Methoprazine Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES..............................................................................................2

TABLE OF CONTENTS ................................................................................................................3

PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................6

1 INDICATIONS ................................................................................................................6

1.1 Pediatrics...........................................................................................................6

1.2 Geriatrics ...........................................................................................................6

2 CONTRAINDICATIONS ...................................................................................................6

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ..............................................................7

4 DOSAGE AND ADMINISTRATION...................................................................................7

4.1 Dosing Considerations........................................................................................7

4.2 Recommended Dose and Dosage Adjustment .....................................................8

4.2.1 Discontinuing Treatment ....................................................................................9

4.4 Administration ...................................................................................................9

4.5 Missed Dose ......................................................................................................9

5 OVERDOSAGE ............................................................................................................. 10

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 10

7 WARNINGS AND PRECAUTIONS .................................................................................. 11

General ....................................................................................................................... 11

Cardiovascular ............................................................................................................ 11

Dependence, Tolerance and/or Abuse Liability............................................................. 12

Driving and Operating Machinery ................................................................................ 12

Endocrine and Metabolism .......................................................................................... 12

Gastrointestinal........................................................................................................... 12

Genitourinary.............................................................................................................. 13

Hematologic................................................................................................................ 13

Hepatic/Biliary/Pancreatic ........................................................................................... 13

Immune ...................................................................................................................... 13

Monitoring and Laboratory Tests ................................................................................. 13

Neurologic .................................................................................................................. 14

Ophthalmologic........................................................................................................... 15

Peri-Operative Considerations ..................................................................................... 15

Renal .......................................................................................................................... 15

Reproductive Health.................................................................................................... 16

Sensitivity/Resistance.................................................................................................. 16

Skin............................................................................................................................. 16

7.1 Special Populations .......................................................................................... 16

7.1.1 Pregnant Women .........................................................................................16

7.1.2 Breastfeeding...............................................................................................17

7.1.3 Pediatrics .....................................................................................................17

7.1.4 Geriatrics .....................................................................................................17

8 ADVERSE REACTIONS .................................................................................................. 18

8.1 Adverse Reaction Overview .............................................................................. 18

8.2 Clinical Trial Adverse Reactions ........................................................................ 18

8.5 Post-Market Adverse Reactions ........................................................................ 20

9 DRUG INTERACTIONS.................................................................................................. 21

9.1 Serious Drug Interactions ................................................................................. 21

9.2 Drug Interactions Overview .............................................................................. 22

9.3 Drug-Behaviour Interactions............................................................................. 22

9.4 Drug-Drug Interactions..................................................................................... 22

9.5 Drug-Food Interactions .................................................................................... 25

9.6 Drug-Herb Interactions..................................................................................... 25

9.7 Drug-Laboratory Test Interactions .................................................................... 25

10 CLINICAL PHARMACOLOGY ......................................................................................... 25

10.1 Mechanism of Action ....................................................................................... 25

10.2 Pharmacodynamics .......................................................................................... 26

10.3 Pharmacokinetics............................................................................................. 26

11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 26

12 SPECIAL HANDLING INSTRUCTIONS............................................................................. 26

PART II: SCIENTIFIC INFORMATION ........................................................................................ 27

13 PHARMACEUTICAL INFORMATION.............................................................................. 27

14 CLINICAL TRIALS.......................................................................................................... 27

14.2 Comparative Bioavailability Studies .................................................................. 27

15 MICROBIOLOGY .......................................................................................................... 28

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 28

17 SUPPORTING PRODUCT MONOGRAPHS...................................................................... 29

PATIENT MEDICATION INFORMATION ................................................................................... 30

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

METHOPRAZINE (Methotrimeprazine Maleate Tablets) is indicated for:

• Psychotic disturbances: acute and chronic schizophrenias, senile psychoses, manic-depressive syndromes.
• Analgesic: In pain due to cancer, zona, trigeminal neuralgia, neurocostal neuralgia, in phantom limb pains, muscular discomforts and as post-operative analgesic adjunct.
• Anti-emetic: For the treatment of nausea and vomiting of central origin.
• Sedative: For the management of insomnia.

