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THERAPEUTIC CLASSIFICATION Psychotropic Agent Pericyazine
is a phenothiazine of the piperidine group. It has been shown to
reduce pathologic arousal and affective tension in some psychotic
patients, while the symptoms of abnormal mental integration are
relatively unaffected.
Neuleptil may be of value as adjunctive
medication in some psychotic patients, for the control of residual
prevailing hostility, impulsivity and aggressiveness.
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 Only available with prescription |
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Pericyazine should not be administered in the presence of circulatory collapse, altered states of consciousness or comatose states, particularly when these are due to intoxication with central depressant drugs such as alcohol, hypnotics, analgesics, narcotics, etc. It should also not be administered in association with spinal or regional anaesthesia. Pericyazine is contraindicated in patients with a history of blood dyscrasias, liver disease or hypersensitivity related to other phenothiazines.
Particular care should be exercised when Neuleptil is given to elderly or debilitated patients as some appear to be unduly sensitive to the effects of the drug. |
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Because drowsiness, slowing of reaction time or impaired judgment may occur, patients should generally not operate a motor vehicle or engage in dangerous activities while under the action of the drug. Since the safety of use of pericyazine
during pregnancy has not been established, it should not be used
in women of childbearing potential unless the expected benefits
outweigh the possible risks to the fetus. Patients who have demonstrated
a hypersensitivity reaction (e.g. blood dyscrasias, jaundice) with
a phenothiazine should not be re-exposed to any phenothiazine unless,
in the judgment of the physician, the potential benefits of treatment
outweigh the possible hazards. As with other neuroleptics, very rare cases of QT prolongation have been reported with Neuleptil. Tardive Dyskinesia: As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. NEULEPTIL should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. The lowest effective dose and the shortest duration of treatment should be used, and treatment should be discontinued at the earliest opportunity, or if a satisfactory response cannot be obtained. If the signs and symptoms of tardive dyskinesia appear during treatment, discontinuation of NEULEPTIL should be considered. Neuroleptic Malignant Syndrome: Neuroleptic
malignant syndrome (NMS) may occur in patients receiving antipsychotic
drugs. NMS is characterized by hyperthermia, muscle rigidity, altered
consciousness, and signs of autonomic instability including irregular
blood pressure, tachycardia, cardiac arrhythmias and diaphoresis.
Additional signs may include elevated serum creatine kinase, myoglobinuria
(rhabdomyolysis), acute renal failure and leukocytosis. Hyperthermia
is often an early sign of this syndrome. Antipsychotic treatment
should be withdrawn immediately and appropriate supportive therapy
and careful monitoring instituted.
Neuleptil may potentiate the action of other drugs; caution should therefore be exercised when it is prescribed with other phenothiazine derivatives or CNS depressants such as barbiturates, analgesics, narcotics or antihistamines, and the usual doses of these compounds should be reduced by at least half while the new treatment is being gradually introduced. Patients should also be advised against ingesting alcohol while under treatment. Therapy should be initiated at low doses and caution used in patients with arteriosclerosis, cardiovascular disease, or other conditions where sudden hypotension is undesirable. Careful adjustments of dosage may be necessary if other drugs likely to cause postural hypotension are being administered concurrently. If hypotension should occur and a pressor agent is required, norepinephrine or phenylephrine may be used. Epinephrine should not be used since it may further lower blood pressure. Because of its anticholinergic action, pericyazine should be used with great caution in patients with glaucoma or prostatic hyperthophy. Paralytic ileus has occurred in patients, particularly in the elderly, taking one or more drugs with anticholinergic action for extended periods. In such patients caution should be observed if constipation develops. Retinal changes and abnormal skin pigmentation have been observed with phenothiazines and may occur after prolonged therapy. Discontinue therapy if these changes are observed. It is generally advisable to perform periodic liver function tests during prolonged medication with Neuleptil. Periodic blood counts should also be performed, particularly during the first two or three months of therapy and patients should be observed for any signs orsymptoms suggestive of blood dyscrasia.
