Tapazole (Knight Therapeutics) Product Monograph

RECENT MAJOR LABEL CHANGES

None at time of most recent authorization.

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics .............................................................................................................. 4

1.2 Geriatrics .............................................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 4

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

4.1 Dosing Considerations .......................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment ..................................................... 5

4.4 Administration ...................................................................................................... 5

4.5 Missed Dose ......................................................................................................... 5

5 OVERDOSAGE .............................................................................................................. 5

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

7 WARNINGS AND PRECAUTIONS .................................................................................. 6

7.1 Special Populations ............................................................................................... 9

7.1.1 Pregnant Women ............................................................................................. 9

7.1.2 Breast-feeding .................................................................................................. 9

7.1.3 Pediatrics .......................................................................................................... 9

7.1.4 Geriatrics .......................................................................................................... 9

8 ADVERSE REACTIONS .................................................................................................. 9

8.1 Adverse Reaction Overview .................................................................................. 9

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 10

8.5 Post-Market Adverse Reactions ......................................................................... 10

9 DRUG INTERACTIONS ................................................................................................ 10

9.2 Drug Interactions Overview ................................................................................ 10

9.4 Drug-Drug Interactions ....................................................................................... 10

9.5 Drug-Food Interactions ....................................................................................... 10

9.6 Drug-Herb Interactions ....................................................................................... 11

9.7 Drug-Laboratory Test Interactions ...................................................................... 11

10 CLINICAL PHARMACOLOGY ....................................................................................... 11

10.1 Mechanism of Action .......................................................................................... 11

10.2 Pharmacodynamics ............................................................................................ 11

10.3 Pharmacokinetics ............................................................................................... 11

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

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 11

PART II: SCIENTIFIC INFORMATION ....................................................................................... 12

13 PHARMACEUTICAL INFORMATION ............................................................................ 12

14 CLINICAL TRIALS ........................................................................................................ 12

15 MICROBIOLOGY ........................................................................................................ 12

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 12

PATIENT MEDICATION INFORMATION .................................................................................. 13

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TAPAZOLE® (methimazole tablets) is indicated in adults for:

• The medical treatment of hyperthyroidism. Long-term therapy may lead to remission of the disease.
• Amelioration of hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy.
• Use when thyroidectomy is contraindicated or not advisable.

1.1 Pediatrics

Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥ 65 years): Clinical studies did not include sufficient numbers of subjects aged 65 years or older to determine the safety and efficacy of methimazole in this geriatric population (see 4.2 Recommended Dose and Dosage Adjustment and 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

Methimazole is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORM, STRENGTHS, COMPOSITION AND PACKAGING.
• Breastfeeding women, as the drug is excreted in breast milk.
• Patients with history of acute pancreatitis after administration of methimazole.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• TAPAZOLE treatment can cause hypothyroidism and adjustments in dosing are necessary to maintain a euthyroid state (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypothyroidism). Excess dosage should be avoided as it can lead to sub-clinical or clinical hypothyroidism and goitre growth (see7 WARNINGS AND PRECAUTIONS, Respiratory). Periodic monitoring of thyroid function should be performed with dosage adjustments as necessary and with more careful monitoring in patients with large goitres (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

• Concomitant administration of TAPAZOLE and warfarin necessitates intensive and frequent monitoring, particularly when initiating, discontinuing, or changing doses of methimazole (see

  7 WARNINGS AND PRECAUTIONS, Hematologic, Anticoagulant Therapy and 9.4 Drug-Drug Interactions).

• TAPAZOLE can only be administered during pregnancy after a strict individual benefit/risk assessment and only at the lowest effective dose, without additional administration of thyroid hormones. Women of childbearing potential should use effective methods of contraception during TAPAZOLE therapy (see

  7.1.1 Pregnant Women).

4.2 Recommended Dose and Dosage Adjustment

Adult (≥18 years of age): The initial daily dose is 15 mg for mild hyperthyroidism, 30 to 40 mg for moderately severe hyperthyroidism, and 60 mg for severe hyperthyroidism, divided into three doses at eight-hour intervals. The maintenance dosage is 5 to 15 mg daily.

Geriatric (≥65 years of age): Clinical studies of methimazole did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric (<18 years of age): Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

Hepatic impairment: The dose should be kept as low as possible, and patients should be closely monitored as the plasma clearance of methimazole is reduced (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Renal impairment: The dose should be kept as low as possible and careful individual dose adjustment under close monitoring is recommended as there is a lack of data regarding the pharmacokinetic behaviour of methimazole in patients with renal impairment.