1.1 Pediatrics

Pediatrics (<1 year of age): METHOPRAZINE is contraindicated in children younger than 1 year. See 2 CONTRAINDICATIONS.

Pediatrics (1 to 18 years of age): See 4.2 Recommended Dose and Dosage Adjustment; and 7.1.3 Pediatrics.

1.2 Geriatrics

Geriatrics (≥65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 4.2 Recommended Dose and Dosage Adjustment; and 7.1.4 Geriatrics.

METHOPRAZINE is not indicated for the treatment of patients with dementia. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

2 CONTRAINDICATIONS

METHOPRAZINE is contraindicated in Children younger than 1 year, due to a possible association between use of phenothiazine-containing products and Sudden Infant Death Syndrome (SIDS).

METHOPRAZINE (methotrimeprazine maleate tablets) is contraindicated in patients with:

• Hypersensitivity to methotrimeprazine, other phenothiazines, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Coma or CNS depression due to alcohol, hypnotics, analgesics or narcotics.
• Concomitant neuroleptics including dopaminergics.
• Blood dyscrasia, including agranulocytosis.
• Bone marrow depression.
• Hepatic impairment.
• Brain damage.
• Pheochromocytoma.
• Circulatory collapse/severe hypotension, or severe heart disorder.
• Myasthenia gravis.
• Regional or spinal anesthesia.
• Risk of urinary retention related to urethroprostatic disorders.
• Risk of closed angle glaucoma.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• 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.
• In high oral doses, orthostatic hypotension may be encountered at the start of treatment. Patients whose treatment is started with high oral doses should be kept in bed during the first few days.
• Medical and laboratory evaluations should be performed prior to initiation of treatment, to rule out cardiovascular risk factors (in particular ventricular arrhythmia and QT prolongation). See 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 8.5 Post-Market Adverse Reactions.
• METHOPRAZINE therapy should be initiated at low doses in patients with arteriosclerosis or cardiovascular problems.
• Careful monitoring of treatment with METHOPRAZINE is required in patients with certain cardiovascular diseases, due to the quinidine-like, tachycardia inducing and hypotensive effects of this product class. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 5 OVERDOSAGE.
• All potential risk factors for venous thromboembolism (VTE) should be identified and preventive measures undertaken prior to initiation of treatment with METHOPRAZINE. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 8.2 Clinical Trial Adverse Reactions, Vascular disorders.
• Because of its anticholinergic effects, METHOPRAZINE must be administered with caution in patients with glaucoma and prostatic hypertrophy.
• During long-term therapy, periodic liver function tests should be performed. In addition, complete blood counts (CBC), white blood cell count (WBC) should be conducted regularly, particularly during the first 2 or 3 months of treatment, and physicians should watch for any signs of blood dyscrasia.
• METHOPRAZINE should be used with caution in epileptic patients, since phenothiazines, including METHOPRAZINE, may lower the seizure threshold. See 7 WARNINGS AND PRECAUTIONS, Neurologic and 8.2 Clinical Trial Adverse Reaction. It is advisable to administer an appropriate anticonvulsant medication to epileptic patients receiving METHOPRAZINE therapy.
• Careful monitoring of patients with severe renal impairment is recommended, due to the risk of accumulation.
• Patients should have baseline and periodic monitoring of blood glucose and body weight.
• Because of the risk of photosensitization, patients should be advised to avoid exposure to direct sunlight.
• Patients are strongly advised not to consume alcoholic beverages or to take medicines containing alcohol during treatment with METHOPRAZINE.
• Phenothiazines may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, general anesthetics, or alcohol.

4.2 Recommended Dose and Dosage Adjustment

Adults

Minor conditions in which METHOPRAZINE may be given in low doses as a tranquilizer, anxiolytic, analgesic or sedative: begin treatment with 6 mg/day 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 mg to 25 mg is usually sufficient.

