Adult Dosing

Depression with anxiety

• 1 tab [25 mg/2 mg] or [25 mg/4 mg] PO tid-qid or 1 tab [50 mg/4 mg] PO bid

Severely ill patients with schizophrenia

• Initial dose: 2 tab [50 mg/8 mg] PO tid; if required, administer a fourth dose qhs

Predominance of anxiety

• Geriatric patients
• Initial dose: 1 tab [10 mg/4 mg] PO tid-qid; adjust as required for subsequent adequate therapy

• After a satisfactory response, reduce dose to the smallest amount necessary for obtaining relief from the symptoms for which this product is administered
• Use 1 tab [25 mg/2 mg] or [25 mg/4 mg] PO bid-qid or 1 tab [50 mg/4 mg] PO bid as a maintenance dose
• Use 10 mg/2 mg and 10 mg/4 mg for increasing flexibility in adjusting maintenance dose to the lowest amount consistent with relief of symptoms

Pediatric Dosing

• Safety and effectiveness in pediatric patients have not been established

[Outline]

• Adult Dosing
• Pediatric Dosing

• For treating patients with moderate-to-severe anxiety and/or agitation and depressed mood
• Treatment of patients with depression having severe anxiety and/or agitation
• Treatment of patients with depression and anxiety in association with chronic physical disease

• Hypersensitivity to any of the ingredients of the product
• Bone marrow depression
• Concomitant use with MAOI
• Acute recovery phase following MI
• Severe CNS depression
• Abrupt withdrawal

• Increased mortality is associated in elderly patients with dementia-related psychosis
• Elderly patients with dementia-related psychosis are at an increased risk of death when treated with antipsychotic drugs. This combination drug is unapproved for the treatment of patients with dementia-related psychosis
• Analysis of 17 placebo-controlled trials (modal duration of 10 wks), conducted largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6-1.7 x the risk of death in placebo-treated patients. During 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. Most of the deaths occurred were either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature
• Observational studies indicate that treatment with conventional antipsychotic drugs may increase mortality, similar to atypical antipsychotic drugs. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristics of the patients is not clear
• Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults compared to placebo in short-term studies of major depressive disorder (MDD) and other psychiatric diseases
• Assess potential benefits/risks before considering the use of amitriptyline/perphenazine in children, adolescents, or young adults
• Depression and other psychiatric disorders are themselves associated with increases in the risk of suicide
• In short-term studies of antidepressants vs. placebo, suicidality risk was not increased in patients >24 yrs and the risk decreased in patients >65 yrs. Carefully weigh the risks and benefits before starting treatment
• Monitor all patients started on antidepressant therapy and observe closely for clinical worsening, suicidal tendencies, or unusual changes in behavior, particularly early during therapy or during dose adjustment. Advise families and caregivers of the need for close observation and communication with the prescriber
• Therapy is not approved for use in pediatric patients