Drowsiness, hypotension and extrapyramidal symptoms are the more frequently reported adverse reactions. Autonomic and psychomotor effects are usually observed at the beginning of treatment and frequently resolve while therapy is being continued or subside upon adjustment of dosage. Extrapyramidal reactions usually occur somewhat later and are mainly observed with higher dosages. Adverse reactions with different phenothiazines vary in type, frequency, and mechanism of occurrence, i.e., some are dose-related, while others involve individual patient sensitivity. Some adverse reactions may be more likely to occur, or occur with greater intensity, in patients with special medical problems e.g., patients with mitral insufficiency or pheochromocytoma have experienced severe hypotension following recommended doses of certain phenothiazines. Not all of the following adverse reactions have been observed with every phenothiazine derivative, but they have been reported with one or more and should be borne in mind when drugs of this class are administered: Behavioral: Drowsiness and impaired psychomotor activity are the most frequent initial untoward reactions but tend to subside within one to three weeks. Small initial doses will test tolerance to the drug. If a toxic-confusional state appears the medication should be stopped immediately. Paradoxical effects, such as agitation, insomnia, inversion of sleep, increased aggressiveness and activation of psychotic symptoms, have been occasionally observed. Autonomic Nervous System: Postural hypotension and acute hypotensive crisis have been observed, particularly in the elderly, and occur more often at the beginning of treatment or when initial high dosages are used. These reactions may be avoided by testing the patient's tolerance with initial low doses. ECG changes and cardiac arrhythmias, including A-V block, paroxysmal tachycardia, and ventricular fibrillation, although not reported with pericyazine, have been observed with some phenothiazines. Predominant anticholinergic effects or sympathetic depression may be responsible for the following adverse reactions: tachycardia, blurred vision, aggravation of glaucoma, dry mouth (sometimes with oral infections and dental caries), nausea, vomiting, constipation, fecal impactation, paralytic ileus, perspiration, diarrhea, and nasal congestion. Changes in body temperature and hyperglycemia have been known to occur with phenothiazines. Central Nervous System: The extrapyramidal reactions include Parkinsonism, dystonic reactions and akathisia. Parkinsonism occurs more frequently
in patients receiving high doses and can usually be controlled by
reducing the dose or temporarily discontinuing medication and, when
necessary, by administering an anti-Parkinson drug. The dystonic
reactions consist mainly of protrusion of the tongue, hyperextension
of the neck and trunk, contraction of muscles of the neck and face,
oculogyric crises, myoclonic twitches and carpopedal spasm. Dystonic
reactions are usually not dose-related but may be quite dramatic
and require urgent treatment. Dystonic reactions have been reported
with pericyazine. EEG changes, disturbed temperature regulation and seizures have also been reported. Pericyazine is generally well tolerated by epileptics maintained on anticonvulsive therapy. However, epileptic attacks have been reported and it has not been established that pericyazine effectively controls arousal or affective tension in these patients. Allergic or Toxic Reactions: Agranulocytosis and other blood dyscrasias are among the more serious adverse reactions to phenothiazines. They may occur suddenly or follow a fall in blood count, usually during the first two or three months of treatment. Cholestatic jaundice occurs uncommonly. Skin reactions, photosensitivity, asthma, laryngeal edema, angioneurotic edema, hyperpyrexia and other allergic reactions may also occur. Abnormal pigmentation, including corneal and lens deposits have been observed, usually when high doses of phenothiazines are given for prolonged periods. Endocrine system: Endocrine effects from phenothiazines such as delayed ovulation, menstrual irregularities, lactation, gynecomastia, changes in libido, inhibition of ejaculation, false positive pregnancy tests, weight gain and edemas, have been known to occur. Voracious appetite and weight gain have been reported in some patients on pericyazine therapy. Miscellaneous: Unexpected sudden deaths,
hypostatic pneumonia, and potentiation of other drugs have occurred
during phenothiazine therapy. In some unexpected deaths, myocardial
lesions have been observed. Previous brain damage or seizures may
also be predisposing factors; high doses should be avoided in known
seizure patients. Several patients have shown sudden exacerbations
of psychotic behaviour patterns shortly before death. Autopsy findings
have also revealed acute fulminating pneumonia or pneumonitis and
aspiration of gastric contents. The physician should therefore be
alerted to the possible development of "silent pneumonias".
