PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE- perphenazine and amitriptyline hydrochloride_tablet, film coated

In common with all members of the piperazine group of phenothiazine derivatives, perphenazine has greater behavioral potency than phenothiazine derivatives of other groups without a corresponding increase in autonomic, hematologic, or hepatic side effects. Extrapyramidal effects, however, may occur more frequently. These effects are interpreted as neuropharmacologic. They usually regress after discontinuation of the drug. Perphenazine is a potent tranquilizer and also a potent antiemetic. Orally, its milligram potency is about 5 or 6 times that of chlorpromazine with respect to behavioral effects. It is capable of alleviating symptoms of anxiety, tension, psychomotor excitement, and other manifestations of emotional stress without apparent dulling of mental acuity. Amitriptyline hydrochloride is an antidepressant with sedative effects. Its mechanism of action in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system.

Perphenazine and amitriptyline hydrochloride tablets are recommended for treatment of (1) patients with moderate to severe anxiety and/or agitation and depressed mood, depression in whom anxiety and/or agitation are severe, depression and anxiety in association with chronic physical disease. Schizophrenic patients

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. 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 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. 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.
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 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.

Tardive Dyskinesia
Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (antipsychotic) drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome. (For further information about the description of tardive dyskinesia and its clinical detection, please refer to the section on ADVERSE REACTIONS
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
Leukopenia,Neutropenia, and Agranulocytosis
In clinical trial and postmarketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue perphenazine and amitriptyline hydrochloride tablets at the first sign of a decline in WBC in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue perphenazine and amitriptyline hydrochloride tablets and have their WBC followed until recovery.
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. 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 The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity. The syndrome is characterized by involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e. , 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. Dystonia: Class Effect: 2. Akathisia: when asked not 3. Pseudoparkinsonism: Hypotension, hypertension, tachycardia, peripheral edema, occasional change in pulse rate, ECG abnormalities (quinidine like effect), reversed epinephrine effect. Extrapyramidal symptoms, including acute dyskinesia (see Neurological Autonomic: Allergic: Hematologic: Gastrointestinal: Dermatologic: Ophthalmic: Endocrine: Other: Other adverse reactions that should be considered because they have been reported with various phenothiazine compounds, but not with perphenazine, include: CNS and Neuromuscular: Gastrointestinal: Dermatologic: Ophthalmic: Endocrine: Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing which follows are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered. Cardiovascular: CNS and Neuromuscular: Anticholinergic: Allergic: Hematologic: Gastrointestinal: Endocrine: Other: After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within 2 weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants.
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 Autonomic: Allergic: Hematologic: Gastrointestinal: Dermatologic: Ophthalmic: Endocrine: Other: Other adverse reactions that should be considered because they have been reported with various phenothiazine compounds, but not with perphenazine, include: CNS and Neuromuscular: Gastrointestinal: Dermatologic: Ophthalmic: Endocrine:

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.

Usage in Pregnancy
Perphenazine and amitriptyline hydrochloride is not recommended for use in pregnant patients or in nursing mothers at this time. Reproduction studies in rats have shown no fetal abnormalities; however, clinical experience and follow-up in pregnancy have been limited, and the possibility of adverse effects on fetal development must be considered.
Pregnancy
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.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING WARNINGS: Clinical Worsening and Suicide Risk

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. 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. , 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. 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, analgesics, antihistamines, barbiturates) can potentiate each other, less than the usual dosage of the added drug is recommended and caution is advised when they are administered concomitantly. Use with caution in patients who are receiving atropine or related drugs because of the additive anticholinergic effects and also in patients who will be exposed to extreme heat or organic phosphate insecticides. The use of alcohol should be avoided, since additive effects and hypotension may occur. Patients should be cautioned that their response to alcohol may be increased while they are being treated with perphenazine and amitriptyline hydrochloride tablets. The risk of suicide and the danger of overdose may be increased in patients who use alcohol excessively due to the potentiation of the drug's effect. When amitriptyline hydrochloride is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required. Hyperpyrexia has been reported when amitriptyline is administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic type drugs. This drug may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Concurrent administration of amitriptyline hydrochloride and electroshock therapy may increase the hazards associated with such therapy. Such treatment should be limited to patients for whom it is essential. Discontinue the drug several days before elective surgery, if possible. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) have been associated with elevations in the serum levels of the tricyclic antidepressant when cimetidine is added to the drug regimen. Additionally, higher than expected steady-state serum concentrations of the tricyclic antidepressant have been observed when therapy is initiated in patients taking cimetidine. Alternatively, decreases in the steady-state serum concentration of the tricyclic antidepressant have been reported in well controlled patients on concurrent therapy upon discontinuance of cimetidine. The therapeutic efficacy of the tricyclic antidepressant may be compromised in these patients as the cimetidine is discontinued. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with 1 g of ethchlorvynol and 75 mg to 150 mg of amitriptyline hydrochloride.

Perphenazine
In common with all members of the piperazine group of phenothiazine derivatives, perphenazine has greater behavioral potency than phenothiazine derivatives of other groups without a corresponding increase in autonomic, hematologic, or hepatic side effects. Extrapyramidal effects, however, may occur more frequently. These effects are interpreted as neuropharmacologic. They usually regress after discontinuation of the drug. Perphenazine is a potent tranquilizer and also a potent antiemetic. Orally, its milligram potency is about 5 or 6 times that of chlorpromazine with respect to behavioral effects. It is capable of alleviating symptoms of anxiety, tension, psychomotor excitement, and other manifestations of emotional stress without apparent dulling of mental acuity.
Amitriptyline Hydrochloride
Amitriptyline hydrochloride is an antidepressant with sedative effects. Its mechanism of action in man is not known. It is not a monoamine oxidase inhibitor and it does not act primarily by stimulation of the central nervous system.
Perphenazine
As with all phenothiazine compounds, perphenazine should not be used indiscriminately. Caution should be observed in giving it to patients who have previously exhibited severe adverse reactions to other phenothiazines. Some of the untoward actions of perphenazine tend to appear more frequently when high doses are used. However, as with other phenothiazine compounds, patients receiving perphenazine in any dosage should be kept under close supervision. The antiemetic effect of perphenazine may obscure signs of toxicity due to overdosage of other drugs, or render more difficult the diagnosis of disorders such as brain tumors or intestinal obstruction. A significant, not otherwise explained, rise in body temperature may suggest individual intolerance to perphenazine, in which case this product should be discontinued. Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro,
Amitriptyline Hydrochloride
Depressed patients, particularly those with known manic depressive illness, may experience a shift to mania or hypomania. Patients with paranoid symptomatology may have an exaggeration of such symptoms. The tranquilizing effect of this product seems to reduce the likelihood of these effects. Both elevation and lowering of blood sugar levels have been reported. Amitriptyline hydrochloride should be used with caution in patients with impaired liver functions.
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 The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
Amitriptyline Hydrochloride
Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing which follows are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered. Cardiovascular: CNS and Neuromuscular: Anticholinergic: Allergic: Hematologic: Gastrointestinal: Endocrine: Other:

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PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE- perphenazine and amitriptyline hydrochloride_tablet, film coated Product manual source documgent