fields. Tests may be required at periodic intervals [usually every 6 to 12 months] during high-dose or prolonged therapy, since deposition of particulate matter in the lens and cornea has occurred with some phenothiazines; therapy should be discontinued if corneal, retinal, or lens changes are noticed; blurred vision, defective color vision, and night blindness are early symptoms of pigmentary retinopathy and may be reversible if detected and the phenothiazine discontinued in the early stages)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Akathisia{01}{03}{04} (restlessness or need to keep moving)
    
blurred vision associated with anticholinergic effect{01}{03}{04}
    
deposition of opaque material in lens, cornea, and retina{01}{03}{04} (blurred vision)
    
extrapyramidal effects, dystonic{01}{03}{04} (muscle spasms of face, neck, and back; tic-like or twitching movements; twisting movements of body; inability to move eyes; weakness of arms and legs)
    
extrapyramidal effects, parkinsonian{01}{03}{04} (difficulty in speaking or swallowing; loss of balance control; mask-like face; shuffling walk; stiffness of arms or legs; trembling and shaking of hands and fingers)
    
hypotension{01}{02}{03}{04} (fainting)
    
pigmentary retinopathy{01}{03}{04} (blurred vision; defective color vision; difficulty seeing at night)
    
tardive dyskinesia{01}{03}{04} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of arms and legs)—more frequent in elderly patients, women, and patients with brain damage

Note: Parkinsonian effects are more frequent in the elderly, whereas dystonias occur more often in younger patients. Symptoms may be seen in the first few days of treatment or after prolonged treatment, and can recur after even a single dose.


Incidence less frequent
    
Aggravation of glaucoma{02} (blurred vision or other changes in vision; eye pain)
    
allergic reaction{01}{02}{03}{04} (skin rash; itching; swelling of face and tongue)
    
anticholinergic effects{01}{02}{03}{04} (constipation or paralytic ileus, especially in the elderly; confusion, delirium, or hallucinations; difficulty in urination)
    
fast, slow, or irregular heartbeat{02}{04}
    
increased sensitivity of skin to sun{01}{02}{03}{04} (rash; severe sunburn)
    
muscle tremors{02}{03}{04} (shakiness)

Incidence rare
    
Alopecia{02}{03}{04} (hair loss)
    
blood dyscrasias, including agranulocytosis{01}{02}{03}{04} (chills, fever, sore throat; unusual tiredness or weakness), eosinophilia{03}{04} (fever), hemolytic anemia{03} (back, leg, or stomach pains; loss of appetite; pale skin; unusual tiredness or weakness or fever), leukopenia{03}{04} (fever, chills, or sore throat), or pancytopenia{03}{04} (nosebleeds, or other unusual bleeding or bruising)
    
cholestatic jaundice{01}{02}{03}{04} (abdominal or stomach pains; aching muscles and joints; fever and chills; severe skin itching; yellow eyes or skin; fatigue; nausea, vomiting, or diarrhea)
    
heat stroke{01}{04} (hot dry skin; inability to sweat; muscle weakness; confusion)
    
melanosis{01}{03} (tanning or blue-gray discoloration of skin)
    
neuroleptic malignant syndrome (NMS){01}{02}{03}{04} (convulsions; difficult or fast breathing; fast heartbeat or irregular pulse; fever; high or low [irregular] blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; unusual tiredness or weakness)
    
priapism{01} (prolonged, painful, inappropriate penile erection)
    
seizures{02}{03}{04}
    
syndrome of inappropriate secretion of antidiuretic hormone [SIADH]{02}{03}{04} (irritability; muscle twitching; weakness)
    
testicular swelling{02}{03}{04}
    
thrombocytopenic purpura{03}{04} (unusual bleeding or bruising)
    
tinnitus{02}{03}{04} (ringing, buzzing, or other unexplained noises in the ears)