Very rare cases of QT interval prolongation have been reported.
Symptoms: In milder cases of phenothiazine overdosage the patient may be agitated, delirious and confused. Frequently he is lethargic or in a comatose state. Twitching, dystonic movements or convulsions may be present and hypotension, cardiovascular collapse, arrhythmias and hypothermia might be observed. Treatment: When indicated,
gastric lavage can remove significant amounts of the drug. Careful
supportive management is required until the patient is well out
of drug-induced C.N.S. depression. Shock, arrhythmia, respiratory
failure and hypothermia are the main management problems. When a
pressor agent is required, norepinephrine or phenylephrine may be
used.
Adults: The following daily
doses have been recommended: For maintenance therapy, the dosage should be reduced to the minimum effective dose. Lower doses of 2.5 to 15 mg in the morning, and 5 to 30 mg in the evening have been suggested. Elderly patients: The initial total daily dosage should be in the order of 5 mg and increased gradually as tolerated, until an adequate response is obtained. A daily dosage of more than 30 mg will rarely be needed. Children and adolescents: (5
years of age and over) - The following dosages are recommended: These dosages approximate a daily dosage-range of 1-3 mg per year of age. In general, for both children and adults, the lower doses should not be exceeded initially. Subsequently, dosage may be gradually increased until the most effective level is reached. Caution is required when these dosages are exceeded. Troublesome initial drowsiness has often been observed after Neuleptil. This may be obviated by giving the drug twice daily and reserving the major portion of the daily dosage for the evening. Neuleptil is not recommended in children
under 5 years of age, since limited clinical experience is available.
Oral capsules: Oral drops:
The pharmacologic properties of pericyazine were studied in various animal tests, by comparing them with the actions of chlorpromazine, on a milligram potency basis. Pericyazine has a relatively pronounced sedative action but its cataleptic effect was rather weak. It produced potentiation of ether and hexobarbital narcosis and morphine analgesia, and had hypothermic activity in the mice, It also produced depression of spontaneous motor activity in mice. In these tests, it was consistently more active than chlorpromazine on a milligram potency basis. In the potentiation of barbiturate narcosis test the ED50 for pericyazine was 3 mg/kg p.o., while the ED50 for chlorpromazine was 8 mg/kg. Pericyazine blocked the conditioned avoidance in rats with an ED50 of 0.65 mg/kg p.o. while the ED50 for chlorpromazine was 5 mg/kg. It also exhibited strong antiapomorphine activity. It has only slight antihistamine action but demonstrated definite antiserotonin activity. It manifested analgesic properties similar to those of methotrimeprazine when tested by various methods in the mouse and rat. It also exhibited spasmolytic activity when tested on the isolated intestine of the rabbit. Pericyazine produced adrenergic blocking effects in the mouse and dog and had an anticholinergic activity greater than that of chlorpromazine in the same animals. Bioavailability: In a bioavailability study, 12 healthy human volunteers were administered two 10 mg capsules of Neuleptil. The average curve of plasma concentration vs time showed that a peak concentration of 150 ng/mL was achieved 2 hours after drug administration and that the half-life was approximately 12 hours. In some subjects, detectable amounts of pericyazine were still present in the blood after 36 hours. It was also demonstrated that the
10 mg capsules and the 1% (10 mg/mL) oral drop preparation are biologically
equivalent.