Severe Conditions such as pyschosis or intense pain in which METHOPRAZINE is employed at higher doses: Begin treatment with 50 mg/day 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 mg/day to 200 mg/day, administer the drug in divided daily doses and keep the patient in bed for the first few days.

Pediatrics (1 to less than 18 years of age)

The initial dose has been established at 0.25 mg/kg daily 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. See 7.1.3 Pediatrics.

Geriatrics (≥65 years of age)

METHOPRAZINE should be used cautiously in the elderly owing to their susceptibility to drugs acting on the central nervous system and a lower initial dosage is recommended. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7.1.4 Geriatrics.

Hepatic Impairment:

METHOPRAZINE is contraindicated in patients with hepatic impairment (see 2 CONTRAINDICATIONS).

Renal Impairment:

METHOPRAZINE should not be used in patients with renal insufficiency. See 7 WARNINIGS AND PRECAUTIONS, Renal.

4.2.1 Discontinuing Treatment

Acute withdrawal symptoms, including nausea, vomiting, headache, anxiety, agitation, dyskinesia, dystonia, disturbed temperature regulation, and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics.

Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable. Symptoms of withdrawal can occur following treatment at any dose.

Withdrawal of treatment should occur under close medical supervision.

4.4 Administration

Tablets are for oral administration.

4.5 Missed Dose

If a dose is missed, it should be taken promptly, unless it is near the time of the next dose, in which case the missed dose should be skipped. The next dose should be taken at the regular time. Doses should not be doubled.

5 OVERDOSAGE

High doses cause depression of the central nervous system, presenting as lethargy, dysarthria, ataxia, stupor, reduction in consciousness into coma, convulsions; mydriasis; cardiovascular symptoms (related to risk of QT interval prolongation), such as hypotension, ventricular tachycardia and arrhythmia; respiratory depression; hypothermia. These effects may be potentiated by other medicines or by alcohol. Anticholinergic syndrome may occur. Severe parkinsonian syndrome may occur.

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. Treatment is symptomatic. Centrally acting emetics are ineffective because of the anti-emetic action of METHOPRAZINE.

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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

Description

METHOPRAZINE 2 mg: Each yellow, round, biconvex, film-coated tablet with straight edges, engraved '2' on one side, plain on the other side, contains methotrimeprazine maleate equivalent to 2 mg of methotrimeprazine. Available in bottles of 100 and 500 tablets.

METHOPRAZINE 5 mg: Each yellow, round, biconvex, film-coated tablet with straight edges, engraved '5' on one side, plain on the other side, contains methotrimeprazine maleate equivalent to 5 mg of methotrimeprazine. Available in bottles of 100 and 500 tablets.

METHOPRAZINE 25 mg: Each yellow, round, biconvex, film-coated tablet with straight edges, engraved 'MT' over '25' on one side, plain on the other side, contains methotrimeprazine maleate equivalent to 25 mg of methotrimeprazine. Available in bottles of 100 and 500 tablets.

METHOPRAZINE 50 mg: Each yellow, round, biconvex, film-coated tablet with straight edges, engraved 'MT' over '50' on one side, plain on the other side, contains methotrimeprazine maleate equivalent to 50 mg of methotrimeprazine. Available in bottles of 100 and 500 tablets.

7 WARNINGS AND PRECAUTIONS

See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Body Temperature Regulation: Phenothiazines like METHOPRAZINE may impair sensitivity and adaptation to changes of environmental temperature so that fatal hyperthermia and heat strokes are possible complications. Appropriate care is advised when prescribing METHOPRAZINE for patients who will be experiencing conditions which may contribute to an elevation of core temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Cardiovascular

METHOPRAZINE is contraindicated in patients with circulatory collapse/severe hypotension, or severe heart disorder. See 2 CONTRAINDICATIONS. It should also be avoided in patients with cardiac failure.