Note: Agranulocytosis can develop within the first 3 months of treatment, with recovery within 1 to 2 weeks after medication is discontinued. It may recur upon rechallenge in recovered patients. {01}
Liver function tests may be abnormal without overt jaundice. Jaundice may appear about 2 weeks after severe pruritus and may progress to chronic active hepatitis. Discontinuing medication may be necessary. {01}
Heat stroke, caused by phenothiazine-induced suppression of central and peripheral temperature regulation in the hypothalamus, may occur in environmental conditions of high heat and high humidity. The effectiveness of sweating as a cooling mechanism may be reduced by humid conditions, by the anticholinergic effects of perphenazine and amitriptyline combination, or by the additive effects when this medication is used concurrently with other anticholinergic medications such as nonprescription cold medications or antihistamines. Adequate interior temperature control (air-conditioning) must be maintained for institutionalized patients during hot weather because of the increased risk of heat stroke and neuroleptic malignant syndrome (NMS). Patients should be advised to avoid exertion, stay in cool areas, and avoid dehydration and other anticholinergic medications. Phenothiazines may also cause hypothermia in cold weather, since the disruption of the thermoregulatory mechanisms results in a poikilothermic state. {01}
NMS may occur at any time during combined treatment with tricyclic antidepressants and neuroleptics and is potentially fatal. It is more commonly seen soon after start of therapy or after patient has switched from one neuroleptic to another, during combined therapy with another psychotropic medication, or after a dosage increase. Along with the overt signs of skeletal muscle rigidity, hyperthermia, autonomic dysfunction, and altered consciousness, differential diagnosis may reveal leukocytosis (9500 to 26,000 cells per cubic millimeter), elevated liver enzyme tests, and elevated creatine phosphokinase (CPK). {01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation{01}{03}{04}
    
decreased sweating{01}
    
drowsiness{01}{02}{03}{04}
    
dryness of mouth{01}{02}{03}{04}
    
headache{02}{03}{04}
    
increased appetite for sweets{02}
    
nasal congestion{01}{04}
    
nausea{02}{03}{04}
    
orthostatic hypotension (dizziness){01}{02}{03}{04}
    
tiredness or weakness, mild{02}{03}{04}
    
unpleasant taste{02}{03}
    
weight gain, unusual{01}{02}{03}{04}

Incidence less frequent
    
Changes in menstrual period{01}{03}{04}
    
decreased sexual ability{01}{02}{03}{04}
    
diarrhea{02}{03}
    
excessive sweating{02}{03}{04}
    
heartburn{02}{03}
    
secretion of milk, unusual{01}{02}{03}{04}
    
swelling or pain in breasts{01}{02}{03}{04}
    
vomiting{02}{03}{04}



Those indicating possible withdrawal and/or the need for medical attention if they occur after medication is discontinued
Incidence more frequent
    
Tardive dyskinesia, persistent{01}{03} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of arms and legs)—more frequent in elderly patients, women, and patients with brain damage

Incidence less frequent
    
Dizziness{01}{03}
    
nausea and vomiting{01}{03}
    
stomach pain{01}{03}
    
trembling of fingers and hands{01}{03}

Occurring upon abrupt withdrawal, due to cholinergic rebound
    
Diarrhea{02}
    
headache{03}{04}
    
trouble in sleeping, with vivid dreams{02}
    
unusual excitement{02}

Occurring with gradual withdrawal after long-term treatment
    
Irritability{02}{04}
    
restlessness{02}{04}
    
trouble in sleeping, with vivid dreams{02}{04}





Overdose
For specific information on the agents used in the management of perphenazine and amitriptyline overdose, see:
   • Anesthetics, Inhalation (Systemic) monograph;
   • Benztropine in Antidyskinetics (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Diphenhydramine in Antihistamines (Systemic) monograph;
   • Paraldehyde (Systemic) monograph;
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph;
   • Physostigmine (Systemic) monograph; and/or
   • Sodium Bicarbonate (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Agitation{02}{03}
    
confusion{02}{03}{04}
    
convulsions{02}{03}{04}
    
drowsiness, severe{02}{03}{04}
    
enlarged pupils{02}{03}{04}
    
fast, slow, or irregular heartbeat{02}{03}{04}
    
fever{02}{03}{04}
    
hallucinations{02}{03}{04}
    
shortness of breath or troubled breathing{02}
    
unusual tiredness or weakness, severe{02}
    
vomiting, severe{02}{03}{04}


Treatment of overdose
Treatment is symptomatic and supportive {03} {04}. Overdose symptoms may result from effects of perphenazine or amitriptyline, or both. The following procedures are often used:


To decrease absorption:
Attempting early gastric lavage {03} {04}, repeated several times; avoiding induction of vomiting because potential phenothiazine-induced dystonic reactions of the head and neck may result in aspiration of vomitus.