Acute toxicity studies The following LD50s were determined in acute toxicity studies in mice: 530 mg/kg p.o.; 44 mg/kg i.v.; 375 mg/kg s.c.; 115 mg/kg i.p. The oral LD50 for chlorpromazine was 380 mg/kg. The signs of toxicity observed were: profound stupor followed by hypothermia and death in respiratory arrest. The approximate oral LD50 in rats was found to be 395 mg/kg. The signs of toxicity observed were: lacrimation, salivation, prostration and conjunctival hemorrhage. No deaths occurred in an acute tolerance
test in dogs with doses up to 960 mg/kg by the oral route. No significant abnormalities were observed in a one month subacute oral toxicity test in rats, at the daily dosages of 2.5 and 5 mg/kg. In a one month oral toxicity study in dogs with daily dosage increasing from 1.25 to 10 mg/kg, slight reduction of hemoglobin levels was observed and a few abnormalities in the liver and renal function tests were noted. Chronic toxicity studies A one year chronic toxicity study with weanling rats using dosage levels of 3.3, 10 and 30 mg/kg per day revealed a slight depression in weight gain and slightly heavy pituitaries in the high dosage group. Neoplasms were observed in two dosed Charles River rats that died during the 16th and 36th week of the study. A six month oral chronic toxicity test was performed in dogs using the dosage levels of 0, 3, 9 and 27 mg/kg per day. Dose-related drug effects were observed in all dosage groups. At the 3 mg/kg dosage level only minimal pharmacologic changes were seen. In the high dosage group all animals exhibited the following signs and symptoms: loss of weight, sedation, ataxia in the first few weeks, relaxation of the nictitating membrane, constriction of the pupils, lacrimation, dry nose, and enophtalmia. Death, preceded by clonic convulsions, occurred in 2 of 4 dogs during the 13th week. In the 9 mg/kg group only relatively mild hepatic changes, chiefly of a congestive nature, were described. At the 27 mg/kg dosage, renal tubular degenerative changes were observed in all animals and liver changes were noted in 2 of 4 dogs. There were associated with increased B.U.N. and S.G.P.T. values and with suggestively heavier livers, kidneys and adrenals. The urine was examined for thiocyanate in 2 mongrel dogs given increasing doses of pericyazine from 30 to 60 mg/kg/day for a period of 4 days. The urine showed a trace of thiocyanate in one dog and was strongly positive in the other, persisting for 3 days after cessation of dosage. In other tests in the rat and dog, pericyazine did not significantly raise the urine or blood levels of thiocyanate. In a long-term human toxicity study, 10 chronic hospitalized patients received 20-40 mg of pericyazine per day for 6 months. One patient became drowsy and constipated, one developed severe extrapyramidal manifestations and another patient had elevated alkaline phosphatase, and S.G.T.O. and S.G.P.T. values. Teratogenicitv studies Reproductive and teratogenic studies were performed in mice, rats and rabbits. The mice received pericyazine by esophageal route once a day from 8 to 14 days post-coitum in dosages of 5 to 15 mg/kg. In this study the incidence of dead fetuses in the experimental group was somewhat higher than in the control group and there appeared to be some slight delay in the ossification process in the high dosage group. Pericyazine was fed in the diet at the rate of 30 mg/kg per day for 12 female and 6 male rats for a pre-mating period of 33 days and then throughout the ensuing pregnancy and lactation. Fertility appeared to be impaired, since average pairing to birth of litter interval was lengthened as compared to the controls. Nine females produced litters and no evidence of a teratogenic effect was seen in a group of rats examined in detail at weaning. In the rabbit, pericyazine was given in daily doses of 5 and 100 mg/kg p.o. from the 8th to the 15th day of pregnancy inclusive. No deleterious effect on the pregnant animals was noted and there was no evidence of a lethal or teratogenic effect on the fetuses born to these rabbits.
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