Nozinan (Sanofi-Aventis Canada, 5 mg) Product Monograph

INDICATIONS AND CLINICAL USE

Psychotic disturbances: acute and chronic schizophrenias, senile psychoses, manic-depressive syndromes.

Conditions associated with anxiety and tension: autonomic disturbances, personality disturbances, emotional troubles secondary to such physical conditions as resistant pruritus, etc.

Nozinan is also employed:

• As an analgesic: In pain due to cancer, zona, trigeminal neuralgia and neurocostal neuralgia and in phantom limb pains and muscular discomforts.
• As a potentiator of anesthetics: In general anesthesia where it can be used as both a pre- and post-operative sedative and analgesic.
• As an antiemetic: For the treatment of nausea and vomiting of central origin.
• As a sedative: For the management of insomnia.

CONTRAINDICATIONS

In cases of coma or CNS depression due to alcohol, hypnotics, analgesics or narcotics.

It is also contraindicated in patients with blood dyscrasia, hepatic troubles or a sensitivity to phenothiazines.

WARNINGS

Occupational Hazards: Nozinan can reduce psychomotor activity especially during the first few days of treatment. Patients should therefore be cautioned not to drive a motor vehicle or to participate in activities requiring total mental alertness.

As with other neuroleptics, very rare cases of QT interval prolongation have been reported with Nozinan. Neuroleptic phenothiazines may potentiate QT interval prolongation, which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalemia, and congenital or acquired (i.e., drug induced) QT prolongation. If the clinical situation permits, medical and laboratory evaluations should be performed to rule out possible risk factors before initiating treatment with a neuroleptic agent and as deemed necessary during treatment (See also ADVERSE REACTIONS and DRUG INTERACTIONS).

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. NOZINAN 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 NOZINAN 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.

Pregnancy: The drug should be used with caution in pregnant women, particularly during the first trimester, unless the benefit to the patient outweighs any possible risk to the fetus.

PRECAUTIONS

In high oral or parenteral doses, orthostatic hypotension may be encountered at the start of treatment. Patients whose treatment is started by the parenteral route should be kept in bed during the first few days.

Nozinan therapy should be initiated at low doses in patients with arteriosclerosis or cardiovascular problems.

Because of its anticholinergic effects, Nozinan must be administered with caution in patients with glaucoma or prostatic hypertrophy.

During long-term therapy, periodic liver function tests should be performed. In addition, blood counts should be conducted regularly, particularly during the first 2 or 3 months of treatment, and physicians should watch for any signs of blood dyscrasia.

Nozinan does not alter EEG activity. Nevertheless, since phenothiazines can lower the threshold of cortical excitation, it is advisable to administer an appropriate anticonvulsant medication to epileptic patients receiving Nozinan therapy.

Drug Interactions

Nozinan potentiates the action of other phenothiazines and CNS depressants (barbiturates, analgesics, narcotics and antihistaminics). The usual doses of these agents should be reduced by half if they are to be given concomitantly with Nozinan until the dosage of the latter has been established.

Nozinan and its non-hydroxylated metabolites are reported to be inhibitors of cytochrome P450 2D6. Coadministration of Nozinan and drugs primarily metabolized by the cytochrome P450 2D6 enzyme system may result in increased plasma concentrations of these drugs.

Neuroleptic phenothiazines may potentiate QT interval prolongation. QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalemia, and congenital or acquired (i.e., drug induced) QT prolongation (See also WARNINGS AND PRECAUTIONS).

Drug-Laboratory Interactions

False positive or negative pregnancy tests have occurred in patients receiving phenothiazine therapy.

ADVERSE REACTIONS

May be classified as follows:

CNS: Drowsiness may appear early in treatment but will gradually disappear during the first weeks or with an adjustment in the dosage.

Extrapyramidal effects are rare and usually appear only after prolonged therapy at high doses. These reactions may be corrected either by reducing the dose of Nozinan or by administering an antiparkinsonian agent.

Autonomic Nervous System: Dryness of the mouth and, in older patients occasional urinary retention, constipation and tachycardia.

