Tapazole

Pronunciation

Generic Name: Methimazole
Class: Antithyroid Agents
ATC Class: H03BB02
VA Class: HS852
CAS Number: 60-56-0

Introduction

Antithyroid agent;101 thioimidazole-derivative.b

Uses for Tapazole

Hyperthyroidism

Used in patients with Graves’ disease with hyperthyroidism or toxic multinodular goiter for whom surgery or radioactive iodine therapy is not an appropriate treatment option.101 118

Amelioration of symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy.101 118

Considered drug of choice by some clinicians for virtually every patient who chooses antithyroid drug therapy for treatment of Graves’ disease, except during first trimester of pregnancy when propylthiouracil is preferred, for treatment of thyroid storm, and in patients with minor adverse reactions to methimazole who refuse radioactive iodine therapy or surgery.118 (See Fetal/Neonatal Morbidity and also Pregnancy under Cautions, and see Thyrotoxic Crisis under Uses.)

Preferred agent when an antithyroid drug is required for a pediatric patient because of postmarketing reports of severe liver injury in pediatric patients receiving propylthiouracil.101 118 (See Pediatric Use under Cautions.)

Therapy maintains patients with Graves’ disease in euthyroid state for a period of several (generally 1–2) years until spontaneous remission occurs;118 b however, spontaneous remission does not occur in all patients, and most patients eventually require ablative therapy (i.e., surgery, radioactive iodine).b Methimazole does not affect underlying cause of hyperthyroidism; minimum duration of therapy necessary before assessing whether spontaneous remission has occurred not clearly established.b Some clinicians state that if methimazole is chosen as the primary therapy for Graves’ disease, continue the drug for approximately 12–18 months in adults or 1–2 years in children, then taper or discontinue if TSH concentrations return to normal at that time.118 122 123 124 125 If patients remain hyperthyroid after completing a course of methimazole, consider treatment with radioactive iodine or thyroidectomy.118 However, may consider treatment with low-dose methimazole for >12–18 months in adult patients not in remission who prefer this pharmacologic approach.118 In pediatric patients, also may continue methimazole therapy until the child is considered old enough for radioactive iodine therapy or surgery.118

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Therapy with methimazole returns the hyperthyroid patient to a normal metabolic state prior to thyroidectomy and controls the thyrotoxic crisis that may accompany thyroidectomy.b Some clinicians recommend that, whenever possible, adults or children with Graves’ disease undergoing thyroidectomy or adults with toxic adenoma or toxic multinodular goiter undergoing surgery be rendered euthyroid with methimazole prior to the procedure.118

Therapy with methimazole controls symptoms of hyperthyroidism before and after radioactive iodine therapy until the ablative effects of iodine occur.118 123 129 130 131 b However, beneficial and detrimental effects and optimal sequencing of antithyroid drugs before or after radioactive iodine therapy not clearly established.129

Some clinicians recommend considering pretreatment with methimazole prior to radioactive iodine therapy for Graves’ disease, toxic adenoma, or toxic multinodular goiter in adults at increased risk for complications due to worsening of hyperthyroidism (e.g., geriatric patients, patients with severe hyperthyroidism [e.g., extremely symptomatic, free thyroxine (T4) estimates 2–3 times the ULN] or substantial comorbidities [e.g., cardiovascular disease]).118 However, other clinicians state pretreatment with methimazole prior to radioactive iodine therapy not necessary because there is insufficient evidence to indicate that radioactive iodine worsens hyperthyroidism, and that pretreatment with methimazole will only delay treatment with radioactive iodine.118 In addition, pretreatment with methimazole may reduce efficacy of subsequent radioactive iodine therapy.118 122 123 129 130

Some clinicians suggest that children with Graves’ disease having total T4 concentrations >20 mcg/dL or free T4 estimates >5 ng/dL who are to receive radioactive iodine therapy be pretreated with methimazole and β-adrenergic blockade until total T4 and/or free T4 estimates normalize before proceeding with radioactive iodine.118