Administering activated charcoal slurry {03} {04}.

Administering a saline cathartic {03}.



Specific treatment:
Controlling cardiac arrhythmias with administration of sodium bicarbonate or phenytoin.

Administering physostigmine (1 to 3 mg intravenously); repeated if arrhythmias, seizures, or deep coma persists or recurs; not recommended for routine administration because of toxicity {03} {04}.

Digitalizing for cardiac failure {03} {04}.

Controlling seizures with an inhalant anesthetic, diazepam, paraldehyde, or anticonvulsants other than barbiturates {03} {04}.

Controlling parkinson-like symptoms with benztropine or diphenhydramine {03}.



Monitoring:
Monitoring cardiac function with ECG for not less than 5 days {03} {04}.



Supportive care:
Maintaining respiration, circulation, body temperature, and fluid intake {03} {04}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Perphenazine and Amitriptyline (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to phenothiazines, tricyclic antidepressants, or possibly maprotiline or trazodone

Pregnancy—

• Amitriptyline: Animal studies have shown teratogenic effects when amitriptyline was given in doses many times larger than the human dose; reports of cardiac problems, muscle spasms, respiratory distress, or urinary retention in neonates of mothers taking amitriptyline just prior to delivery


• Perphenazine: Phenothiazines have been found to depress spermatogenesis in animals; not recommended for use during pregnancy, because of reports of prolonged jaundice, hypo- or hyperreflexia, and extrapyramidal effects in neonates






Breast-feeding—Distributed into breast milk, possibly causing drowsiness, dystonias, and tardive dyskinesia in the baby; increased prolactin secretion in mother





Use in children—Adolescents more sensitive to effects, requiring lower doses; children more prone to develop extrapyramidal reactions






Use in the elderly—Elderly more likely to develop extrapyramidal, anticholinergic, hypotensive, and sedative effects; lower doses and more gradual increases required





Dental—Decreased salivary flow contributes to caries, periodontal disease, candidiasis, and discomfort; blood dyscrasias may cause increased infections, delayed healing, and gingival bleeding; increased extrapyramidal motor activity of head, face, and neck may cause difficulty with occlusal and other procedures
Other medications, especially alcohol and other CNS depressants, antithyroid agents, epinephrine, levodopa, lithium, cimetidine, other EPS-causing medications, MAO inhibitors, metrizamide, or sympathomimetics
Other medical problems, especially alcoholism (active), bipolar disorder, blood disorders, cardiovascular disorders, gastrointestinal disorders, glaucoma, hepatic function impairment, renal function impairment, hyperthyroidism, prostatic hypertrophy, latent psychosis, Reye's syndrome, severe CNS depression, seizures, or urinary retention

Proper use of this medication
Taking after meals or with food to reduce gastrointestinal irritation

» Compliance with therapy; not taking more or less medication than the amount prescribed

» Several weeks of therapy may be required to produce optimal therapeutic effects

» Proper dosing
Missed dose: Taking as soon as possible; not taking at all if less than 2 hours to next dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

Avoiding use of antacids or antidiarrheals within 2 hours of taking this medication

» Avoiding use of alcoholic beverages or other CNS depressants during therapy

» Caution if any kind of surgery, dental treatment, or emergency treatment is required

» Possible drowsiness or blurred vision; caution when driving, using machines or doing jobs requiring alertness or accurate vision {03} {04}

» Possible dizziness or lightheadedness; caution when getting up suddenly from a lying or sitting position

» Possible heat stroke: caution during exercise, hot weather, or hot baths or saunas

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

Possible skin photosensitivity; avoiding unprotected exposure to sun; using protective clothing; using a sun block product that includes protection against both UVA-caused photosensitivity reactions and UVB-caused sunburn reactions; avoiding use of sunlamp, tanning bed, or tanning booth