Cardiovascular: Orthostatic hypotension may be encountered at the start of treatment by the parenteral route or with high oral doses. Very rare cases of QT interval prolongation have been reported. There have been isolated reports of sudden death, with possible causes of cardiac origin (see WARNINGS and DRUG INTERACTIONS), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Blood: Rare instances of agranulocytosis have been reported.

Endocrine: Weight gain has been occasionally reported in patients during prolonged treatment with high doses.

Gastrointestinal: Rare cases of cholostatic jaundice without liver damage have been observed. Necrotizing enterocolitis, which can be fatal, has been very rarely reported in patients treated with Nozinan.

Skin Reactions: Skin reactions due to photosensitivity or allergies are extremely rare.

Urogenital System: Priapism has been very rarely reported.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms: Symptoms of acute intoxication may include: simple CNS depression, spasms, tremor or tonic and clonic convulsions, coma accompanied by hypotension and respiratory depression.

Treatment: There is no specific antidote. After gastric lavage, treatment is symptomatic. Centrally acting emetics are ineffective because of the anti-emetic action of Nozinan.

Hypotension: A 5% glucose solution may be administered. If a hypertensive agent is required, norepinephrine or phenylephrine may be used, but not epinephrine, which can aggravate hypotension.

Respiratory depression: Oxygen by inhalation or controlled respiration after tracheal intubation.

Respiratory infection: Wide spectrum antibiotics.

Extrapyramidal reactions: An antiparkinsonian agent or chloral hydrate, however the latter must be used with caution because of its depressant effect on respiration.

Any CNS stimulant should be used with caution.

DOSAGE AND ADMINISTRATION

Dosage must be adjusted according to the indication and individual needs of the patient. If sedation during the day is too pronounced, lower doses may be given during the day and higher doses at night.

Adults

Oral:

Minor conditions in which Nozinan may be given in low doses as a tranquilizer, anxiolytic, analgesic or sedative: begin treatment with 6 to 25 mg/day in 3 divided doses at mealtimes. Increase the dosage until the optimum level has been reached. As a sedative, a single night time dose of 10 to 25 mg is usually sufficient.

Severe conditions: Such as psychoses or intense pain in which Nozinan is employed at higher doses: Begin treatment with 50 to 75 mg/day divided into 2 or 3 daily doses; increase the dosage until the desired effect is obtained. In certain psychotics doses may reach 1 g or more/day. If it is necessary to start therapy with higher doses, i.e., 100 to 200 mg/day, administer the drug in divided daily doses and keep the patient in bed for the first few days.

Parenteral:

I.M.: To be used primarily for the initial treatment of psychoses for certain severe pain as a premedication or for the treatment of postoperative pain. In psychoses and pain, doses vary from 75 to 100 mg given as 3 or 4 deep i.m. injections in a large muscle. When given as a premedication or post-operative analgesic, the average dose varies from 10 to 25 mg every 8 hours, which is equivalent to 20 to 40 mg given orally. The last dose during premedication, given 1 hour before surgery, can be 25 to 50 mg i.m.

I.V.: To be used primarily as an infusion during surgery or labour. The dose may range from 10 to 25 mg in 500 mL of a 5% glucose solution administered at a rate of 20 to 40 drops/minute. If Nozinan is administered with a barbiturate or narcotic, the doses of the latter must be reduced by at least one-half.

Children

Oral:

The initial dose has been established at 1/4 mg/kg daily given in 2 or 3 divided doses. This dosage may be increased gradually until an effective level is reached which should not surpass 40 mg/day for a child less than 12 years of age.

Parenteral:

I.M.: A dose of 1/16 to 1/8 mg/kg/day in one or divided among several injections. Oral medication should be substituted as soon as possible.

I.V.: In anesthesia, 1/16 mg/kg in 250 mL of a 5% glucose solution may be administered as a slow infusion (20 to 40 drops per minute) during surgery.