Does not induce remission in patients with nodular thyroid disease (i.e., toxic adenoma, toxic multinodular goiter); discontinuance of therapy results in relapse.118 Therefore, some clinicians suggest to treat adults with overt toxic adenoma or toxic multinodular goiter with either radioactive iodine therapy or thyroidectomy, and to avoid long-term methimazole therapy.118 However, long-term (life-long) antithyroid drug therapy may be best choice for some geriatric or otherwise ill patients with limited longevity and increased surgical risk who can be monitored regularly (e.g., residents of nursing homes or other care facilities where compliance with radiation safety regulations may be difficult) or for patients who prefer this pharmacologic approach.118

Thyrotoxic Crisis

May be used for management of thyrotoxic crisis,118 b although not considered antithyroid agent of first choice.103 118 Usually initiated before iodide (e.g., potassium iodide, strong iodine solution) therapy.b

Tapazole Dosage and Administration

General

  • May use a β-adrenergic blocking agent (e.g., propranolol) concomitantly to manage peripheral signs and symptoms of hyperthyroidism, particularly cardiovascular effects (e.g., tachycardia).b

Administration

Administer orally.101

Oral Administration

Manufacturer recommends administering total daily dosage usually in 3 equally divided doses at approximately 8-hour intervals.101 Alternatively, some clinicians state that drug may be administered as a single daily dose.118

Dosage

Pediatric Patients

Hyperthyroidism
Graves’ Disease with Hyperthyroidism or Toxic Multinodular Goiter
Oral

Initially, 0.4 mg/kg daily, usually given in 3 equally divided doses at approximately 8-hour intervals.101 Alternatively, some clinicians recommend usual dosage of 0.2–0.5 mg/kg daily (range: 0.1–1 mg/kg daily).118 These clinicians also suggest the following general dosages, calculated based on the patient's age and rounded to the nearest quarter-, half-, or whole-tablet dosage strengths: 1.25 mg daily for infants; 2.5–5 mg daily for children 1–5 years of age; 5–10 mg daily for children 5–10 years of age; and 10–20 mg daily for children 10–18 years of age.118 Patients with severe clinical or biochemical hyperthyroidism may receive dosages that are 50–100% higher than those usually recommended.118

Maintenance dosage: Approximately half of initial dosage or less.101 118

Optimum duration of therapy not clearly established.b However, some clinicians suggest administering drug for 1–2 years, then discontinue or reduce dosage to assess whether patient is in remission.118 If patient is not in remission following 1–2 years of therapy, consider treatment with radioactive iodine or thyroidectomy.118 Alternatively, may continue methimazole therapy for extended periods as long as adverse effects do not occur and hyperthyroidism is controlled; may use methimazole therapy as a bridge to radioactive iodine therapy or surgery at a later age if remission still has not occurred.118 May continue low-dose methimazole in selected situations in which radioactive iodine therapy or surgery may not be suitable or possible.118

Preparation for Surgical Treatment
Oral

Initially, 0.4 mg/kg daily, usually given in 3 equally divided doses at approximately 8-hour intervals.101

Some clinicians recommend administering methimazole usually for 1–2 months to achieve euthyroidism in preparation for thyroidectomy in patients with Graves’ disease.118

Preparation for Radioactive Iodine Therapy
Oral

Initially, 0.4 mg/kg daily, usually given in 3 equally divided doses at approximately 8-hour intervals.101

Some clinicians recommend discontinuing methimazole 3–5 days before radioactive iodine therapy.118 Although some clinicians restart antithyroid drugs after radioactive iodine therapy, this practice is seldom required in children.118

Adults

Hyperthyroidism
Graves’ Disease with Hyperthyroidism or Toxic Multinodular Goiter
Oral

Initially, 15 mg daily for mild hyperthyroidism, 30–40 mg daily for moderately severe hyperthyroidism, or 60 mg daily for severe hyperthyroidism.101 Alternatively, some clinicians recommend an initial dosage of 10–20 mg daily to restore euthyroidism.118

Considerable improvement or normal thyroid function generally achieved following 4–12 weeks of therapy, after which dosage may be decreased while maintaining normal thyroid function.118 122 123 124 Carefully adjust subsequent dosage according to patient’s tolerance and therapeutic response.b (See Laboratory Monitoring under Cautions.)

