Amitriptyline and perphenazine

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
Based on the amitriptyline component:

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder (MDD) and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults treated with antidepressants should be observed similarly 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. A medication guide should be dispensed with each prescription.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose 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 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.

Often causes drowsiness/sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is very high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. Consider discontinuing, when possible, prior to elective surgery.. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

May cause orthostatic hypotension; the risk of this problem is very high relative to other antidepressants. Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants; use with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.

Use 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. May lower seizure threshold - use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.

Based on the perphenazine component:

May cause hypotension. May be sedating; use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; predisposition to seizures; severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of pneumonia (eg, Alzheimer's disease). Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life-threatening arrhythmias have occurred with therapeutic doses of phenothiazines. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose).

Phenothiazines may cause anticholinergic effects (confusion, agitation, constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Older patients are at increased risk for developing tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.

This combination is not FDA approved for use in children or for the treatment of bipolar depression.

RESTRICTIONS — An FDA-approved medication guide concerning the use of antidepressants in children and teenagers must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and teenagers receiving this medication.

DRUG INTERACTIONS
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)

Also see individual agents.

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): $8.99
2-25 mg (30): $7.99
4-25 mg (60): $11.99
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)

CANADIAN BRAND NAMES — Etrafon®

INTERNATIONAL BRAND NAMES — Etrafon (CA); Mutabase (ES); Mutabon A (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon D (AE, AR, BH, CL, CY, EG, ID, IL, IQ, IR, JO, LY, OM, PY, QA, SA, SY); Mutabon F (AE, BH, CY, EG, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon M (AE, BH, CY, EG, ID, IL, IQ, IR, JO, LY, OM, QA, SA, SY); Mutabon-A (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-D (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-F (AN, BB, BM, BS, BZ, GY, JM, SR, TT); Mutabon-M (AN, BB, BM, BS, BZ, GY, JM, 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.