4.4 Administration

• TAPAZOLE is administered orally.
• TAPAZOLE is usually given in three equal doses per day at approximately eight-hour intervals.

4.5 Missed Dose

If a dose is missed, patients should contact their healthcare professional. Patients should not take a double dose to make up for a forgotten dose. Patients should take their next scheduled dose as usual.

5 OVERDOSAGE

Symptoms: Symptoms may include nausea, vomiting, epigastric distress, headache, fever, joint pain, pruritus, and edema. Aplastic anemia (pancytopenia) or agranulocytosis may be manifested in hours to days. Less frequent events are hepatitis, nephrotic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression. Although not well studied, methimazole-induced agranulocytosis is generally associated with doses of 40 mg or more in patients older than 40 years of age.

Overdose may also lead to hypothyroidism with corresponding symptoms of a reduced metabolism and, through the feedback effect, to activation of the adenohypophysis with subsequent goitre growth. This can be avoided by dose reduction as soon as a euthyroid metabolic condition is achieved.

No information is available on the median lethal dose (LD₅₀) of the drug or the concentration of methimazole in biologic fluids associated with toxicity and/or death.

Treatment: In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

The patient’s bone marrow function should be monitored.

In case of suspected overdose, patients should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment should be instituted as required.

Forced diuresis, peritoneal dialysis, hemodialysis or charcoal hemoperfusion have not been established as beneficial for an overdose of methimazole.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

5 mg tablets: Each round, white, scored tablet is debossed with ‘J94’ on one side and plain on the other side.

10 mg tablets: Each round, white tablet is debossed with ‘10’ on one side and plain on the other side.

TAPAZOLE tablets are supplied in bottles of 100.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Patients who receive methimazole should be under close surveillance. Physicians should encourage patients to immediately report any evidence of illness or unusual clinical symptoms, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be made to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving additional drugs known to cause agranulocytosis.

The development of arthralgias should prompt drug discontinuation, since this symptom may indicate a severe transient migratory polyarthritis known as “the antithyroid arthritis syndrome”.

Carcinogenesis and Mutagenesis

Animal data has shown thyroid hyperplasia, thyroid adenoma, and carcinoma formation (see 16 NON-CLINICAL TOXICOLOGY, carcinogenicity).

Cardiovascular

Vasculitis

Cases of vasculitis have been observed very rarely in patients receiving methimazole therapy. The cases of vasculitis include: leukocytoclastic cutaneous vasculitis, glomerulonephritis, and systemic vasculitis (with fatal outcome). Many cases were associated with anti-neutrophilic cytoplasmic antibodies (ANCA)-positive vasculitis. Early recognition of vasculitis is important to prevent long term organ damage and/or death. Inform patients to promptly report symptoms that may be associated with vasculitis including rash, hematuria or decreased urine output, dyspnea or hemoptysis. If vasculitis is suspected, discontinue methimazole therapy and initiate appropriate intervention.

Driving and Operating Machinery

Patients should be warned to exercise caution when driving or operating machinery while on treatment with TAPAZOLE. Adverse reactions of vertigo and drowsiness were reported with TAPAZOLE treatment (see 8.1 Adverse Reaction Overview).

Endocrine and Metabolism

Hypothyroidism

TAPAZOLE can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Excess dosage can lead to sub-clinical or clinical hypothyroidism and goitre growth due to TSH increase (see 7 WARNINGS AND PRECAUTIONS, Respiratory).

Lactose

TAPAZOLE contains lactose monohydrate. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product.

Hematologic

Agranulocytosis

Agranulocytosis is potentially the most serious side effect of therapy with methimazole. Patients should be instructed to report to their physicians any symptoms of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. The drug should be discontinued in the presence of agranulocytosis or aplastic anemia (pancytopenia). The patient’s bone marrow function should be monitored. See 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

Anticoagulant Therapy

Treating patients with both methimazole and warfarin necessitates intensive and frequent monitoring, in particular when initiating, discontinuing, or changing doses of methimazole, since alterations in the thyroid function affect the response to anticoagulation. See 9.4 Drug-Drug Interactions.

