General Articles

Amitriptyline and perphenazine

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088622.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Antipsychotic Agent, Typical, Phenothiazine

DOSING: ADULTS — Depression and anxiety: Oral: 1 tablet 2-4 times/day

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Avoid use in severe hepatic failure.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
2-10: Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
2-25: Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
4-10: Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
4-25: Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
4-50: Amitriptyline hydrochloride 50 mg and perphenazine 4 mg

DOSAGE FORMS: CONCISE
Tablet:
Generics:
2-10: Amitriptyline 10 mg and perphenazine 2 mg
2-25: Amitriptyline 25 mg and perphenazine 2 mg
4-10: Amitriptyline 10 mg and perphenazine 4 mg
4-25: Amitriptyline 25 mg and perphenazine 4 mg
4-50: Amitriptyline 50 mg and perphenazine 4 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Treatment of patients with moderate-to-severe anxiety and depression

USE – UNLABELED / INVESTIGATIONAL — Depression with psychotic features

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to amitriptyline, perphenazine, or any component of the formulation (cross-sensitivity with other phenothiazines may exist); angle-closure glaucoma; bone marrow depression; severe liver or cardiac disease; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Dementia: See “Disease-related concerns” below. Suicidal thinking/behavior: See “Major psychiatric warnings” below.

Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥ 65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12 years of age; this combination is not FDA approved for use in children. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. This combination is not FDA approved for the treatment of bipolar depression. Concerns related to adverse effects: Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics. Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade and relative to other antidepressants amitriptyline has a high potential for cholinergic blockade. Blood dyscrasias: Check blood counts periodically and discontinue at first signs of blood dyscrasias; use is contraindicated in patients with bone marrow suppression. Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer’s disease). Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Hyperprolactinemia: Perphenazine use is associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Neuroleptic malignant syndrome (NMS): Use of perphenazine may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Ocular effects: Perphenazine may cause pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy. Orthostatic hypotension: Both agents may cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Sedation: Both agents may cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is high relative to other antidepressants. SIADH and hyponatremia: Has been associated with the development of SIADH and hyponatremia. Temperature regulation: Impaired core body temperature regulation may occur with perphenazine use; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

SEE MORE:  Acacia albida Del.
Disease-related concerns: Cardiovascular disease: Use both agents with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants. Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Perphenazine is not approved for the treatment of dementia-related psychosis. Diabetes: Use amitriptyline with caution in patients with diabetes mellitus; may alter glucose regulation. Glaucoma: Use with caution in patients wit h narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade. Hepatic impairment: Use both agents with caution in patients with hepatic impairment. Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade. Parkinson’s disease: Use perphenazine with caution in patients with Parkinson’s disease; they may be more sensitive to adverse effects. Renal impairment: Use both agents with caution in patients with renal impairment. Seizure disorder: Use both agents with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation. Concurrent drug therapy issues: Antiemetic effects: Perphenazine may mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye’s syndrome, brain tumor) due to antiemetic effects. Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol. Special populations: Elderly: Use with caution in the elderly; increased risk for developing tardive dyskinesia from perphenazine. Poor metabloizers: Use with caution in patients with reduced functional alleles of CYP2D6. Poor metabolizers may have higher plasma concentrations at usual doses, increasing risk for adverse reactions. Other warnings/precautions: Discontinuation of therapy: Recommended to discontinue several days prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods. Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment. METABOLISM / TRANSPORT EFFECTS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)

Perphenazine: Substrate of CYP1A2 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2D6 (weak)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy

SEE MORE:  Total hip replacement (arthroplasty)

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy

Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

Analgesics (Opioid): Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Antacids: May decrease the absorption of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Antimalarial Agents: May increase the serum concentration of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy

Anti-Parkinson’s Agents (Dopamine Agonist): Antipsychotics (Typical) may diminish the therapeutic effect of Anti-Parkinson’s Agents (Dopamine Agonist). Risk D: Consider therapy modification

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

Beta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Risk C: Monitor therapy

BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Risk X: Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

NSAID (COX-2 Inhibitor): Antid

epressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy

NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy

SEE MORE:  Agalsidase bet

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy

Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (due to increased sedation).

PREGNANCY RISK FACTOR — D (show table)

LACTATION — Enters breast milk/contraindicated

PRICING — (data from drugstore.com)
Tablets (Perphenazine-Amitriptyline)
2-10 mg (60): $16.99
2-25 mg (30): $13.99
4-25 mg (60): $19.99
4-50 mg (60): $27.99

MONITORING PARAMETERS — Vital signs; lipid profile, fasting blood glucose/Hb A1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS), suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)

CANADIAN BRAND NAMES — Etrafon®

INTERNATIONAL BRAND NAMES — Mutabon A (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon D (AE, AR, BH, CN, CY, EG, ID, IL, IQ, IR, JO, KW, LB, LY, OM, PY, QA, SA, SY, YE); Mutabon F (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon M (AE, BH, CY, EG, ID, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon-A (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-D (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-F (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-M (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Neuragon-A (TH); Neuragon-B (TH); Polybon (TH); Triptafen (GB); Triptafen M (GB)

MECHANISM OF ACTION
Amitriptyline increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane.

Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones.

PHARMACODYNAMICS / KINETICS — See individual agents.

July 2010
M T W T F S S
« Jun   Aug »
 1234
567891011
12131415161718
19202122232425
262728293031