Hypotension: Hypotension, which is typically orthostatic, may occur, especially in elderly, in alcoholic patients and/or at the start of treatment with high oral doses. Patients whose treatment is starting with high oral doses should be kept in bed during the first few days.

QT interval prolongation: As with other neuroleptics, very rare cases of QT interval prolongation have been reported with methotrimeprazine maleate tablets. 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 8.2 Clinical Trial Adverse Reactions, Cardiac disorders and 9.4 Drug-Drug

Interactions.

Vascular disorders: Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs, including methotrimeprazine maleate tablets, in case reports and/or observational studies. See 8.2 Clinical Trial Adverse Reactions. When prescribing METHOPRAZINE all potential risk factors for VTE should be identified and preventative measures undertaken.

In randomized, placebo-controlled, clinical trials placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3‐fold increased risk of cerebrovascular events has been observed. The mechanism of this risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded.

METHOPRAZINE should be used with caution in patients with stroke risk factors or with a history of stroke as well as patients with risk factors for thromboembolism. See 7.1.4 Geriatrics.

Dependence, Tolerance and/or Abuse Liability

In general, phenothiazines do not produce psychic dependence. However, gastritis, nausea, vomiting, dizziness, and tremulousness have been reported following abrupt cessation of high dose therapy. See 4.2.1 Discontinuing Treatment.

Driving and Operating Machinery

METHOPRAZINE, like other antipsychotics, has the potential to impair judgement, thinking, or motor skills.

Patients should be warned about drowsiness, dizziness, and blurred vision and advised not to drive or operate machinery or engage in activities that require alertness or physical coordination, particularly during the early days of treatment, until they know how METHOPRAZINE affects them.

Endocrine and Metabolism

METHOPRAZINE should be avoided in patients with hypothyroidism. It is contraindicated in patients with pheochromocytoma. See 2 CONTRAINDICATIONS.

Hyperglycemia: Hyperglycemia or intolerance to glucose has been reported in patients treated with methotrimeprazine maleate tablets. Diabetic ketoacidosis (DKA) has occurred in patients with no reported history of hyperglycemia. Patients should have baseline and periodic monitoring of blood glucose and body weight.

Hyperprolactinemia: Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects.

Gastrointestinal

The onset of paralytic ileus, which may be manifested by distension and abdominal pain, should be treated as an emergency.

Very rare cases of potentially life-threatening necrotizing colitis have been reported. See 8.2 Clinical Trial Adverse Reactions, Gastrointestinal disorders.

Genitourinary

Rare cases of priapism have been reported with antipsychotic use, such as methotrimeprazine maleate tablets. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment. The most likely mechanism of action of priapism is a relative decrease in sympathetic tone.

Hematologic

METHOPRAZINE is contraindicated in patients with blood dyscrasia, including bone marrow depression and agranulocytosis. See 2 CONTRAINDICATIONS.

Neutropenia, leukopenia, granulocytopenia and agranulocytosis have been reported during antipsychotic use. Therefore, it is recommended that patients have their complete blood count (CBC) and white blood cell count (WBC) tested prior to starting METHOPRAZINE and then periodically throughout treatment. Most cases of agranulocytosis associated with the administration of phenothiazine derivatives have occurred between the fourth and tenth week of treatment. Therefore, observe patients on prolonged therapy with particular care during that time for the appearance of such signs as sore throat, fever and weakness. The occurrence of unexplained infections or fever may be evidence of blood dyscrasia and requires immediate hematological investigation. See 8 ADVERSE REACTIONS.

Hepatic/Biliary/Pancreatic

METHOPRAZINE is contraindicated in patients with hepatic impairment. See 2 CONTRAINDICATIONS.

Immune

METHOPRAZINE is contraindicated in patients with myasthenia gravis. See 2 CONTRAINDICATIONS.

Monitoring and Laboratory Tests

The following assessments should be done before and periodically during treatment with METHOPRAZINE.