Hepatic/Biliary/Pancreatic

Hepatotoxicity is a rare adverse reaction in patients treated with methimazole. Although there have been reports of hepatotoxicity (including acute liver failure) associated with TAPAZOLE, the risk of hepatotoxicity appears to be less with methimazole than with propylthiouracil, especially in the pediatric population. There have been rare reports of fulminant hepatitis, hepatic necrosis, encephalopathy, and death. Cholestatic jaundice has occurred rarely. Patients should be instructed to report symptoms of hepatic dysfunction such as jaundice, anorexia, pruritus, and/or right upper-quadrant pain. Their presence should prompt evaluation of liver function tests and discontinuation of methimazole. Drug treatment should be discontinued promptly in the event of clinically significant evidence of liver abnormality, including hepatic transaminase values exceeding 3 times the upper limit of normal. See

7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests.

There have been post-marketing reports of acute pancreatitis in patients receiving methimazole. In case of acute pancreatitis, TAPAZOLE should be discontinued immediately. Do not start treatment in patients with a history of acute pancreatitis that has been attributed to methimazole. Re-exposure may result in recurrence of acute pancreatitis with decreased time to onset. See 8.5 Post-Market Adverse Reactions section.

Monitoring and Laboratory Tests

The patient’s liver function, hepatic transaminase levels, and the complete blood count should be closely monitored. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and 7 WARNING AND PRECAUTIONS, Hematologic and Hepatic/Biliary/Pancreatic. Because methimazole may cause hypoprothrombinemia and bleeding, prothrombin time/INR should also be monitored during therapy with the drug, especially before surgical procedures.

Periodic monitoring of thyroid function is warranted. A laboratory result indicating elevated TSH warrants a decrease in the dosage of methimazole. Once clinical evidence of hyperthyroidism has resolved, the finding of a rising serum TSH indicates that a lower maintenance dose of TAPAZOLE should be employed. Careful monitoring is necessary in patients with large goitres with constriction of the trachea because of the risk of goitre growth.

Reproductive Health: Female and Male Potential

See 7.1.1 Pregnant Women.

• Fertility

No data exist regarding the effect of TAPAZOLE on fertility.

• Teratogenic Risk

Methimazole can cause fetal harm when administered to a pregnant woman. Methimazole has been reported to cause congenital malformations when administered during pregnancy, particularly in the first trimester of pregnancy and at high doses. If TAPAZOLE is used during pregnancy or if the patient becomes pregnant while taking TAPAZOLE, the patient should be warned of the potential hazard to the fetus. Women of childbearing potential should use effective methods of contraception during methimazole therapy (see 7.1.1 Pregnant Women).

Respiratory

Treating patients with intrathoracic goitres necessitates caution and monitoring since intrathoracic goitre can grow during treatment causing tracheal obstruction. Goitre growth due to increased TSH levels may indicate excess dosage.

Skin

TAPAZOLE should be discontinued in the presence of exfoliative dermatitis.

7.1 Special Populations

7.1.1 Pregnant Women

Pregnant Women: Hyperthyroidism in pregnant women should be adequately treated to prevent serious maternal and fetal complications.

Methimazole can cause fetal harm when administered to a pregnant woman. Methimazole readily crosses the placental membranes and can induce goiter and hypothyroidism in the developing fetus.

Based on human experience from epidemiological studies and spontaneous reporting, methimazole is suspected to cause congenital malformations when administered during pregnancy, particularly in the first trimester of pregnancy and at high doses. Reported malformations include aplasia cutis congenital, craniofacial malformations (choanal atresia; facial dysmorphism), exomphalos, oesophageal atresia, omphalomesenteric duct anomaly, and ventricular septal defect.

Methimazole must only be administered during pregnancy after a strict individual benefit/risk assessment and only at the lowest effective dose, without additional administration of thyroid hormones. If methimazole is used during pregnancy or if the patient becomes pregnant while taking TAPAZOLE, the patient should be warned of the potential hazard to the fetus. Close maternal, fetal, and neonatal monitoring is recommended, with adjustment of methimazole as necessary.

Women of Childbearing potential: Women of childbearing potential should use effective methods of contraception during methimazole therapy.

7.1.2 Breast-feeding

Methimazole is excreted in human breast milk and its use is contraindicated in breastfeeding women (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥ 65 years) Clinical studies of methimazole did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Serious adverse reactions (which occur less frequently than the minor less serious adverse reactions) include inhibition of myelopoiesis (agranulocytosis, granulocytopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome, insulin autoimmune syndrome (which can result in hypoglycemic coma), hepatitis (jaundice may persist for several weeks after discontinuation of the drug), periarteritis, and hypoprothrombinemia. Nephritis occurs very rarely. Cholestatic jaundice, fulminant hepatitis, encephalopathy, hepatic necrosis, and death have been rarely reported. See 7 WARNINGS AND PRECAUTIONS.

