Perphenazine And Amitriptyline Hydrochloride

FDA Drug Information • Also known as: Perphenazine And Amitriptyline Hydrochloride

Brand Names: Perphenazine And Amitriptyline Hydrochloride
Drug Class: Phenothiazine [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over 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. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Perphenazine and amitriptyline hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS ). Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of perphenazine and amitriptyline or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Perphenazine and amitriptyline hydrochloride is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use .)

Description

DESCRIPTION Perphenazine and amitriptyline hydrochloride, a broad spectrum psychotherapeutic agent for the management of outpatients and hospitalized patients with psychoses or neuroses characterized by mixtures of anxiety or agitation with symptoms of depression, is a combination of perphenazine and amitriptyline hydrochloride. Since such mixed syndromes can occur in patients with various degrees of intensity of mental illness, perphenazine and amitriptyline hydrochloride tablets are provided in multiple combinations to afford dosage flexibility for optimum management. Perphenazine is a phenothiazine derivative. The formula is 4-[3-(2-chloro-10 H -phenothiazin-10yl) propyl]-piperazineethanol. Perphenazine, USP is a white, odorless, bitter tasting powder that is insoluble in water. The molecular weight is 403.97. Its structural formula is: Amitriptyline is a dibenzocycloheptadiene derivative. The formula is 10,11-dihydro- N , N -dimethyl-5 H -dibenzo[a,d]cycloheptene-∆ 5 ,γ -propylamine hydrochloride. Amitriptyline hydrochloride, USP is a white, odorless, crystalline compound which is freely soluble in water. The molecular weight is 313.87. Its structural formula is: Each tablet for oral administration contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate and titanium dioxide. The following additional product specific inactive ingredients are employed: 2 mg/10 mg - hydroxypropyl cellulose 2 mg/25 mg - hydroxypropyl cellulose 4 mg/10 mg - polysorbate 80 4 mg/25 mg - hydroxypropyl cellulose 4 mg/50 mg - hydroxypropyl cellulose The following product specific coloring agents are employed: 2 mg/10 mg - calcium sulfate, talc 2 mg/25 mg - D&C Red No. 7 Calcium Lake, FD&C Blue No. 1 Aluminum Lake 4 mg/10 mg - FD&C Blue No. 1 Aluminum Lake 4 mg/25 mg - FD&C Yellow No. 6 Aluminum Lake 4 mg/50 mg - D&C...

What Is Perphenazine And Amitriptyline Hydrochloride Used For?

INDICATIONS AND USAGE Perphenazine and amitriptyline hydrochloride tablets are recommended for treatment of (1) patients with moderate to severe anxiety and/or agitation and depressed mood, (2) patients with depression in whom anxiety and/or agitation are severe, and (3) patients with depression and anxiety in association with chronic physical disease. In many of these patients, anxiety masks the depressive state so that, although therapy with a tranquilizer appears to be indicated, the administration of a tranquilizer alone will not be adequate. Schizophrenic patients who have associated depressive symptoms should be considered for therapy with perphenazine and amitriptyline hydrochloride tablets.

Dosage and Administration

DOSAGE AND ADMINISTRATION Since dosage for children has not been established, this product is not recommended for use in children. The total daily dose of perphenazine and amitriptyline hydrochloride tablets should not exceed 16 mg of perphenazine and 200 mg of amitriptyline hydrochloride. Initial Dosage In psychoneurotic patients when anxiety and depression are of such a degree as to warrant combined therapy, one tablet of the 2 mg/25 mg or 4 mg/25 mg three or four times a day or one tablet of the 4 mg/50 mg combination twice a day is recommended. In more severely ill patients with schizophrenia , the 4 mg/25 mg combination is recommended in an initial dose of two tablets three times a day. If necessary, a fourth dose may be given at bedtime. In elderly patients and adolescents, and some other patients in whom anxiety tends to predominate, perphenazine and amitriptyline hydrochloride tablet 4 mg/10 mg combination may be administered three or four times a day initially, then adjusted as required for subsequent adequate therapy. Maintenance Dosage Depending on the condition being treated, therapeutic response may take from a few days to a few weeks or even longer. After a satisfactory response is noted, dosage should be reduced to the smallest amount necessary to obtain relief from the symptoms for which this product is being administered. A useful maintenance dosage is one tablet of the 2 mg/25 mg or 4 mg/25 mg combination two to four times a day or one tablet of the 4 mg/50 mg combination twice a day. Perphenazine and amitriptyline hydrochloride tablets, 2 mg/10 mg and 4 mg/10 mg can be used to increase flexibility in adjusting maintenance dosage to the lowest amount consistent with relief of symptoms. In some patients, maintenance dosage is required for many months.