• Blood glucose and body weight
• Complete blood count (CBC)
• WBC and differential counts and liver function tests
• Sore throat, fever and weakness in patients on prolonged therapy may indicate agranulocytosis. If these symptoms appear, discontinue the drug and perform liver function tests
• Blood pressure
• Renal function

Neurologic

METHOPRAZINE is contraindicated in patients with brain damage. See 2 CONTRAINDICATIONS.

METHOPRAZINE is not indicated for the treatment of patients with dementia. See 3 WARNINGS AND PRECAUTIONS BOX; 7.1.4 Geriatrics.

Seizures: METHOPRAZINE should be used with caution in epileptic patients, since phenothiazines, including METHOPRAZINE, may lower the seizure threshold. It is advisable to administer an appropriate anticonvulsant medication to epileptic patients receiving METHOPRAZINE therapy.

Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic drugs, including methotrimeprazine maleate tablets. See 3 SERIOUS WARNINGS AND PRECAUSIONS BOX.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue METHOPRAZINE and provide intensive symptomatic treatment and monitoring.

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, including METHOPRAZINE, 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. See 8.5 Post-Market Adverse Reactions.

Parkinson’s disease: Apart from exceptional situations, METHOPRAZINE should not be used in patients with Parkinson’s disease.

Tardive Dyskinesia: A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although the prevalence of tardive dyskinesia with conventional antipsychotics appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the beginning of treatment, which patients are likely to develop the syndrome. See 8.2 Clinical Trials Adverse Reactions, Nervous system disorders.

Both the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic 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 antipsychotic drug treatment is withdrawn.

Antipsychotic drug treatment itself, however, may suppress (or partially suppress) the signs and symptoms of tardive dyskinesia and thereby may possibly mask the underlying process.

The effect that symptom suppression has upon the long-term course of the syndrome is unknown.

METHOPRAZINE 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 METHOPRAZINE should be considered.

Ophthalmologic

METHOPRAZINE is contraindicated in patients with risks of closed angle glaucoma. See 2 CONTRAINDICAITONS.

Phenothiazines have been associated with retinopathy and lenticular or corneal deposits. Discontinue METHOPRAZINE if retinal changes are observed.

Peri-Operative Considerations

METHOPRAZINE is contraindicated in patients who will receive spinal or general anesthesia. See 2 CONTRAINDICATIONS.

Psychotic patients on large doses of a phenothiazine drug who are undergoing surgery should be watched carefully for possible hypotensive phenomena. Moreover, it should be remembered that reduced amounts of anesthetics or CNS depressants may be required.

Renal

METHOPRAZINE is contraindicated in patients with risks of urinary retention related to urethroprostatic disorders. See 2 CONTRAINDICATIONS. It should be avoided in patients with renal dysfunction or prostate hypertrophy.

Monitor the renal function of patients on long-term therapy with METHOPRAZINE, due to the risk of accumulation. If abnormal values are observed, discontinue the drug. Patients who may develop urinary retention should be carefully observed. This drug should not be used in patients with renal insufficiency.

Reproductive Health

• Fertility

  There are no fertility data in animals. In humans, because of the interaction with dopamine receptors, METHOPRAZINE may cause hyperprolactinemia which can be associated with impaired fertility in women. Some data suggest that METHOPRAZINE treatment is associated with impaired fertility in men.

Sensitivity/Resistance

Hypersensitivity reactions including urticaria and angioedema have been reported with methotrimeprazine maleate tablets use. In case of allergic reaction, treatment with METHOPRAZINE must be discontinued and appropriate symptomatic treatment initiated. See 8.5 Post-Market Adverse Reactions, Immune system disorders.

Skin

Photosensitivity may occur. Patients should use sunscreens when exposed to sunlight for prolonged periods of time.

7.1 Special Populations

7.1.1 Pregnant Women

The use of METHOPRAZINE is not recommended during pregnancy and in women of childbearing potential not using contraception unless the potential benefits outweigh the potential risks to the fetus.