Observing precautions for 3 to 7 days after stopping medication


Side/adverse effects
» Stopping medication and getting emergency treatment if symptoms of neuroleptic malignant syndrome (NMS) appear

» Notifying physician as soon as possible if early symptoms of tardive dyskinesia appear

Possibility of withdrawal symptoms

Signs of potential side effects, especially anticholinergic effects; hypotension; dystonias; fast, slow, or irregular heartbeat; tardive dyskinesia or Parkinsonian syndrome; akathisia; shakiness or tremors; NMS; heat stroke; testicular swelling; allergic reactions; alopecia; blood dyscrasias; cholestatic jaundice; photosensitivity; ophthalmologic effects; melanosis; priapism; seizures; SIADH; or tinnitus


General Dosing Information
Potentially suicidal patients should not have access to large quantities of this drug since depressed patients, particularly those who may use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs.

Dosage must be individualized by titration from the lower dose range. After a favorable psychiatric response is noted (within several days to several weeks), that dosage should be continued for about 2 weeks, then gradually decreased to the lowest level that will maintain an adequate clinical response.

Although a sedative action may occur following the initial dose, 1 to 6 weeks of therapy may be required before the desired antidepressant response is obtained.

Upon cessation of extended therapy a gradual reduction in dosage over several weeks is recommended, since abrupt withdrawal may cause some patients on high or long-term dosage to experience transient dyskinetic signs, nausea, vomiting, diarrhea, gastritis, headache, trembling, trouble in sleeping (with vivid dreams), unusual excitement, and dizziness.

The antiemetic effect of perphenazine may mask signs of drug toxicity or obscure diagnosis of conditions whose primary symptom is nausea. Perphenazine has no antiemetic effect when nausea is a result of vestibular stimulation or local gastrointestinal irritation.

Patients on high dosage or extended maintenance dosage should be observed for symptoms of persistent tardive dyskinesia, which occurs most often in geriatric patients, especially females. The condition is persistent, difficult to control, and is characterized by rhythmic, involuntary movements of the tongue, face, mouth, or jaw (e.g., rapid protrusions or worm-like movements of the tongue, puffing of cheeks, puckering of mouth, chewing movements).

Antidyskinetic agents such as trihexyphenidyl or benztropine may be used concurrently to control phenothiazine-induced extrapyramidal symptoms (except tardive dyskinesia). They should be used only when required (not prophylactically), and, generally, are only needed for a few weeks to two or three months.

Diet/Nutrition
Dose may be taken with or immediately following meals to lessen gastric irritation.

Requirements for riboflavin may be increased in patients receiving phenothiazines {08}.

For treatment of adverse effects


Neuroleptic malignant syndrome (NMS):
Treatment is essentially symptomatic and supportive and may include the following: {01}

   • Discontinuing perphenazine and amitriptyline combination immediately {03} {04}.
   • Hyperthermia—Administering antipyretics (aspirin or acetaminophen); using cooling blanket.
   • Dehydration—Restoring fluids and electrolytes.
   • Cardiovascular instability—Monitoring blood pressure and cardiac rhythm closely.
   • Hypoxia—Administering oxygen; considering airway insertion and assisted ventilation.
   • Muscle rigidity—Administering dantrolene sodium (100 to 300 mg a day in divided doses; 1.25 to 1.5 mg/kg, intravenously); or administering amantadine (100 mg twice a day), or bromocriptine (5 mg three times a day), to restore central balance of dopamine and acetylcholine at the receptor site.



Parkinsonism:
Treatment may include: {01}

   • Reducing the perphenazine dosage, if possible, for treating milder effects.
   • Administering oral antidyskinetic agents such as trihexyphenidyl (2 mg three times a day), or benztropine {04}, for treating more severe parkinsonism and acute motor restlessness; using sparingly, only when side effects appear, and then usually for no longer than 3 months. Observing caution to prevent hyperpyrexia with concomitant use of phenothiazines and other medications with anticholinergic action.
   • In the elderly patient, using amantadine (100 to 200 mg at bedtime), to minimize severe anticholinergic effects that may occur with other antidyskinetics.
   • Levodopa is not useful in the treatment of phenothiazine-induced parkinsonism because the dopamine receptors are blocked by the phenothiazine.