Renal Dose Adjustment

• Renal impairment: Use with caution; dose adjustments not defined

Hepatic Dose Adjustment

• Hepatic impairment: Use with caution; dose adjustments not defined

See Supplemental Patient Information

• Elderly patients with dementia-related psychosis are at an increased risk of death when treated with antipsychotic drugs. This combination drug is unapproved for the treatment of patients with dementia-related psychosis [US Black Box Warning]
• Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in patients with MDD; this risk may persist until significant remission occurs
• Younger patients are more prone to suicidality; suicidality risk did not increase in patients >24 yrs of age and the risk decreased in patients >65 yrs of age [US Black Box Warning]
• Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have occurred in adults and pediatric patients receiving antidepressants; such symptoms may represent precursors to emerging suicidality
• Monitor and closely observe patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial few months of a course of drug therapy or at times of dose modifications
• Consider changing the therapeutic regimen or discontinuation of therapy on persistent worsening of depression, or on experiencing emergent suicidality, or on abrupt onset of symptoms suggesting worsening of depression or suicidality, especially if these symptoms are severe, abrupt in onset, and were not part of the patient’s presenting symptoms
• Considering discontinuation of treatment, taper medication as rapidly as feasible, but with due recognition that abrupt discontinuation can be associated with certain symptoms
• Alert families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and also for the emergence of suicidality, and to report such symptoms immediately to health care providers
• Prescribe smallest quantity of tablets consistent with good patient management to reduce the risk of overdose
• A major depressive episode may be the initial presentation of bipolar disorder. Prior to initiating treatment with an antidepressant, adequately screen patients with depressive symptoms to determine if they are at risk for bipolar disorder, as treating with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Consider a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression
• This combination drug is not approved for treating bipolar depression
• Risk of developing irreversible tardive dyskinesia increases as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increases. Elderly women are more prone to the syndrome of potentially irreversible, involuntary, dyskinetic movements. Syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn
• Prescribe this drug in a manner that is most likely to minimize the risk of tardive dyskinesia. Discontinue therapy on occurrence of signs and symptoms of tardive dyskinesia. Periodically reassess the need for continued treatment
• Potentially fatal symptom complex, referred to as neuroleptic malignant syndrome (NMS), has occurred in association with administration of antipsychotic drugs. Manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability
• Carefully diagnose patients for serious medical illness (e.g. pneumonia, systemic infection, etc.), untreated or inadequately treated extrapyramidal signs and symptoms, central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology
• Immediately discontinue antipsychotic drugs and other drugs not essential for concomitant therapy, provide intensive symptomatic treatment, carefully monitor patients and provide treatment for concomitant serious medical problems for management of NMS
• Carefully consider potential reintroduction of drug therapy in patients recovered from NMS as recurrences of NMS may occur
• Avoid concomitant administration of guanethidine or similarly acting compounds as amitriptyline may block the antihypertensive effect of these agents
• Use with caution in patients with cardiovascular diseases because of the tendency of the drug to produce tachycardia, hypotension, arrhythmias, and prolonged conduction time. Therapy may cause myocardial infarction and stroke
• Closely monitor hyperthyroid patients or those on thyroid medication
• Periodically perform LFTs and blood counts in patients undergoing prolonged treatment
• This drug is not recommended for use in pregnant patients or in nursing mothers. Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at increased risk for extrapyramidal and/or withdrawal symptoms following delivery; agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorders may occur. Use this combination drug during pregnancy only if the potential benefit justifies the potential risk to the fetus
• Exercise caution while administering this combination drug to patients having a history of severe adverse reactions to phenothiazine component of this drug; closely monitor patients during therapy
• The antiemetic effect of perphenazine component may obscure signs of toxicity due to overdosage of other drugs or render more complicated the diagnosis of disorders such as intestinal obstruction or brain tumors
• Discontinue therapy on observation of intolerance. Elevation of prolactin levels are associated with perphenazine component of this combination drug
• Shift to mania or hypomania may occur in patients with known manic depressive illness. Exaggeration of such symptoms may occur in patients with paranoid symptomatology
• Both elevation as well as lowering of blood sugar levels have been reported during therapy
• Avoid administration of large doses in depressed patients
• Patients receiving this combination drug should be warned of the risks involved in performing hazardous tasks such as operating machinery or driving a car because the drug may impair the mental and/or physical abilities necessary for performing such tasks
• Discontinue the drug several days before elective surgery

Cautions: Use cautiously in

• Renal impairment
• Hepatic impairment
• Hypersensitivity to sulfites
• Diabetes mellitus
• Risk of diabetes mellitus
• QT prolongation
• History of conduction abnormalities
• Schizophrenia
• Electroconvulsive therapy
• Risk of suicide
• Alcohol abuse
• GI obstruction
• GU obstruction
• Urinary retention
• Prostatic hypertrophy
• Angle-closure glaucoma
• Increased IOP
• History or risk of seizure disorder
• Parkinson disease
• Dehydration
• Brain injury
• Asthma
• Concurrent use with alcohol or other CNS depressants
• History of drug-induced leukopenia or neutropenia
• Leukopenia
• High environmental temperature

Supplemental Patient Information

• Advise patients to refrain from hazardous activities requiring mental alertness such as operating a machinery or driving an automobile
• Advise patients to communicate with their physicians if they become pregnant during a course of therapy or intend to become pregnant
• Inform the patients, families and caregivers to be alert for the unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and during dose adjustments; instruct them to immediately report such symptoms to the health professional
• Patients should be advised to avoid excessive use of alcohol during therapy

Pregnancy Category:NR

Breastfeeding: Amitriptyline and its metabolites are excreted in small amounts in breastmilk. Immediate adverse events have not been reported and limited data on follow-up found no adverse effects on infant growth and development. Usually not expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. However, other agents with fewer active metabolites may be preferred when large doses are required, especially while nursing a newborn/preterm infant. Perphenazine is produced in low levels in milk. No adverse developmental effects have been reported when other phenothiazines are used alone. Monitor the infant for excessive drowsiness during breastfeeding and for developmental milestones, especially if other antipsychotics are used concurrently. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 22 June 2011). As many drugs are excreted in human milk, manufacturer advises to avoid nursing while a patient is treated with this combination drug.

