Antithyroid Agents (Systemic)

This monograph includes information on the following:

1) Methimazole
2) Propylthiouracil


INN:
Methimazole— Thiamazole

VA CLASSIFICATION
Primary: HS852

Commonly used brand name(s): Propyl-Thyracil2; Tapazole1.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihyperthyroid agent—

Indications

Accepted

Hyperthyroidism (treatment)—Methimazole and propylthiouracil are indicated in the treatment of hyperthyroidism, including prior to surgery or radiotherapy, and as adjuncts in the treatment of thyrotoxicosis or thyroid storm {52}8 {52}7 {52}6 {52}5 {52}4 {52}3 {52}2 {52}1 {52}0 {53}9 {53}8 {53}7 {53}6 {53}5 {53}4 {53}3 {53}2 {53}1 {53}0 {74}9 {74}8 {74}7 {74}6 {74}5. Propylthiouracil may be preferred over methimazole for use in thyroid storm, since propylthiouracil inhibits peripheral conversion of thyroxine [T 4] to triiodothyronine [T 3] {74}4 {74}3 {74}2 {74}1 {74}0 {147}9 {147}8 {147}7 {147}6 {147}5 {147}4 {147}3 {147}2 {147}1 {147}0.

—Further studies are needed to establish the safety and efficacy of using propylthiouracil for the treatment of alcoholic liver disease {05}9 {05}8 {05}7 {05}6 {05}5.

Unaccepted
Efficacy of antithyroid medications has been inconsistent in the treatment of angina pectoris. These agents are probably useful for this purpose only in hyperthyroid patients with angina pectoris {05}4.

Antithyroid medications are not effective in the treatment of thyrotoxicosis resulting from exogenous thyroid hormone overdosage {05}3 {05}2 {05}1 {05}0 {20}9 {20}8 {20}7.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Methimazole and propylthiouracil are thioamide derivatives {20}6.
Molecular weight—
    Methimazole: 114.16 {20}5
    Propylthiouracil: 170.23 {20}4

pKa—
    Propylthiouracil: 7.8 {20}3 {20}2

Mechanism of action/Effect:

Inhibit synthesis of thyroid hormone within the thyroid gland by serving as substrates for thyroid peroxidase, which catalyzes the incorporation of oxidized iodide into tyrosine residues in thyroglobulin molecules and couples iodotyrosines {20}1 {20}0 {27}9 {27}8 {27}7 {27}6 {27}5 {27}4 {27}3 {27}2 {27}1. This diverts iodine from the synthesis of thyroid hormones {27}0 {47}9 {47}8 {47}7 {47}6 {47}5 {47}4. Antithyroid agents do not interfere with the actions of exogenous thyroid hormone or inhibit the release of thyroid hormones {47}3 {47}2 {47}1 {47}0. Therefore, stores of thyroid hormones must be depleted before clinical effects will be apparent {49}9 {49}8. Antithyroid agents may also have moderating effects on the underlying immunologic abnormalities in hyperthyroidism due to Graves' disease (toxic diffuse goiter), but evidence on this point reported to date is inconclusive {49}7 {49}6 {49}5 {49}4 {49}3 {49}2 {49}1 {49}0 {50}9.


Propylthiouracil:

Additionally, inhibits peripheral conversion of T 4 to T 3, which may theoretically make it more effective in the treatment of thyroid storm {50}8 {50}7 {50}6 {50}5 {50}4 {50}3 {50}2 {50}1 {50}0 {55}9 {55}8 {55}7 {55}6 {55}5 {55}4 {55}3 {55}2 {55}1 {55}0 {64}9 {64}8.


Absorption:

Rapid {64}7 {64}6 {64}5 {64}4 {64}3 {64}2 {64}1 {64}0 {68}9 {68}8 {68}7 {68}6 {68}5 {68}4 {68}3.


Methimazole:

Oral: Bioavailability 93% {68}2 {68}1. Absorption may be unpredictably affected by food {68}0.

Rectal: In one study in healthy subjects, absorption of extemporaneously compounded 60-mg rectal suppositories was similar to that of oral tablets {110}9.



Propylthiouracil:

Oral: Bioavailability 65 to 75% {110}8 {110}7 {110}6 {110}5.

Rectal: In one study in healthy subjects, absorption of extemporaneously compounded 100-mg rectal suppositories was slower and less extensive than that of oral tablets (AUC 0 to 8h: 23.77 ± 1.24 mcgohr/mL [oral], 6.16 ± 2.07 mcgohr/mL [rectal]) {110}4.


Distribution:

Both methimazole and propylthiouracil are actively concentrated by the thyroid {110}3 {110}2 {110}1 {110}0 {113}9 {113}8 {113}7 {113}6 {113}5 {113}4.

Methimazole—Volume of distribution is approximately 0.6 liter per kilogram (L/kg) of body weight {113}3.

