MAR-METHIMAZOLE

1 Dosing Considerations • MAR-METHIMAZOLE treatment can cause hypothyroidism and adjustments in dosing are necessary to maintain a euthyroid state (see Endocrine and Metabolism, Hypothyroidism). Excess dosage should be avoided as it can lead to sub-clinical or clinical hypothyroidism and goitre growth (see Respiratory).

Periodic monitoring of thyroid function should be performed with dosage adjustments Serious Warnings and Precautions • Agranulocytosis (see 7 Warnings and Precautions, Hematologic and 8 Adverse Reactions) • Liver toxicity (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic)) Page 5 of 19 as necessary and with more careful monitoring in patients with large goitres (see Monitoring and Laboratory Tests).

4 Drug-Drug Interactions). • MAR-METHIMAZOLE 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. 1 Pregnant Women).

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.

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 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.

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.

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.

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).

1 Pregnant Women).

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 For management of a suspected drug overdose, contact your regional poison control centre.

Page 7 of 19 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 MAR-METHIMAZOLE.

MAR-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 Forms, Strengths, Composition and Packaging.

• Breastfeeding women, as the drug is excreted in breast milk. • Patients with history of acute pancreatitis after administration of methimazole.