• CNS: Paradoxical excitement, ataxia, hypnotic effects, mild insomnia, lassitude, headache, altered cerebrospinal fluid proteins, orthostatic hypotension, tremors, coma, syncope, seizures, confusional states, disorientation, incoordination, disturbed concentration, excitement, anxiety, agitation, insomnia, restlessness, nightmares, drowsiness, dizziness, weakness, fatigue, headache, alteration in EEG patterns, abuse
• NEURO: Tardive dyskinesia, severe extrapyramidal symptoms, neuroleptic malignant syndrome, dystonia, akathisia, pseudoparkinsonism, tremor, hyperflexia, peripheral neuropathy; numbness, tingling and paresthesias of the extremities; dysarthria
• PSYCHIATRY: Exacerbation of psychosis, hypomania, mania, suicidality, worsening depression, anticholinergic psychosis, catatonic-like states, hallucinations, delusions, vivid dreams
• CV: Orthostatic hypotension, hypertension, tachycardia, peripheral edema, occasional change in pulse rate, ECG abnormalities, QT prolongation, torsades de pointes, AV block, MI, stroke, heart block, ventricular arrhythmias, hypotension, tachycardia, palpitation, edema
• GI: Liver damage (jaundice, biliary stasis), obstipation, vomiting, nausea, constipation, anorexia, hepatitis (including altered LFTs and jaundice), epigastric distress, anorexia, stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue, dry mouth, salivation, paralytic ileus, dilatation of urinary tract, constipation, bloating, increased appetite, cholestatic jaundice
• MUSC: Muscle weakness
• METABOLIC: Anorexia, weight gain
• GU: Urinary frequency or incontinence, urinary retention
• EENT: Nasal congestion, pigmentation of the cornea and lens, blurred vision, tinnitus, disturbance of accommodation, increased intraocular pressure, mydriasis
• DERM: Eczema, exfoliative dermatitis, urticaria, erythema, itching, photosensitivity, alopecia, sweating, rash, pruritus
• HEMA: Pancytopenia, agranulocytosis, leukopenia, neutropenia, thrombocytopenic purpura, eosinophilia
• HYPERSENSITIVITY: Anaphylactoid reactions, laryngeal edema, asthma, angioneurotic edema, urticaria, photosensitization, edema of face and tongue
• ENDO: Lactation, galactorrhea, hyperglycemia, gynecomastia, menstrual irregularities, testicular swelling, breast enlargement and galactorrhea in the female, increased or decreased libido, elevation and lowering of blood sugar levels, impotence, SIADH, libido changes
• MISC: False positive pregnancy, fatigue, lethargy, neonatal withdrawal (third trimester use), hyperthermia, heat stroke, angioedema, photo-sensitivity

Amitriptyline

• Tricyclic antidepressant; inhibits presynaptic reuptake of norepinephrine and serotonin in the CNS
• Well absorbed after oral administration
• Extensively metabolized in the liver; CYP450: 1A2, 2D6, 3A4 substrate
• Primarily excreted in urine
• Half-life: 10-50 hrs

Perphenazine

• Phenothiazine; exact mechanism of action unknown; selectively antagonizes the effects of dopamine in the CNS
• Extensively metabolized by the liver, GI tract; CYP450: 2D6
• Primarily excreted in urine, feces/bile
• Half-life: 9-12 hrs

US Trade Name(s)

• Only generic available

US Availability

amitriptyline/perphenazine (generic)

• TABS:
• 10 mg/2 mg
• 10 mg/4 mg
• 25 mg/2 mg
• 25 mg/4 mg
• 50 mg/4 mg

Canadian Trade Name(s)

• Peram Tab 2-25
• Peram Tab 3-15
• Levazine 2/25 Tab
• Levazine 3/15 Tab
• Levazine 4/25 Tab

Canadian Availability

Peram Tab 2-25, Levazine 2/25 tab (amitriptyline/perphenazine)

• TABS: 25 mg/2 mg

Peram Tab 3-15, Levazine 3/15 Tab (amitriptyline/perphenazine)

• TABS: 15 mg/3 mg

Levazine 4/25 Tab (amitriptyline/perphenazine)

• TABS: 25 mg/4 mg

UK Trade Name(s)

• Triptafen

UK Availability

Triptafen (amitriptyline/perphenazine)

• TABS: 25 mg/2 mg

Australian Trade Name(s)

• N/A

Australian Availability

• N/A

[Outline]

Psychiatric

Antipsychotics

Combination Agents

• Amitriptyline Hydrochloride 10 MG / Perphenazine 2 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
• Amitriptyline Hydrochloride 10 MG / Perphenazine 4 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
• Amitriptyline Hydrochloride 25 MG / Perphenazine 2 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
• Amitriptyline Hydrochloride 25 MG / Perphenazine 4 MG Oral Tablet (Mylan Pharmaceuticals Inc.)
• Amitriptyline Hydrochloride 50 MG / Perphenazine 4 MG Oral Tablet (Mylan Pharmaceuticals Inc.)