Amitriptyline and Perphenazine
Special Alerts
Antidepressant Use in Pediatric Patients - October 15, 2004
In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of
ALL
antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.
The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:
Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.
Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.
Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.
A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).
Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.
Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.
The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.
Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.
Pronunciation
(a mee TRIP ti leen & per FEN a zeen)
U.S. Brand Names
Triavil®
Synonyms
Perphenazine and Amitriptyline
Generic Available
Yes
Canadian Brand Names
Etrafon®; Triavil®
Use
Treatment of patients with moderate to severe anxiety and depression
Use - Unlabeled/Investigational
Depression with psychotic features
Pregnancy Risk Factor
D
Lactation
Enters breast milk/contraindicated
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
See individual agents. Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with 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. A medication guide should be dispensed with each prescription. This combination is not FDA approved for use in children.
Adverse Reactions
Based on
amitriptyline
component: Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs). Frequency not defined:
Cardiovascular: Orthostatic hypotension, tachycardia, nonspecific ECG changes, changes in AV conduction
Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, impaired cognitive function, seizure, extrapyramidal symptoms
Dermatologic: Allergic rash, urticaria, photosensitivity
Gastrointestinal: Weight gain, xerostomia, constipation
Genitourinary: Urinary retention
Ocular: Blurred vision, mydriasis
Miscellaneous: Diaphoresis
Based on
perphenazine
component: Frequency not defined:
Cardiovascular: Hyper-/hypotension, orthostatic hypotension, tachycardia, bradycardia, dizziness, cardiac arrest
Central nervous system: Extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, cerebral edema, seizure, headache, drowsiness, paradoxical excitement, restlessness, hyperactivity, insomnia, neuroleptic malignant syndrome (NMS), impairment of temperature regulation
Dermatologic: Increased sensitivity to sun, rash, discoloration of skin (blue-gray)
Endocrine & metabolic: Hypoglycemia, hyperglycemia, galactorrhea, lactation, breast enlargement, gynecomastia, menstrual irregularity, amenorrhea, SIADH, libido (changes in)
Gastrointestinal: Constipation, weight gain, vomiting, stomach pain, nausea, xerostomia, salivation, diarrhea, anorexia, ileus
Genitourinary: Difficulty in urination, ejaculatory disturbances, incontinence, polyuria, ejaculating dysfunction, priapism
Hematologic: Agranulocytosis, leukopenia, eosinophilia, hemolytic anemia, thrombocytopenic purpura, pancytopenia
Hepatic: Cholestatic jaundice, hepatotoxicity
Neuromuscular & skeletal: Tremor
Ocular: Pigmentary retinopathy, blurred vision, cornea and lens changes
Respiratory: Nasal congestion
Miscellaneous: Diaphoresis
Drug Interactions
Amitriptyline:
Substrate
of CYP1A2 (minor), 2B6 (minor), 2C8/9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor);
Inhibits
CYP1A2 (weak), 2C8/9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)
Perphenazine:
Substrate
of CYP1A2 (minor), 2C8/9 (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).
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.
Dosage
Oral: 1 tablet 2-4 times/day
Monitoring Parameters
Vital signs; lipid profile, fasting blood glucose/Hgb A1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS)
Patient Education
See individual agents. Do not drink alcoholic beverages.
Pregnancy/breast-feeding precautions:
Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Nursing Implications
Monitor blood pressure and pulse rate prior to and during initial therapy; evaluate mental status; monitor weight; may increase appetite and possibly a craving for sweets; offer patient sugarless hard candy for dry mouth
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment:
Amitriptyline: Xerostomia (normal salivary flow resumes upon discontinuation). The most anticholinergic and sedating of the antidepressants; pronounced effects on the cardiovascular system; long-term treatment with TCAs such as amitriptyline increases the risk of caries by reducing salivation and salivary buffer capacity. In a study by Rundergren, et al, pathological alterations were observed in the oral mucosa of 72% of 58 patients; 55% had new carious lesions after taking TCAs for a median of 5
1
/2 years. Current research is investigating the use of the salivary stimulant pilocarpine (Salagen®) to overcome the xerostomia from amitriptyline.
Perphenazine: Extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, seizures, headache, drowsiness, paradoxical excitement, restlessness, and hyperactivity.
Tardive dyskinesia: Prevalence rate may be 40% in elderly; development of the syndrome and the irreversible nature are proportional to duration and total cumulative dose over time. Extrapyramidal reactions are more common in elderly with up to 50% developing these reactions after 60 years of age. Drug-induced Parkinson's syndrome occurs often; akathisia is the most common extrapyramidal reaction in elderly.
Increased confusion, memory loss, psychotic behavior, and agitation frequently occur as a consequence of anticholinergic effects. Antipsychotic associated sedation in nonpsychotic patients is extremely unpleasant due to feelings of depersonalization, derealization, and dysphoria.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Amitriptyline: Use with caution; epinephrine, norepinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs
Perphenazine: No information available to require special precautions
Dosage Forms
Tablet:
2-10 (Triavil®): Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
2-25 (Triavil®): Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
4-10: Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
4-25 (Triavil®): Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
4-50: Amitriptyline hydrochloride 50 mg and perphenazine 4 mg
References
Boakes AJ, Laurence DR, Teoh PC, et al, "Interactions Between Sympathomimetic Amines and Antidepressant Agents in Man,"
Br Med J
, 1973, 1(849):311-5.
Jastak JT and Yagiela JA, "Vasoconstrictors and Local Anesthesia: A Review and Rationale for Use,"
J Am Dent Assoc
, 1983, 107(4):623-30.
Larochelle P, Hamet P, and Enjalbert M, "Responses to Tyramine and Norepinephrine After Imipramine and Trazodone,"
Clin Pharmacol Ther
, 1979, 26(1):24-30.
Mitchell JR, "Guanethidine and Related Agents. III Antagonism by Drugs Which Inhibit the Norepinephrine Pump in Man,"
J Clin Invest
, 1970, 49(8):1596-604.
Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings,"
Chest
, 2003, 123(3):897-922.
Rundegren J, van Dijken J, Mörnstad H, et al, "Oral Conditions in Patients Receiving Long-Term Treatment With Cyclic Antidepressant Drugs,"
Swed Dent J
, 1985, 9(2):55-64.
Svedmyr N, "The Influence of a Tricyclic Antidepressive Agent (Protriptyline) on Some of the Circulatory Effects of Noradrenaline and Adrenalin in Man,"
Life Sci
, 1968, 7(1):77-84.
International Brand Names
Etrafon® (CA); Triavil® (CA)
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