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Perphenazine and Amitriptyline (Perphenazine / Amitriptyline Hydrochloride) - Side Effects and Adverse Reactions



To date, clinical evaluation of perphenazine has not revealed any adverse reactions peculiar to the combination. The adverse reactions that occurred were limited to those that have been reported previously for perphenazine and amitriptyline.

Treatment with perphenazine and amitriptyline hydrochloride is commonly associated with sedation, hypertension, neurological impairments and dry mouth.


The common acute neurological effects of neuroleptic drugs, including perphenazine, consist of dystonia, akathisia or motor restlessness, and pseudoparkinsonism.

More chronic use of neuroleptics may be associated with the development of tardive dyskinesia. The salient features of this syndrome are described in the WARNINGS section and below.

The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.


Tardive Dyskinesia

The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk and extremities. The severity of the syndrome and the degree of impairment produced vary widely.

The syndrome may become clinically recognizable either during treatment, upon dosage reduction, or upon withdrawal of treatment. Movements may decrease in intensity and may disappear altogether if further treatment with neuroleptics is withheld. It is generally believed that reversibility is more likely after short rather than long term neuroleptic exposure. Consequently, early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of neuroleptic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. It has been suggested that fine vermicular movements of the tongue may be an early sign of the syndrome, and that the full blown syndrome may not develop if medication is stopped when lingual vermiculation appears.

  • 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.
  • Akathisia: Akathisia presents as constant motor restlessness. The patient with akathisia often complains, when asked, about his/her inability to stop moving. Akathisia should not be treated with an increased dose of neuroleptic; rather, the dose of antipsychotic may be lowered until the motor restlessness has subsided. The efficacy of anticholinergic treatment of this side effect is unestablished.
  • Pseudoparkinsonism: Pseudoparkinsonism refers to a drug-induced state similar to the classic syndrome. Generally, anticholinergic antiparkinsonian agents (i.e., benztropine, biperiden, procyclidine, or trihexphenidyl) and amantadine are helpful in alleviating symptoms that cannot be managed by neuroleptic dose reduction. The value of prophylactic antiparkinsonian drug therapy has not been established. The need for continued use of antiparkinsonian medication should be reevaluated periodically.


Hypotension, hypertension, tachycardia, peripheral edema, occasional change in pulse rate, ECG abnormalities (quinidine like effect), reversed epinephrine effect.

CNS and Neuromuscular

Extrapyramidal symptoms, including acute dyskinesia (see Neurological), reactivation of psychoses and production of catatonic like states, paradoxical excitement, ataxia, muscle weakness, hypnotic effects, mild insomnia, lassitude, headache, hyperflexia, altered cerebrospinal fluid proteins.

Autonomic: Urinary frequency or incontinence, dry mouth or salivation, nasal congestion.

Allergic: Anaphylactoid reactions, laryngeal edema, asthma, angioneurotic edema.

Hematologic: Blood dyscrasias including pancytopenia, agranulocytosis, leukopenia, thrombocytopenic purpura, eosinophilia.

Gastrointestinal: Liver damage (jaundice, biliary stasis), obstipation, vomiting, nausea, constipation, anorexia.

Dermatologic: Eczema up to exfoliative dermatitis, urticaria, erythema, itching, photosensitivity.

Ophthalmic: Pigmentation of the cornea and lens, blurred vision.

Endocrine: Lactation, galactorrhea, hyperglycemia, gynecomastia, disturbances in menstrual cycle.

Other: False positive pregnancy tests, including immunologic.

Other adverse reactions that should be considered because they have been reported with various phenothiazine compounds, but not with perphenazine, include:

CNS and Neuromuscular: Grand mal convulsions, cerebral edema.

Gastrointestinal: Polyphagia.

Dermatologic: Photophobia, pigmentation.

Ophthalmic: Pigmentary retinopathy

Endocrine: Failure of ejaculation.

Amitriptyline Hydrochloride

Within each category the following adverse reactions are listed in order of decreasing severity. 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 is administered.

Cardiovascular: Myocardial infarction, stroke, heart block, arrhythmias, hypotension, particularly orthostatic hypotension, hypertension, tachycardia, palpitation.

CNS and Neuromuscular: Coma, seizures, hallucinations, delusions, confusional states, disorientation, incoordination, ataxia, tremors, peripheral neuropathy, numbness, tingling and paresthesias of the extremities, extrapyramidal symptoms, dysarthria, disturbed concentration, excitement, anxiety, insomnia, restlessness, nightmares, drowsiness, dizziness, weakness, fatigue, headache, syndrome of inappropriate ADH (antidiuretic hormone) secretion, tinnitus, alteration in EEG patterns.

Anticholinergic: Paralytic ileus, hyperpyrexia, urinary retention, dilatation of urinary tract, constipation, blurred vision, disturbance of accommodation, increased intraocular pressure, mydriasis, dry mouth.

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

Hematologic: Bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia.

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

Endocrine: 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.

Other: Alopecia, edema, weight gain or loss, urinary frequency, increased perspiration.

Withdrawal Symptoms

After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within 2 weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants.

Drug label data at the top of this Page last updated: 2014-07-29

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