Restlessness (akathisia):
May respond to antiparkinsonian drugs or propranolol (30 to 80 mg a day); nadolol (40 mg a day); or diazepam (2 mg two or three times a day), but often requires dosage reduction of the phenothiazine {01}.



Dystonia:
Acute dystonic postures or oculogyric crisis may be relieved by parenteral administration of benztropine (2 mg intramuscularly or intravenously); diphenhydramine (50 mg intramuscularly); or diazepam (5 to 7.5 mg intravenously), to be followed by oral antidyskinetic medication for one or two days to prevent recurrent dystonic episodes. Dosage adjustments of the phenothiazine may control these effects, and discontinuation of the phenothiazine may reverse severe symptoms. {01}



Tardive dyskinesia:
No known effective treatment. Dosage of perphenazine should be lowered or medication discontinued at earliest signs of tardive dyskinesia to prevent irreversible effects. {01} {02}



Oral Dosage Forms

PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE TABLETS USP

Usual adult dose
Oral, 2 mg of perphenazine and 25 mg of amitriptyline hydrochloride to 4 mg of perphenazine and 25 mg of amitriptyline hydrochloride three or four times a day initially, the daily dosage being adjusted as needed and tolerated {03} {04} {05} {06} {07}.

Note: Debilitated patients usually require a lower initial dose, which is then gradually increased as needed and tolerated.


Usual adult prescribing limits
Up to a total of 32 mg of perphenazine and 200 mg of amitriptyline hydrochloride daily {03} {04} {05} {06} {07}.

Usual pediatric dose
Children up to 12 years of age—Safety and efficacy have not been established.

Children over 12 years of age—Adolescent patients usually require a lower initial dose, which is then gradually increased as needed and tolerated. Dosage must be individualized by physician.

Usual geriatric dose
Oral, 4 mg of perphenazine and 10 mg of amitriptyline hydrochloride three or four times a day initially, the dosage being adjusted as needed and tolerated {03} {04} {05} {06} {07}.

Strength(s) usually available
U.S.—


2 mg of perphenazine and 10 mg of amitriptyline hydrochloride (Rx) [Etrafon] [Triavil][Generic]


2 mg of perphenazine and 25 mg of amitriptyline hydrochloride (Rx) [Etrafon] [Triavil][Generic]


4 mg of perphenazine and 10 mg of amitriptyline hydrochloride (Rx) [Etrafon-A] [Triavil][Generic]


4 mg of perphenazine and 25 mg of amitriptyline hydrochloride (Rx) [Etrafon-Forte] [Triavil][Generic]


4 mg of perphenazine and 50 mg of amitriptyline hydrochloride (Rx) [Triavil][Generic]

Canada—


2 mg of perphenazine and 10 mg of amitriptyline hydrochloride (Rx) [Etrafon]


2 mg of perphenazine and 25 mg of amitriptyline hydrochloride (Rx) [Elavil Plus] [Etrafon-D] [PMS Levazine]


3 mg of perphenazine and 15 mg of amitriptyline hydrochloride (Rx) [Triavil]


4 mg of perphenazine and 10 mg of amitriptyline hydrochloride (Rx) [Etrafon-A]


4 mg of perphenazine and 25 mg of amitriptyline hydrochloride (Rx) [Etrafon-F] [PMS Levazine]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container. Protect from light.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Revised: 01/27/1992



References
  1. Phenothiazine monograph, revised version for USP DI 89.
  1. Antidepressants, Tricyclic monograph, revised version for USP DI 89.
  1. Etrafon (Schering) package insert, revised 6/87; 3/90.
  1. Triavil (MSD) package insert, rev. 7/87; 9/90.
  1. Bolar package insert, rev. 1/88.
  1. Cord package insert, rev. 7/88
  1. Mylan package insert, rev. 12/88.
  1. JT Pinto and RS Rivlan. Drugs that promote renal excretion of riboflavin. Drug-Nutrient Interactions 1987; 5: 143-51.
  1. Probucol (Lorelco-Marion Merrell Dow) package insert, rev. 2/89.
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