Side Effects (Adverse Reactions)

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. Perphenazine 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. Neurological 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. 1. 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. 2. 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. 3. 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. Cardiovascular 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...

Warnings and Precautions

WARNINGS Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Perphenazine and amitriptyline hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING ). Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality Per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the...

Drug Interactions

Drug Interactions Topiramate Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient’s clinical response and not on the basis of plasma levels. Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. Perphenazine Patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, reduced amounts of anesthetics or central nervous system depressants may be necessary. Since phenothiazines and central nervous system depressants (opiates,...

Contraindications

CONTRAINDICATIONS Perphenazine and amitriptyline hydrochloride tablets are contraindicated in depression of the central nervous system from drugs (barbiturates, alcohol, narcotics, analgesics, antihistamines); in the presence of evidence of bone marrow depression; and in patients known to be hypersensitive to phenothiazines or amitriptyline. It should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase inhibitors simultaneously. When it is desired to replace a monoamine oxidase inhibitor with perphenazine and amitriptyline hydrochloride, a minimum of 14 days should be allowed to elapse after the former is discontinued. Perphenazine and amitriptyline hydrochloride should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. Amitriptyline hydrochloride is not recommended for use during the acute recovery phase following myocardial infarction.

Pregnancy and Breastfeeding

Pregnancy Nonteratogenic Effects Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Perphenazine and amitriptyline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Overdosage

OVERDOSAGE* Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after overdose, therefore, hospital monitoring is required as soon as possible. Manifestations Overdosage of perphenazine and amitriptyline hydrochloride tablets may cause any of the adverse reactions listed for perphenazine or amitriptyline hydrochloride. Overdosage of perphenazine usually produces extrapyramidal symptoms such as dyskinesia and dystonia as described under ADVERSE REACTIONS , but this may be masked by the anticholinergic effects of amitriptyline. Other symptoms may include stupor or coma; children may have convulsive seizures. Critical manifestations of tricyclic antidepressant overdose includes: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS . Management General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients...

How Supplied

HOW SUPPLIED Perphenazine and Amitriptyline Hydrochloride Tablets, USP are available in the following combinations: DOSAGE FORM ACTIVE INGREDIENT 2 mg/10 mg Perphenazine, USP 2 Amitriptyline hydrochloride, USP 10 2 mg/25 mg Perphenazine, USP 2 Amitriptyline hydrochloride, USP 25 4 mg/10 mg Perphenazine, USP 4 Amitriptyline hydrochloride, USP 10 4 mg/25 mg Perphenazine, USP 4 Amitriptyline hydrochloride, USP 25 4 mg/50 mg Perphenazine, USP 4 Amitriptyline hydrochloride, USP 50 The 2 mg/10 mg combination tablets are white, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 330 on the other side. They are available as follows: NDC 0378-0330-01 bottles of 100 tablets The 2 mg/25 mg combination tablets are purple, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 442 on the other side. They are available as follows: NDC 0378-0442-01 bottles of 100 tablets The 4 mg/10 mg combination tablets are blue, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 727 on the other side. They are available as follows: NDC 0378-0042-01 bottles of 100 tablets The 4 mg/25 mg combination tablets are orange, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 574 on the other side. They are available as follows: NDC 0378-0574-01 bottles of 100 tablets The 4 mg/50 mg combination tablets are purple, film-coated, round, unscored tablets debossed with MYLAN on one side of the tablet and 73 on the other side. They are available as follows: NDC 0378-0073-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription. * Poisindex Toxicologic Management. Topic: Antidepressants, Tricyclic. Micromedex Inc. Vol 85.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.