Maintenance dosage: Manufacturer recommends 5–15 mg daily.101 Alternatively, some clinicians recommend 5–10 mg daily.118

Optimum duration of therapy not clearly established.b However, some clinicians suggest continuing therapy for approximately 12–18 months, then taper or discontinue drug if TSH concentrations return to normal at that time.118 122 123 124 125 If patient remains hyperthyroid after completing a course of methimazole, consider treatment with radioactive iodine or thyroidectomy.118 However, may also consider long-term (>12–18 months) low-dose methimazole therapy in patients not in remission who prefer this pharmacologic approach.118

Preparation for Surgical Treatment
Oral

Initially, 15 mg daily for mild hyperthyroidism, 30–40 mg daily for moderately severe hyperthyroidism, or 60 mg daily for severe hyperthyroidism.101

Discontinue methimazole at time of procedure.118

Preparation for Radioactive Iodine Therapy
Oral

Initially, 15 mg daily for mild hyperthyroidism, 30–40 mg daily for moderately severe hyperthyroidism, or 60 mg daily for severe hyperthyroidism.101

Some clinicians recommend discontinuing methimazole 2–7 days before radioactive iodine; may restart methimazole 3–7 days after radioactive iodine, then generally taper over 4–6 weeks as thyroid function normalizes and radioactive iodine becomes effective.118 122 123 130

Thyrotoxic Crisis
Oral

Some clinicians recommend 60–80 mg daily.118

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.101

Renal Impairment

No specific dosage recommendations at this time.101

Geriatric Patients

No specific dosage recommendations at this time.101

Pregnancy

If used during pregnancy for management of hyperthyroidism, a sufficient, but not excessive, dosage is necessary; use lowest possible dosage.101 Thyroid dysfunction diminishes in many women as pregnancy proceeds; may be possible to reduce antithyroid dosage, and, in some patients, may discontinue antithyroid therapy 2–3 weeks before delivery.101 (See Pregnancy under Cautions.)

Cautions for Tapazole

Contraindications

  • Known hypersensitivity to methimazole or any ingredient in the formulation.101

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity

May cause fetal harm, particularly during first trimester of pregnancy.101 Teratogenic effects, including aplasia cutis, craniofacial malformations (facial dysmorphism, choanal atresia), and GI malformations (esophageal atresia with or without tracheoesophageal fistula, umbilical abnormalities) reported rarely in infants.101 May cause fetal goiter and hypothyroidism (cretinism) when administered during pregnancy.101

Congenital malformations reported approximately 3 times more often with prenatal exposure to methimazole compared with propylthiouracil.112 Distinct and consistent pattern of congenital malformations associated with use of methimazole, but not with propylthiouracil, particularly craniofacial malformations (e.g., scalp epidermal aplasia [aplasia cutis], facial dysmorphism, choanal atresia).112 Specific birth defects were associated with use of methimazole during the first trimester of pregnancy and not found when the drug was administered later in pregnancy.112 FDA has not found a consistent pattern of birth defects associated with use of propylthiouracil and has concluded there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the first trimester.112 (See Pregnancy under Cautions and also see Distribution under Pharmacokinetics.)

Hematologic Effects

Risk of agranulocytosis;101 usually occurs within first 2 months of therapy, but rarely may occur after 4 months of therapy.b May be dose related (possibly occurring more frequently with higher dosages); however, may occur irrespective of dosage, length of treatment, or previous exposure to antithyroid drug, and may occur more frequently in geriatric patients.118 122 123 126 127 128

Leukopenia, thrombocytopenia, and/or aplastic anemia (pancytopenia) may occur.101 Hypoprothrombinemia and bleeding also may occur.101 (See Laboratory Monitoring under Cautions.)