Propylthiouracil—Volume of distribution is approximately 0.4 L/kg of body weight {113}2 {113}1.

Protein binding:

Methimazole—Not significant {113}0 {127}9 {127}8 {127}7 {127}6 {127}5.

Propylthiouracil—High (80%), primarily to albumin {127}4 {127}3 {127}2 {127}1 {127}0 {133}9 {133}8 {133}7 {133}6.

Biotransformation:

Primarily hepatic {133}5 {133}4 {133}3 {133}2 {133}1; active metabolites of either compound have not been demonstrated {133}0 {135}9.

Propylthiouracil—Primarily undergoes glucuronidation {135}8 {135}7. Approximately 33% of an orally administered dose is metabolized by a first-pass effect {135}6.

Half-life:

Methimazole—5 to 6 hours {135}5 {135}4 {135}3 {135}2 {135}1 {135}0 {160}9 {160}8 {160}7.

Propylthiouracil—1 to 2 hours {160}6 {160}5 {160}4 {160}3 {160}2 {160}1 {160}0 {29}9 {29}8 {29}7 {29}6 {29}5 {29}4 {29}3.

Onset of action:

Methimazole—In one study, substantial reductions in mean serum thyroxine and triiodothyronine concentrations were seen after 5 days of methimazole therapy at 40 mg per day. {29}2 {29}1

Time to peak serum concentration


Methimazole:


Oral/Rectal—

Approximately 30 to 60 minutes (occurrence of peak blood concentrations, after administration of a 60-mg rectal suppository or a 60-mg oral dose to healthy subjects) {29}0.




Propylthiouracil:


Oral—

1.99 ± 0.26 hours (after administration of a 100-mg dose to healthy subjects) {52}9.



Rectal—

Solution—Approximately 3 hours (after administration of a 400-mg rectal dose of propylthiouracil in an aqueous solution of sodium phosphates to a patient with thyroid storm) {52}8.

Suppository—4.72 ± 0.96 hours (after administration of a 100-mg suppository to healthy subjects) {52}7.



Peak serum concentration:


Methimazole:


Oral—

1.184 ± 0.12 mcg/mL (blood concentrations, after administration of a 60-mg dose to healthy subjects) {52}6.



Rectal—

1.163 ± 0.15 mcg/mL (blood concentrations, after administration of a 60-mg suppository to healthy subjects) {52}5.




Propylthiouracil:


Oral—

7.12 ± 0.48 mcg/mL (after administration of a 100-mg dose to healthy subjects) {52}4.



Rectal—

Solution—3.1 mcg/mL (approximate, after administration of a 400-mg rectal dose of propylthiouracil in an aqueous solution of sodium phosphates to a patient with thyroid storm) {52}3.

Suppository—1.2 ± 0.31 mcg/mL (after administration of a 100-mg rectal suppository to healthy subjects) {52}2.



Time to peak effect:

Methimazole—7 weeks (average) to normalize serum T 3 and T 4 concentrations with use of 30 mg per day {52}1. In one study, 4 weeks (approximate) to normalize serum T 3 and T 4 concentrations with use of 40 mg per day {52}0 {71}9.

Propylthiouracil—17 weeks (average) to normalize serum T 3 and T 4 concentrations with use of 300 mg per day {71}8 {71}7.

Elimination:


Methimazole—
        Less than 10% is excreted in the urine unchanged {71}6 {71}5 {71}4 {71}3. Total body clearance is approximately 10 L per hour {71}2.



Propylthiouracil—
        Less than 1% is excreted in the urine unchanged {71}1 {71}0 {79}9 {79}8 {79}7. Total body clearance is approximately 7 L per hour {79}6.
        In dialysis: Elimination and pharmacokinetics are not significantly altered in hemodialysis {79}5. In one patient undergoing hemodialysis, 5% of a 200-mg oral dose was removed by 3 hours of hemodialysis {79}4; elimination rate was not significantly altered {79}3. Peak serum concentration was decreased (from 7.9 to 4.9 mcg/mL), although it remained within an approximate therapeutic range {79}2.



Precautions to Consider

Cross-sensitivity and/or related problems

Cross-sensitivity may occur frequently (in about 50% of patients) between antithyroid thioamide medications {79}1 {79}0 {87}9 {87}8 {87}7 {87}6 {87}5 {87}4.

If a persistent or severe reaction necessitates withdrawal of one agent, therapy may be switched to the other, although there is a risk of cross-reactivity occurring {87}3 {87}2 {87}1 {87}0 {110}9 {110}8 {110}7 {110}6 {110}5 {110}4. However, if agranulocytosis, thrombocytopenia, or hepatic dysfunction occurs, substitution with another thioamide is not recommended {110}3 {110}2 {110}1 {110}0 {05}9 {05}8 {05}7 {05}6 {05}5 {05}4.