PHARMACEUTICAL INFORMATION

Drug substance

Proper name : Methotrimeprazine hydrochloride

Chemical name : 2-methoxy-N,N,β-trimethyl-10H-phenothiazine-10-propamine hydrochloride

Structural formula :

• HCl

Molecular formula : C₁₉H₂₄N₂OS • HCl

Molecular weight : 364.9

Physical form : White to very slightly yellow, slightly hygroscopic powder Solubility : Freely soluble in water and in alcohol, practically insoluble in ether Melting point : 142˚C and 162˚C

Drug substance

Proper name : Methotrimeprazine maleate

Chemical name : 2-methoxy-N,N,β-trimethyl-10H-phenothiazine-10-propamine maleate

Structural formula :

• C₄H₄O₄

Molecular formula : C₁₉H₂₄N₂OS • C₄H₄O₄

Molecular weight : 444.5

Physical form : White to very slightly yellow crystalline powder Solubility : Slightly soluble in water and in alcohol, practically insoluble in ether, sparingly soluble in dichloromethane Melting point : 186˚C

pH : 3.5 to 5.5

Composition

Injectable: Each mL contains: methotrimeprazine base 25 mg (as the hydrochloride). Non-medicinal ingredients: 0.1% ascorbic acid, 0.65% sodium chloride, 0.05% sodium sulfite and water for injection.

Syrup: Each 5 mL of brown liquid contains: methotrimeprazine base 25 mg (as the hydrochloride). Non-medicinal ingredients: alcohol, apricot essence, ascorbic acid, caramel, citric acid, glycerin, purified water and sucrose.

Tablets: Each yellow tablet contains: methotrimeprazine base 5, 25 or 50 mg (as the maleate). Non-medicinal ingredients: croscarmellose sodium, colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, dicalcium phosphate, FD&C Yellow #6 Aluminium Lake, magnesium stearate, microcrystalline cellulose, Opadry II White Y-22-7719, polyethylene glycol and talc.

Stability and storage recommendation

Nozinan (methotrimeprazine hydrochloride) injectable, syrup and Nozinan (methotrimeprazine maleate) tablets should be stored at 15˚ to 30˚C. Protect from light.

AVAILABILITY OF DOSAGE FORMS

Nozinan (methotrimeprazine base) 25 mg/mL (as hydrochloride) injectable is available in amber glass ampoules of 1 mL in boxes of 10 ampoules.

Nozinan (methotrimeprazine base) 25 mg/5 mL (as hydrochloride) syrup is available in amber glass bottles of 500 mL.

Nozinan (methotrimeprazine base) 5, 25 and 50 mg (as maleate) tablets are available in white HDPE bottles of 100 and 500 tablets.

PHARMACOLOGY

Nozinan possesses strong sedative properties. It potentiates ether and hexobarbital anesthesia as well as morphine analgesia. It also exerts a potent anti-apomorphine effect, a hypothermic action 3 times more potent than that of chlorpromazine and strong antispasmodic and anti-histaminic effects.

Nozinan is capable of reversing epinephrine-induced hypertension but has practically no effect against norepinephrine and acetylcholine. It readily protects rats against traumatic shock and produces deep local anesthesia following parasciatic injections.

TOXICOLOGY

In mice the LD₅₀ of Nozinan is 70 mg/kg i.v., 250 mg/kg s.c., 344 mg/kg i.p. and 380 mg/kg p.o. Signs of acute toxicity consist of CNS depression interrupted by periods of convulsions and uncoordinated movements.

In the rat, a daily dose of 5 or 10 mg/kg p.o. for 4 consecutive weeks did not produce any digestive troubles or weight loss. During the first days of treatment, a state of depression appeared, which was most pronounced on the third or fourth day and then almost completed disappeared. Laboratory and function tests indicated no renal, hepatic or blood anomalies. Microscopic visceral examinations revealed no toxic lesions.

In the dog, a daily dose of 2.5 or 5 mg/kg p.o. for 4 consecutive weeks did not affect weight stability but animals appeared lethargic. Some relaxation of the nictitating membrane and a transient reduction of blood pressure were observed. During treatment, the leucocyte count and blood coagulation remained normal. Anatomopathological examination of the visceral parenchyma of sacrificed animals confirmed that all organs remain normal.

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