Perform baseline CBC, including white count and differential, prior to initiating therapy in patients with Graves’ disease.118

Monitor patient carefully for signs or symptoms of illness (e.g., sore throat, skin eruptions, fever, chills, headache, general malaise), particularly during early stages of therapy.b If fever, sore throat, or other signs or symptoms of illness occur, determine leukocyte and differential counts to assess whether agranulocytosis has developed.101 b

If agranulocytosis or aplastic anemia (pancytopenia) occurs, discontinue methimazole and monitor bone marrow indices.101 In patients who develop agranulocytosis or other serious adverse effects while receiving methimazole or propylthiouracil, use of the other drug is contraindicated because of risk of cross-sensitivity between the two drugs.118

Hepatotoxicity

Hepatotoxicity (including acute liver failure) reported; risk appears to be lower with methimazole than with propylthiouracil, especially in pediatric patients.101 (See Pediatric Use under Cautions.)

Jaundice associated with methimazole-induced hepatitis may persist for several weeks after discontinuance of the drug.101

Perform liver function tests (e.g., alkaline phosphatase, aminotransferase, bilirubin) prior to initiating therapy in patients with Graves’ disease.118

Promptly evaluate liver function (alkaline phosphatase, bilirubin) and hepatocellular integrity (ALT, AST) if symptoms suggestive of hepatic dysfunction (e.g., anorexia, pruritus, right upper-quadrant pain) occur.101 If clinically relevant liver abnormality (e.g., hepatic aminotransferase concentrations >3 times the ULN) is detected, discontinue methimazole promptly.101 If hepatitis occurs, discontinue methimazole.101

Hypothyroidism

May cause hypothyroidism necessitating routine monitoring of TSH and free T4 concentrations with dosage adjustments to maintain a euthyroid state.101

May cause fetal goiter and cretinism when administered to a pregnant woman, because the drug readily crosses the placenta.101 (See Fetal/Neonatal Morbidity and also see Pregnancy under Cautions.)

Sensitivity Reactions

Cross-sensitivity

Cross-sensitivity between thioamides may occur118 121 (i.e., in approximately 50% of patients switched from one thioamide agent to the other).122

In patients who develop serious adverse effects (e.g., agranulocytosis) while receiving either methimazole or propylthiouracil, use of other drug also is contraindicated, because of risk of cross-sensitivity between the two drugs.118 In patients experiencing serious allergic reactions to methimazole, use of the alternative antithyroid drug (i.e., propylthiouracil) not recommended.118

General Precautions

Laboratory Monitoring

Before initiating thioamide therapy in patients with Graves’ disease, some clinicians recommend obtaining baseline free T4 and TSH concentrations; CBC, including white count and differential; and liver function tests (e.g., alkaline phosphatase, aminotransferase, bilirubin).118

Monitor thyroid function (e.g., serum free T4, serum free or total triiodothyronine [T3], TSH) periodically (e.g., every 4–8 weeks [with subsequent dosage adjustments as needed] until thyroid function is stable or patient is euthyroid); once euthyroidism is achieved, monitor thyroid function every 2–3 months.101 118 122 123 124 Serum TSH not a reliable parameter to monitor early in therapy because it may remain suppressed for several months after initiation of therapy despite normalization of free T4 concentrations.118 122 123 124 A suppressed TSH concentration during this period does not indicate a need for dosage increase.123 However, once hyperthyroidism resolves, decrease maintenance dosage if serum TSH is elevated.101 123 Monitoring serum T3 concentrations may sometimes be useful for dosage adjustment; if total or free T3 concentrations remain elevated despite low, normal, or reduced free T4 concentrations, may need to increase antithyroid dosage.122 123 124 When methimazole is discontinued in patients with Graves’ disease, monitor thyroid function every 1–3 months for 6–12 months to diagnose relapse early.118

Determine leukocyte and differential counts in patients who develop any signs or symptoms of illness (e.g., fever, sore throat) during therapy.101 b

Monitor PT during therapy, particularly before surgical procedures, because of possible risk of hypoprothrombinemia and bleeding.101

Dermatologic Effects

If exfoliative dermatitis occurs, discontinue methimazole.101

Immunologic Effects

Antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis with acute renal failure, arthritis, skin ulcerations, and a vasculitic rash reported rarely.122 If ANCA-positive vasculitis occurs, discontinue methimazole.101

Specific Populations

Pregnancy

Category D.101 (See Fetal/Neonatal Morbidity under Cautions and also see Distribution under Pharmacokinetics.)