Less serious adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesia, loss of taste, abnormal loss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, anorexia, right upper-quadrant pain, and lymphadenopathy.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

It should be noted that about 10% of patients with untreated hyperthyroidism have leucopenia (white-blood-cell count of less than 4,000/mm³), often with relative granulopenia.

8.5 Post-Market Adverse Reactions

The following adverse reactions have been reported from marketing experience with methimazole.

Acute pancreatitis (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Vasculitis (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).

Cases of congenital anomalies have been reported in neonates, whose mothers were treated with methimazole during pregnancy: aplasia cutis congenital, craniofacial malformations (choanal atresia; facial dysmorphism), exomphalos, oesophageal atresia, omphalomesenteric duct anomaly, and ventricular septal defect (see 7.1.1 Pregnant Women).

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

TAPAZOLE may interact with anticoagulants and treatment of patients with both methimazole and warfarin necessitates intensive and frequent monitoring (see 7 WARNINGS AND PRECAUTION, Hematologic, Anticoagulant Therapy).

9.4 Drug-Drug Interactions

Increases and decreases in warfarin-induced anticoagulation have been reported in patients taking methimazole. In hyperthyroid patients, the metabolism of vitamin K clotting factors is increased, resulting in increased sensitivity to oral anticoagulants. Antithyroid drugs, by reducing the extent of hyperthyroidism, decrease the metabolism of clotting factors and thus reduce the effects of oral anticoagulants. On the other hand, patients on anticoagulant therapy who are euthyroid due to antithyroid agents may develop marked hypoprothrombinemia if the antithyroid medications are ceased and they become thyrotoxic again. Treating patients with both methimazole and warfarin necessitates intensive and frequent monitoring, in particular when initiating, discontinuing, or changing doses of methimazole, since alterations in thyroid function affect the response to anticoagulation.

As methimazole is used in the treatment of hyperthyroidism, once a patient becomes euthyroid, the following drug interactions may need to be considered:

• β-adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid.
• Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.
• Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

9.5 Drug-Food Interactions

Interactions with foods have not been studied.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been studied.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Methimazole inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triiodo-thyroxine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection.

The actions and use of methimazole are similar to those of propylthiouracil. On a weight basis, the drug is at least ten times as potent as propylthiouracil, but methimazole may be less consistent in action.

10.2 Pharmacodynamics

Methimazole inhibits dose-dependently the incorporation of iodine into tyrosine and thereby the neosynthesis of thyroid hormones. This property permits symptomatic therapy of hyperthyroidism regardless of its cause. Whether methimazole furthermore affects the ‘natural course’ taken by the immunologically induced type of hyperthyroidism (Graves’ disease), i.e., whether it suppresses the underlying immunopathogenitic process, can presently not be decided with certainty. The release of previously synthesized thyroid hormones from the thyroid is not affected. This explains why the length of the latency period until normalization of the serum concentrations of thyroxine and triiodothyronine, and thus until clinical improvement, differs in individual cases. Hyperthyroidism due to the release of hormones after destruction of thyroid cells, e.g., after radioiodine therapy or in thyroiditis, is also not affected.

10.3 Pharmacokinetics

Absorption: Methimazole is readily absorbed from the gastrointestinal tract.

Metabolism: Methimazole is metabolized rapidly in the liver and requires frequent administration.

Elimination: Methimazole is excreted in the urine.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15 to 30^oC). Protect from light. Keep tightly closed. Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

None required.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Methimazole

Chemical name: 1-Methylimidazole-2-thiol

Molecular formula and molecular mass: C₄H₆N₂S

114.16 g / mol

Structural formula:

Physicochemical properties:

Description: White to slightly cream-coloured crystalline powder.

It differs chemically from the drugs of the thiouracil series primarily because it has a five- instead of a six-membered ring.

Melting range: 143 - 146°C

Solubility: Freely soluble in water, alcohol and in acetone

14 CLINICAL TRIALS

The clinical trial data on which the original indication was authorized are not available.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Carcinogenicity:

Rats treated for 2 years with methimazole demonstrated thyroid hyperplasia and thyroid adenoma and carcinoma formation. Such findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents. Pituitary adenomas have also been observed (see 7 WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis).