Perphenazine

Name: Perphenazine

Perphenazine Brand Names

Perphenazine may be found in some form under the following brand names:

  • Etrafon

  • Triavil

  • Trilafon

Perphenazine Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • tricyclic antidepressants such as trimipramine (Surmontil), amitriptyline (Elavil), nortriptyline (Pamelor, Aventyl), protriptyline (Vivactil), and clomipramine (Anafranil)
  • selective serotonin reuptake inhibitors (SSRIs) such as escitalopram (Lexapro), sertraline (Zoloft), citalopram (Celexa), vilazodone (Viibryd), paroxetine (Paxil), fluoxetine (Prozac, Sarafem, Symbyax), and fluvoxamine (Luvox)
  • medications that block a protein in the body (CYP2D6) such as quinidine (Qualaquin)
  • atropine
  • other central nervous system depressants such as opiates, analgesics, antihistamines, and barbiturates

This is not a complete list of perphenazine drug interactions. Ask your doctor or pharmacist for more information.

 

Perphenazine and Pregnancy

Tell your doctor if you are pregnant or plan to become pregnant.

Safe use of perphenazine during pregnancy has not been established. Perphenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

 

Perphenazine Overdose

If you take too much perphenazine, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Perphenazine FDA Warning

WARNING

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Perphenazine is not approved for the treatment of patients with dementia-related psychosis.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of perphenazine can be fatal.

What other drugs will affect perphenazine?

Taking perphenazine with other drugs that make you sleepy or slow your breathing can cause dangerous or life-threatening side effects. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Many drugs can interact with perphenazine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with perphenazine.

How is this medicine (Perphenazine) best taken?

Use perphenazine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food. Take with food if it causes an upset stomach.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Perphenazine Description

Perphenazine (4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol), a piperazinyl phenothiazine, having the chemical formula, C21H26CIN3OS. It is available as oral tablets containing 2 mg, 4 mg, 8 mg, and 16 mg of Perphenazine.

Inactive ingredients: lactose (monohydrate), microcrystalline cellulose, magnesium stearate, polyethylene glycol, starch (corn) titanium dioxide, hypromellose and polysorbate 80. Its structural formula is:

Contraindications

Perphenazine products 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 Perphenazine products, their components, or related compounds.

Perphenazine products 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.

Precautions

Leukopenia, Neutropenia and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/ neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue Perphenazine tablets USP at the first sign of a decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Perphenazine tablets USP and have their WBC followed until recovery.

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.

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 products in any dosage should be kept under close supervision.

Antipsychotic 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 antipsychotic 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 it should be discontinued.

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 phosphorus 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 Perphenazine products. 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.

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, including Perphenazine, 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.

Drug Interactions

Metabolism of a number of medications, including antipsychotics, antidepressants, ß-blockers, and antiarrhythmics, occurs through the cytochrome P450 2D6 isoenzyme (debrisoquine hydroxylase). Approximately 10% of the Caucasian population has reduced activity of this enzyme, so-called “poor” metabolizers. Among other populations the prevalence is not known. Poor metabolizers demonstrate higher plasma concentrations of antipsychotic drugs at usual doses, which may correlate with emergence of side effects. In one study of 45 elderly patients suffering from dementia treated with Perphenazine, the 5 patients who were prospectively identified as poor P450 2D6 metabolizers had reported significantly greater side effects during the first 10 days of treatment than the 40 extensive metabolizers, following which the groups tended to converge. Prospective phenotyping of elderly patients prior to antipsychotic treatment may identify those at risk for adverse events.

The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. Among these are tricyclic antidepressants and selective serotonin reuptake inhibitors, e.g., fluoxetine, sertraline and paroxetine. When prescribing these drugs to patients already receiving antipsychotic therapy, close monitoring is essential and dose reduction may become necessary to avoid toxicity. Lower doses than usually prescribed for either the antipsychotic or the other drug may be required.

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 antipsychotics 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.

Geriatric Use

Clinical studies of Perphenazine products did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic function, concomitant disease or other drug therapy.