Despite potential fetal hazard, antithyroid agents still considered therapy of choice for management of hyperthyroidism during pregnancy.108 118 119 122 Since methimazole may be associated with the rare development of fetal abnormalities (e.g., aplasia cutis, craniofacial malformations [facial dysmorphism, choanal atresia], GI malformations [esophageal atresia with or without tracheoesophageal fistula, umbilical abnormalities]),101 propylthiouracil is preferred when an antithyroid drug is indicated during organogenesis, in the first trimester of pregnancy, or just prior to the first trimester of pregnancy.100 103 106 107 108 109 118 119 (See Fetal/Neonatal Morbidity under Cautions.) Switch patients receiving methimazole to propylthiouracil if pregnancy is confirmed in first trimester.119 May be preferable to switch from propylthiouracil to methimazole for the second and third trimesters (i.e., after the first trimester), because of potential maternal adverse effects of propylthiouracil (e.g., hepatotoxicity).108 109 118 119 If switching from propylthiouracil to methimazole, assess thyroid function after 2 weeks and then every 2–4 weeks thereafter.108 Not known if risk of methimazole-induced aplasia cutis or embryopathy outweighs risk of propylthiouracil-induced hepatotoxicity.104

If used during pregnancy, a sufficient, but not excessive, dosage is necessary; use lowest possible dosage to control maternal disease.101 Initiate or adjust antithyroid drug therapy to maintain maternal free T4 concentrations at or just above the ULN of nonpregnant reference range, or to maintain total T4 concentrations at 1.5 times the ULN or the free T4 index in the ULN, while using lowest possible dosage.108 119 Monitor free T4 and TSH concentrations approximately every 2–6 weeks in women receiving antithyroid drugs during pregnancy.119 As thyroid dysfunction diminishes in many women as pregnancy proceeds, may be possible to reduce dosage of antithyroid drug; in some patients, may discontinue antithyroid drug 2–3 weeks before delivery.101

If used during pregnancy or if patient becomes pregnant while receiving the drug, apprise of potential hazard to the fetus; inform patient of risks of methimazole-associated fetal malformations and risks of propylthiouracil-associated hepatotoxicity when considering antithyroid drug use during pregnancy.101 104 106 109

Lactation

Distributed into milk.101 However, no effect on clinical status and no toxicity observed in nursing infants.101

Generally compatible with breast-feeding; moderate dosages (i.e., 20–30 mg daily) appear to be safe.110 119 120 121 122 Preferred antithyroid drug in nursing women because maternal use of propylthiouracil associated with severe hepatotoxicity (i.e., hepatic necrosis in either woman or child).118 119 If antithyroid drug is used in nursing women, some clinicians recommend administering drug after a feeding and in divided doses, and monitoring thyroid function of nursing infants.119

Pediatric Use

Preferred over propylthiouracil when an antithyroid drug is required for a pediatric patient because of postmarketing reports of severe liver injury in pediatric patients receiving propylthiouracil.101 118 (See Hyperthyroidism under Uses.) Postmarketing cases of severe liver injury, including hepatic failure requiring liver transplantation or resulting in death, reported in pediatric patients receiving propylthiouracil; however, no such reports observed with methimazole.109 117 (See Hepatotoxicity under Cautions.)