Non-Teratogenic Effects: Neonates exposed to antipsychotic drugs (including METHOPRAZINE) during the third trimester of pregnancy are at risk for:

• neurological disorders such as extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence.
• various degrees of respiratory disorders ranging from tachypnoea to respiratory distress and bradycardia. Although these events occurred most often when other drugs such as psychotropic or antimuscarinic drugs were coadministered, they may also occur with antipsychotic use alone.
• signs related to atropinic properties of phenothiazines such as meconium ileus, delayed meconium passage, abdominal bloating, tachycardia and initial feeding difficulties in neonates can also occur.

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.

Appropriate monitoring and treatment of neonates born to mothers receiving METHOPRAZINE are recommended.

Congenital malformations: Animal studies are insufficient with respect to reproductive toxicity. Most studies indicate that these agents are not teratogenic but there are reports of defects in infants exposed to these drugs in utero during the first trimester. Risk of congenital malformations cannot be excluded.

7.1.2 Breastfeeding

Phenothiazines, including methotrimeprazine maleate, are excreted in milk, therefore, breastfeeding is not recommended during treatment with METHOPRAZINE.

7.1.3 Pediatrics

Pediatrics (<1 year of age): METHOPRAZINE is contraindicated in children younger than 1 year. See 2 CONTRAINDICATIONS.

Pediatrics (1 to 18 years of age): The dosage should be titrated gradually until reaching an effective level. It should not exceed 40 mg/day for children under 12 years of age. See 4.2 Recommended Dose and Dosage Adjustment.

7.1.4 Geriatrics

Geriatrics (≥65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

Careful monitoring of treatment with METHOPRAZINE is required when administered in elderly patients exhibiting greater susceptibility to orthostatic hypotension, sedation, and extrapyramidal effects; chronic constipation (risk of ileus paralytic); possible prostatic hypertrophy.

Paralytic ileus, even resulting in death, may occur, appropriate measures should be taken if constipation develops.

METHOPRAZINE should be used cautiously in the elderly owing to their susceptibility to drugs acting on the central nervous system and a lower initial dosage is recommended. There is an increased risk of drug induced Parkinsonism in the elderly particularly after prolonged use.

METHOPRAZINE should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-, hypothermia).

Use in Geriatric Patients with Dementia

METHOPRAZINE is not indicated for the treatment of elderly patients with dementia-related psychosis. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Overall Mortality: In a meta-analysis of 13 controlled clinical trials, elderly patients with dementia treated with atypical antipsychotic drugs had an increased risk of mortality compared to placebo.

Observational studies suggest that, similar to atypical antipsychotics, 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.

Cerebrovascular Adverse Events (CVAEs) including stroke in Elderly Patients with Dementia: A 3-fold increase in risk of cerebrovascular adverse events has been seen in the dementia population in randomized clinical trials versus placebo with some atypical antipsychotics. The mechanism for this increased risk is not known. There is insufficient data to know if there is an increased risk of cerebrovascular events associated with METHOPRAZINE. An increased risk with other antipsychotic drugs or with other populations of patients cannot be excluded.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse effects 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 effects 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.

Phenothiazines have been observed to exert marked sedative effects and have a definite potential to induce parkinsonian syndrome, cause cholestatic hepatitis with intrahepatic obstructive jaundice and precipitate dermatological reactions.

8.2 Clinical Trial Adverse Reactions

Not all of the following adverse reactions have been reported 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.

Blood and lymphatic system disorders: Rare instances of agranulocytosis have been reported. Cases of neutropenia and granulocytopenia have also been reported.

Cardiac disorders: Rare cardiac rhythm disturbances, including tachycardia or fibrillation have occurred.

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 7 WARNINGS AND PRECAUTIONS, Cardiovascular, QT interval prolongation and 9.4 Drug-Drug Interactions.

