ACTION

Majeptil is a potent neuroleptic with antipsychotic properties.

INDICATIONS

All types of acute and chronic schizophrenia, including those which did not respond to the usual neuroleptics; manic syndromes.

CONTRAINDICATIONS

Comatose or depressive states including those induced by C.N.S. depressants; Parkinson's disease; blood dyscrasias; in patients with spastic diseases and in senile patients with pre-existing Parkinson-like symptoms; in children under 3 years of age and in patients generally sensitive to phenothiazines.

WARNINGS

Very rare cases of QT prolongation have been reported with other neuroleptics.

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. MAJEPTIL 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 MAJEPTIL 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 Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

PRECAUTIONS

Before starting treatment with Majeptil, it is recommended to ascertain that the cardiovascular system and the liver and kidney functions are unimpaired.

Treatment should be initiated preferably by the oral route with a low initial dosage, increased progressively.

Since thioproperazine may potentiate the action of general anesthetics, morphine-like analgesics, barbiturates, alcohol, and other C.N.S. depressants, care should be exercised when these agents are given with it.

The antiemetic effect of thioproperazime may obscure symptoms such as vomiting and nausea, normally associated with some types of organic disease (intestinal obstruction and brain tumor).

Thioproperazine should be used cautiously in patients with a history of seizures.

The safety of thioproperazine in pregnant women has not been clearly established, therefore it should not be used during the first trimester of pregnancy.

ADVERSE REACTIONS

Neuromuscular (extrapyramidal) reactions are the most frequently observed. They are usually dose related and generally subside when the dose is reduced or when the drug is temporarily discontinued. Administration of an anti- parkinsonian is usually, but not always, effective in reversing the neuro- muscular reactions associated with this and other phenothiazines.

Anxiety or apathy, elation or depression, drowsiness and/or insomnia are not infrequently observed.

Occasional disturbances of accommodation, rare cases of headache and exceptionally, cases of nausea and vomiting, constipation or diarrhea have been reported. Lacrimation, sialorrhea and profuse sweating are more frequent. Oliguria may occur. Very rare cases of QT prolongation have been reported with other phenothiazines.

SYMPTOMS and TREATMENT OF OVERDOSAGE

Symptoms - Overdosage may result in severe extrapyramidal symptoms with dysphagia, marked sialorrhea, persistent and rapidly increasing hyperthermia, pulmonary syndrome, state of shock with pallor and profuse sweating, which may be followed by collapse and coma.

Treatment - There is no specific antidote. When mild symptoms are present (e.g. in regular therapy) corrective measures are usually sufficient:

- administration of Majeptil should be discontinued

- against dyskinetic manifestations: an antiparkinsonian or chloral hydrate, but the latter should be used with caution, as it may further depress the respiration.

In the presence of severe symptoms (e.g. in cases of overdosage) in addition to the above corrective messures, the following supportive treatment should be carried out:

- gastric lavage. Because of the antiemetic effect of Majeptil, centrally acting emetics will remain ineffective

- in cases of severe hypotension or collapse: norepinephrine and adreno- cortical hormones to restore blood pressure. Since phenothiazines are known to reverse the pressor action of epinephrine, the latter should not be used as it may further lower blood pressure

- against respiratory depression: oxygen inhalation and, if necessary, tracheal intubation

- against dehydration: intravenous infusion of dextrose in normal saline

- against respiratory infection: broad spectrum antibiotics.

DOSAGE and ADMINISTRATION

Initial Treatment

ADULTS:
Oral route(usual route of administration): It is recommended to start treatment at a low dosage of about 5 mg per day in a single dose or in divided doses. The initial dosage is gradually increased by the same amount every 2 to 3 days until the usual effective dosage of 30 to 40 mg per day is reached. In some cases higher doses of 90 mg or more per day, are necessary to control the psychotic manifestations.

CHILDREN:
Oral route: In children over 10 years, start treatment with a daily dosage of 1 to 3 mg following the method of treatment described for adults.

Maintenance therapy
ADULTS and CHILDREN:
Dosage should be reduced gradually to the lowest effective level, which may be as low as a few milligrams per day, and maintained as long as necessary.

Other method of treatment
Occasionally, Majeptil is prescribed in the form of "discontinuous treatment" at 5 or 10 mg, 3 times a day orally until the onset of severe extrapyramidal symptoms. Then, treatment is discontinued until spontaneous full recovery from these symptoms. The same course of therapy is repeated for at least 3 consecutive treatments. Discontinuous treatment should be reserved for resistant cases and performed in hospitalized patients, under close medical supervision.

AVAILABILITY OF DOSAGE FORMS

Each scored orange tablet contains: thioproperazine base 10 mg (as the mesylate). Nonmedicinal ingredients: acetic anhydride, calcium phosphate, carnauba wax, cellulose, colloidal silicon dioxide, diethyl phthalate, FD&C Yellow No. 6 aluminium lake, magnesium stearate, polacrillin potassium, sodium oleate, titane oxide and zein. Bottles of 100 and 500 tablets.

PHARMACOLOGY

Thioproperazine has a marked cataleptic and antiapomorphine activity associated with relatively slight sedative, hypothermic and spasmolytic effects. It is virtually without antiserotonin and hypotensive action and has no antihistaminic property.

TOXICOLOGY

Acute toxicity - in the mouse, the LD50 of Majeptil is 70 mg/kg I.V., 120 mg/kg I.P., 500 mg/kg S.C. and 830 mg/kg P.O. Signs of toxicity in this species consist of akinesia, muscular hypertonicity with stiffness of the limbs; a state of prostration precedes death caused by respiratory arrest. Chronic toxicity - Daily dosages of 10 and 25 mg/kg to rats and of 5 to 19 mg/kg to dogs, for one month, were relatively well tolerated. The weight curves of the treated rats, at a daily dose of 10 mg/kg P.O., were superposable on those of a control group. On the other hand, at a daily dose of 25 mg/kg P.O., a significant loss of weight was observed, when compared to the controls. In the dogs, weights remained more or less unchanged during the treatment period regardless of the dosage administered. A very pronounced state of catalepsy was observed in all the treated rats; this lasted throughout the treatment in the animals receiving 25 mg/kg P.O. daily but diminished, or even disappeared, after the first week in the group given 10 mg/kg P.O. per day. In the dogs, a light state of catalepsy observed in the hours directly following the administration of Majeptil, disappeared after one week of treatment. The drug produced no deaths in the dogs while half of the rats, at the dose of 23 mg/kg P.O., died during the fourth week of treatment, presumably from partial starvation resulting from the cataleptic state.