Common Adverse Effects

Rash,101 urticaria,101 pruritus,101 skin pigmentation,101 abnormal hair loss,101 nausea,101 vomiting,101 arthralgia,101 myalgia,101 paresthesia,101 loss of taste,101 epigastric distress,101 edema,101 headache,101 drowsiness,101 neuritis,101 vertigo,101 jaundice,101 sialadenopathy,101 lymphadenopathy.101

Interactions for Tapazole

Drugs Known to Cause Agranulocytosis

Use concomitantly with extreme caution.101 (See Hematologic Effects under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral (e.g., warfarin)

Potential inhibition of vitamin K activity, resulting in increased activity of oral anticoagulants (e.g., warfarin);101 however, anticoagulant effect of warfarin also may be decreased122

Consider additional monitoring of PT/INR, particularly prior to surgery;101 adjustment of warfarin dosage may be needed122

β-Adrenergic blocking agents

Possible increased clearance of β-adrenergic blocking agents with a high extraction ratio during hyperthyroid state101

Reduction of β-blocker dosage may be needed when patient becomes euthyroid101

Digitalis glycosides

Possible increased serum digitalis concentrations when hyperthyroid patients receiving a stable digitalis glycoside regimen become euthyroid101

Reduction of digitalis glycoside dosage may be needed when patient becomes euthyroid101

Theophylline

Possible decreased theophylline clearance when hyperthyroid patients on a stable theophylline regimen become euthyroid101

Reduction of theophylline dosage may be needed when patient becomes euthyroid101

Tapazole Pharmacokinetics

Absorption

Bioavailability

Readily and rapidly absorbed from the GI tract following oral administration.101 b Peak plasma concentrations attained within about 1 hour.b

Distribution

Extent

Readily crosses the placenta.101 b

Distributed into milk101 (in concentrations approximately equal to those in maternal serum).b

Elimination

Metabolism

Metabolized in the liver.101

Elimination Route

Excreted in urine;101 b approximately 12% of dose excreted in urine within 24 hours.b

Half-life

5–13 hours.b

Stability

Storage

Oral

Tablets

15–30°C.101

Actions

  • Inhibits the synthesis of thyroid hormones101 by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin;b also inhibits the coupling of these iodotyrosyl residues to form iodothyronine.b

  • Exact mechanism(s) not fully elucidated; however, methimazole may interfere with the oxidation of iodide ion and iodotyrosyl groups.b

  • Limited evidence suggests that coupling reaction is more sensitive to antithyroid agents than the iodination reaction.b

  • Does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation; also does not interfere with effectiveness of exogenously administered thyroid hormones.101 b Patients whose thyroid gland contains a relatively high concentration of iodine (e.g., from prior ingestion, from administration during diagnostic radiologic procedures) may respond relatively slowly to antithyroid agents.b

  • Unlike propylthiouracil, does not inhibit peripheral deiodination of T4 to triiodothyronine (T3).b

Advice to Patients

  • Importance of informing clinicians immediately if signs or symptoms of illness (e.g., sore throat, skin eruptions, fever, chills, headache, general malaise) occur.101 b Importance of immediately discontinuing the drug and contacting clinicians if signs or symptoms suggestive of agranulocytosis (e.g., fever, sore throat) occur.101 118 (See Hematologic Effects under Cautions.)

  • Importance of immediately discontinuing the drug and promptly informing clinicians if symptoms suggestive of hepatic injury (e.g., pruritic rash, jaundice, acholic stools, dark urine, arthralgias, abdominal pain, nausea, fatigue) occur.118 (See Hepatotoxicity under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.101

  • Importance of women immediately informing clinicians if they are or plan to become pregnant or plan to breast-feed.101 Necessity for clinicians to advise women of methimazole-associated fetal malformations, as well as risks of propylthiouracil-associated hepatotoxicity when considering antithyroid drug use during pregnancy.101 104 106 109

  • Importance of informing patients of other important precautionary information.101 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Methimazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

5 mg*

Methimazole Tablets

Tapazole (scored)

King

10 mg*

Methimazole Tablets

Tapazole (scored)

King

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Methimazole 10MG Tablets (PAR): 100/$63.99 or 200/$119.98

Methimazole 5MG Tablets (SANDOZ): 90/$31.00 or 100/$34.00

Tapazole 10MG Tablets (KING PHARMA): 100/$146.00 or 200/$282.96

Tapazole 5MG Tablets (KING PHARMA): 100/$91.99 or 300/$264.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 25, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Food and Drug Administration. FDA Alert: Propylthiouracil-induced liver failure. Rockville, MD; 2009 Jun 4. From FDA website. Accessed 2009 Oct 28.