Endocrine disorders: Hyperglycemia or glucose tolerance impaired has been reported in patients treated with methotrimeprazine maleate tablets. See 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism.

Gastrointestinal disorders: Dryness of the mouth. Chronic constipation, including paralytic ileus.

Patients should be advised of the risk of severe constipation during METHOPRAZINE treatment, and that they should tell their healthcare professional if constipation occurs or worsens, as they may need laxatives.

Necrotizing enterocolitis, which can be fatal, has been very rarely reported in patients treated with methotrimeprazine maleate tablets.

Hepatobiliary disorders: Rare cases of cholestatic jaundice and liver injury have been observed.

Investigations: Weight gain has been occasionally reported in patients during prolonged treatment with high doses. False positive pregnancy tests.

Metabolism and nutrition disorders: Hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Nervous system disorders: Drowsiness may appear early in treatment but will gradually disappear during the first weeks or with an adjustment in the dosage. Cases of confusional states, delirium, and seizures have been reported. Phenothiazines, such as METHOPRAZINE, may impair sensitivity and adaptation to changes of environmental temperature, so that fatal hyperthermia and heat strokes are possible complications.

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

As with other antipsychotic agents, tardive dyskinesia may occur in patients on long-term therapy and symptoms may persist long after therapy is discontinued or may be permanent, in some cases. The risk appears to be greater in children (including dystonias) and elderly patients. If the signs and symptoms of tardive dyskinesia appear during treatment, dosage reduction or discontinuation of METHOPRAZINE should be considered. Anticholinergic antiparkinsonian agents have no effect and may cause exacerbation. See 8.5 Post-Market Adverse Reactions.

Renal and urinary disorders: In older patients occasional urinary retention.

Reproductive system and breast disorders: Priapism has been very rarely reported. Altered libido, menstrual irregularities, lactation, inhibition of ejaculation, gynecomastia.

Skin and subcutaneous tissue disorders: Skin reaction, rash, photosensitivity reactions, pigmentation disorder are extremely rare.

Vascular disorders: Orthostatic hypotension may be encountered at the start of treatment with high oral doses.

Cases of venous thromboembolism, including cases of pulmonary embolism, sometimes fatal, and cases of deep vein thrombosis have been reported with antipsychotic drugs. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular.

8.5 Post-Market Adverse Reactions

Blood and lymphatic system disorders:

• Leukopenia, eosinophilia, thrombocytopenia (including thrombocytopenic purpura).

Cardiac disorders:

• There have been reports of sudden death, with possible causes of cardiac origin as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular.
• Torsades de pointes.
• ECG changes include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, atrioventricular block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage.

Endocrine disorders:

• Temperature regulation disorder, hyperprolactinemia which may result is galactorrhea, gynecomastia, amenorrhea, erectile dysfunction.

Eye disorders:

• Accommodation disorder, corneal deposits (brownish deposits in the anterior segment of the eye caused by accumulation of the drug and generally without effect on vision).

Immune System Disorders:

• Hypersensitivity, urticaria, angioedema.

Investigations:

• Positive serology for antinuclear antibodies without clinical lupus erythematosus.
• Liver function test abnormal.

Nervous system disorders:

• Parkinsonism.
• Dizziness, insomnia.
• Dystonia (spasmodic torticollis, oculogyric crises, trismus, etc.).
• Tardive dyskinesia occurring with long-term treatment. Tardive dyskinesia may occur after the neuroleptic agent is withdrawn and resolve after rechallenge or if the dose is increased. Anticholinergic antiparkinsonian agents have no effect and may cause exacerbation.
• Extrapyramidal syndrome: akinesia with or without hypertonia, partially relieved by anticholinergic antiparkinsonian agents, hyperkinetic-hypertonic movements, motor excitation, akathisia.
• Neuroleptic malignant syndrome. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX; 7 WARNINGS AND PRECAUTIONS, Neurologic, Neuroleptic malignant syndrome.
• Anticholinergic effects such as ileus paralytic, risk of accommodation disorders.