Geriatric patients are particularly sensitive to the side effects of antipsychotics, including Perphenazine. These side effects include extrapyramidal symptoms (tardive dyskinesia, antipsychotic-induced parkinsonism, akathisia), anticholinergic effects, sedation and orthostatic hypotension (See WARNINGS). Elderly patients taking psychotropic drugs may be at increased risk for falling and consequent hip fractures. Elderly patients should be started on lower doses and observed closely.

Adverse Reactions

Not all of the following adverse reactions have been reported with this specific drug; 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 (e.g., 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.

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

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 children. 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 (e.g., 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, or 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 antipsychotic drugs (see WARNINGS).

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, bladder paralysis, polyuria, nasal congestion, pallor, myosis, mydriasis, blurred vision, glaucoma, perspiration, hypertension, hypotension, and 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, syndrome of inappropriate ADH (antidiuretic hormone) secretion, false positive pregnancy tests, hyperglycemia, hypoglycemia, glycosuria.

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 antipsychotics.

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.

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dosing Renal Impairment

There are no dosage adjustments provided in manufacturer’s labeling; use with caution.

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, fatigue, diarrhea, lack of appetite, nausea, vomiting, or rhinitis. Have patient report immediately to prescriber signs of infection, signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), suicidal ideation, abnormal movements, twitching, change in balance, difficulty swallowing, difficulty speaking, severe dizziness, passing out, severe headache, angina, tremors, difficulty moving, rigidity, urinary retention, severe loss of strength and energy, bruising, bleeding, behavioral changes, vision changes, eye pain, severe eye irritation, drooling, seizures, bradycardia, pale skin, severe constipation, agitation, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

For the Consumer

Applies to perphenazine: oral fixed-combination tablets, oral tablets

Side effects include:

Extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia, tardive dyskinesia), drowsiness, muscular weakness, dry mouth, blurred vision, weight gain, skin reactions, amenorrhea, galactorrhea.

Usual Pediatric Dose for Psychosis

12 years and older:
Moderately disturbed, nonhospitalized patients:
-Recommended dose: 4 to 8 mg orally 3 times a day, with a dose reduction to the minimum effective dose as soon as possible
-Maximum dose: 24 mg/day

Hospitalized patients:
-Recommended dose: 8 to 16 mg orally 2 to 4 times a day
-Maximum dose: 64 mg/day

Comments:
-Nonhospitalized patients should be limited to a daily dose of 24 mg; maximum doses of 64 mg should be used in hospitalized patients.

Use: Treatment of schizophrenia

Precautions

US BOXED WARNING:
-INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: This drug has an increased risk of mortality when administered to elderly patients with dementia-related psychosis. Elderly patients with dementia-related psychosis treated with antipsychotic drugs have an increased risk of death. This drug is not approved for use in patients with dementia-related psychosis.

Safety and efficacy have not been established in patients younger than 12 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:
-For some patients, this drug may be given before bed.

Storage requirements:
-See manufacturer product information.

General:
-All patients on prolonged treatment should be reassessed regularly.
-Patients receiving long-term treatment may have a higher risk of developing liver damage, corneal/lenticular deposits, and/or irreversible dyskinesia.
-Treatment has not been effective for the management of behavioral complications in patients with mental impairments.

Monitoring:
-ECG monitoring for patients at risk of QT prolongation
-Periodic WBC with differential tests, especially in patients with signs/symptoms of infection/sore throat, at increased risk of blood dyscrasias, and/or with a history of low WBCs or drug-induced neutropenia/leukopenia
-Periodic liver function tests
-Blood pressure, especially in patients with impaired cardiovascular systems
-Eye examinations, especially in patients on prolonged treatment
-Heart rate, especially in patients with arrhythmias and/or taking QT prolonging drugs concurrently
-Periodic renal function tests, especially in patients on prolonged treatment

Patient advice:
-Patients should be warned to avoid abrupt discontinuation of this drug.
-Patients should be instructed to immediately report any signs/symptoms of neutropenia/leukopenia, neuroleptic malignant syndrome, or tardive dyskinesia.
-Inform patients that this drug may cause or impair mental/physical abilities, and they should avoid driving or operating machinery until the full effects of the drug are seen.
-Patients should be advised to speak to a healthcare provider if they are pregnant, intend to become pregnant, or are breastfeeding.

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