101. King Pharmaceuticals, Inc. Tapazole (methimazole) tablets prescribing information. Bristol, TN; 2012 Feb.

103. Bahn RS, Burch HS, Cooper DS et al. The Role of Propylthiouracil in the Management of Graves’ Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid. 2009; 19:673-4. [PubMed 19583480]

104. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Hepatic toxicity following treatment for pediatric Graves’ disease meeting: October 28, 2008. Conference proceeding. Available from website. Accessed 2009 Oct 30.

106. Rivkees SA, Mattison DR. Propylthiouracil (PTU) hepatotoxicity in children and recommendations for discontinuation of use. Int J Pediatr Endocrinol. 2009. Article ID 132041. DOI:10.1155/2009/132041.

107. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab. 2009; 94:1881-2. [PubMed 19401361]

108. De Groot L, Abalovich M, Alexander EK et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; 97:2543-65. [PubMed 22869843]

109. Actavis Elizabeth LLC. Propylthiouracil tablets prescribing information. Elizabeth, NJ; 2012 Jul.

110. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001; 108:776-89. [IDIS 468574] [PubMed 11533352]

112. Food and Drug Administration. FDA drug safety communication: New boxed warning on severe liver injury with propylthiouracil. Rockville, MD; 2010 Apr 21. Available from FDA website (). Accessed 2010 Sep 8.

117. Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab. 2010; 95:3260-7. [PubMed 20427502]

118. Bahn Chair RS, Burch HB, Cooper DS et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011; 21:593-646. [PubMed 21510801]

119. Stagnaro-Green A, Abalovich M, Alexander E et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011; 21:1081-125. [PubMed 21787128]

120. Methimazole. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:920-5.

121. American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists, number 37, August 2002: Thyroid disease in pregnancy. Obstet Gynecol. 2002; 100:387-96. [PubMed 12166417]

122. . Drugs for thyroid disorders. Treat Guidel Med Lett. 2009; 7:57-64; quiz 2p following 64. [PubMed 19636287]

123. Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet. 2012; 379:1155-66. [PubMed 22394559]

124. Cooper DS. Antithyroid drugs. N Engl J Med. 2005; 352:905-17. [PubMed 15745981]

125. Abraham P, Avenell A, McGeoch SC et al. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev. 2010; :CD003420. [PubMed 20091544]

126. Mutharasan P, Oatis W, Kwaan H et al. Delayed anithyroid drug-induced agranulocytosis. Endocr Pract. 2012 Jul-Aug; 18:e69-72.

127. Yang J, Zhong J, Zhou LZ et al. Sudden onset agranulocytosis and hepatotoxicity after taking methimazole. Intern Med. 2012; 51:2189-92. [PubMed 22892501]

128. Takata K, Kubota S, Fukata S et al. Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid. 2009; 19:559-63. [PubMed 19445623]

129. Walter MA, Briel M, Christ-Crain M et al. Effects of antithyroid drugs on radioiodine treatment: systematic review and meta-analysis of randomised controlled trials. BMJ. 2007; 334:514. [PubMed 17309884]

130. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011; 364:542-50. [PubMed 21306240]

131. Seigel SC, Hodak SP. Thyrotoxicosis. Med Clin North Am. 2012; 96:175-201. [PubMed 22443970]

b. AHFS drug information 2014. McEvoy GK, ed. Methimazole. Bethesda, MD: American Society of Health-System Pharmacists; 2014.

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