Pregnancy, puerperium and perinatal conditions:

• Drug withdrawal syndrome in neonatal. See 7.1.1 Pregnant Women.

Psychiatric disorders:

• Indifference, anxiety, mood altered.

Renal and urinary disorders:

• Risk of urinary retention.

Respiratory, thoracic and mediastinal disorders:

• Respiratory depression, nasal congestion.

Reproductive System and Breast Disorders:

• Ejaculation disorder.

Vascular disorders:

• Orthostatic hypotension.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

Contraindicated combinations: METHOPRAZINE is contraindicated in patients using concomitant dopaminergics, due to mutual antagonism between dopaminergics and neuroleptics. Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonize the antiparkinsonian action of dopaminergics.

Dopaminergics may cause or exacerbate psychotic disorders. If treatment with neuroleptics is required in patients with Parkinson's disease treated with a dopaminergic, the latter should be tapered off gradually, as sudden discontinuation of dopaminergic agents exposes the patient to a risk of neuroleptic malignant syndrome (NMS). For parkinsonian patients who require treatment with both a neuroleptic and a dopaminergic agent, use the minimum effective doses of both medications.

Combinations not recommended or requiring precaution: The action of some drugs may be opposed by phenothiazine neuroleptics; these include amphetamine, clonidine, and adrenaline.

9.3 Drug-Behaviour Interactions

The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol. Respiratory depression may occur. Impaired vigilance may make it dangerous to drive or use machines. Avoid consumption of alcoholic beverages and medications containing alcohol.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 - Established or Potential Drug-Drug Interactions

T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

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

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

METHOPRAZINE possesses antipsychotic, tranquilizing, anxiolytic, and analgesic properties.

METHOPRAZINE possesses strong sedative properties. It potentiates the pharmacological actions of anesthetics and opioids. 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.

Methotrimeprazine maleate tablets is capable of reversing epinephrine-induced hypertension but has practically no effect against norepinephrine and acetylcholine. It readily protects rats against traumatic shock.

10.2 Pharmacodynamics

Information is not available.

10.3 Pharmacokinetics

Information is not available.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15°C to 30°C. Protect from light.

METHOPRAZINE should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Non-proprietary name of the drug product: methotrimeprazine maleate

Chemical name: (1) 10H-phenothiazine-10-propanamine, 2-methoxy-N,N,β-trimethyl-, (-)-maleate

(2) (-)-10-[3-(dimethylamino)-2-methylpropyl]-2-methoxyphenothiazine maleate

Molecular formula and molecular mass: C₁₉H₂₄N₂OS • C₄H₄O₄ and 444.6 g/mol

Structural formula:

Physicochemical properties: Methotrimeprazine is a fine, white, practically odorless, crystalline powder which melts at about 126°C. It is practically insoluble in water; freely soluble in chloroform and in ether; sparingly soluble in methanol. It is sparingly soluble in alcohol at 25°C, but is freely soluble in boiling alcohol.

14 CLINICAL TRIALS

14.2 Comparative Bioavailability Studies

A comparative bioavailability study was performed using healthy human volunteers. The rate and extent of absorption of methotrimeprazine were measured and compared following a single oral 25 mg dose of METHOPRAZINE or Nozinan. The results from measured data are summarized as follows:

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

In mice the LD₅₀ of methotrimeprazine maleate 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 mg/kg 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 mg/kg 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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1 NOZINAN®, Methotrimeprazine Hydrochloride Injection, 25 mg/mL, submission control: 279974, Product Monograph, Neuraxpharm Arzneimittel GmbH. (NOV 15, 2023).
2. 2 NOZINAN®, Methotrimeprazine Maleate Tablets 5, 25, 50 mg and Methotrimeprazine Hydrochloride Injection, 25 mg/mL, submission control: 111761, Product Monograph, sanofi-aventis Canada Inc. (May 18, 2007)