Carcinogenicity/Mutagenicity

Methimazole—In a two-year study, thyroid hyperplasia, adenoma, and carcinoma have developed in rats when given methimazole at doses of 3 and 18 mg per kg of body weight per day (mg/kg/day) (2 and 12 times the 15 mg/day maximum human maintenance dose calculated on the basis of surface area){05}3.

Propylthiouracil—Thyroid hyperplasia and carcinoma have occurred in laboratory animals treated with propylthiouracil for longer than 1 year {05}2. Similar effects are seen with continuous thyroid suppression with various antithyroid agents, dietary iodine deficiency, subtotal thyroidectomy, and ectopic thyrotropin-secreting pituitary tumors {05}1. Pituitary adenomas have also occurred {05}0.

Pregnancy/Reproduction

Pregnancy—
Methimazole and propylthiouracil cross the placenta and can cause fetal hypothyroidism and goiter {06}9 {06}8 {06}7 {06}6 {06}5 {06}4 {06}3 {06}2 {06}1 {06}0 {12}9 {12}8 {12}7 {12}6 {12}5 {12}4 {12}3 {12}2 {12}1 {12}0. However, the possible risks of adverse effects due to antithyroid agents must be weighed against the risks of possible adverse effects due to continuing hyperthyroidism during pregnancy {13}9 {13}8 {13}7 {13}6 {13}5 {13}4 {13}3 {13}2 {13}1 {13}0 {18}9 {18}8. Propylthiouracil is considered by some clinicians as the agent of choice for women who require antithyroid medications during pregnancy {18}7 {18}6 {18}5 {18}4 {18}3 {18}2 {18}1 {18}0 {64}9 {64}8 {64}7 {64}6 {64}5 {64}4 {64}3 {64}2 {64}1 {64}0 {77}9 {77}8 {77}7. Propylthiouracil crosses the placenta less readily than methimazole {77}6 {77}5 {77}4 {77}3 {77}2 {77}1 {77}0 {78}9 {78}8 {78}7 {78}6 {78}5 {78}4 {78}3 {78}2 {78}1 {78}0 {96}9 {96}8 {96}7 {96}6, and the use of methimazole during pregnancy has been associated with several cases of scalp defects (aplasia cutis) in the infant {96}5 {96}4 {96}3 {96}2 {96}1 {96}0 {64}9 {64}8 {64}7 {64}6 {64}5 {64}4 {64}3. Rare instances of congenital defects including esophageal atresia with tracheoesophageal fistula and choanal atresia with absent/hypoplastic nipples have occurred in infants whose mothers were treated with methimazole during pregnancy.{64}2 The reduced placental transfer of propylthiouracil is presumably due to its high level of serum protein binding and high level of ionization at a pH of 7.4 {64}1 {64}0 {81}9 {81}8 {81}7 {81}6 {81}5 {81}4 {81}3.

The actual risk of fetal death, goiter, hypothyroidism, or certain congenital abnormalities with administration of antithyroid agents appears to be low, especially if maternal doses are low (for example, less than 100 to 150 mg of propylthiouracil or an equivalent dose of methimazole per day) {81}2 {81}1 {81}0 {64}9 {64}8 {64}7 {64}6 {64}5 {64}4 {64}3 {64}2 {64}1 {64}0 {172}9 {172}8 {172}7. Fetal goiters induced by antithyroid agents are generally not as large as iodide-induced fetal goiters and have not usually been reported to be obstructive {172}6 {172}5 {172}4 {172}3. Fetal hypothyroidism and goiter usually occur when the antithyroid agents are used close to term, since the fetal thyroid does not begin to produce thyroid hormones until the 11th or 12th week of gestation {172}2 {172}1 {172}0. In long-term follow-up of some children exposed in utero to maternal therapeutic doses of propylthiouracil, gross abnormalities in development or diminished intellectual performance have not been observed {172}9 {172}8 {172}7 {172}6 {172}5 {172}4.

It is recommended that antithyroid medication be prescribed at the lowest effective dose to maintain maternal thyroid function within the upper-normal range for normal pregnant women, especially during the last trimester, to reduce the risk of fetal and maternal hypothyroidism and goiter {172}3 {172}2 {172}1 {172}0 {172}9 {172}8 {172}7 {172}6 {172}5. Thyroid hyperfunction may diminish as pregnancy progresses, allowing a reduction in antithyroid dosage and, in some cases, withdrawal of antithyroid therapy 2 to 3 months before delivery {172}4 {172}3 {172}2 {172}1 {172}0 {172}9 {172}8 {172}7 {172}6. However, thyroid function may vary and dosing should be based on frequent and careful monitoring {172}5 {172}4 {172}3 {172}2 {172}1 {172}0. Hyperthyroidism may recur soon after delivery {159}9 {159}8 {159}7 {159}6 {159}5 {159}4. Because radioactive iodine is absolutely contraindicated during pregnancy, thyroidectomy may be very rarely required in refractory cases of hyperthyroidism or in patients who are noncompliant with the use of antithyroid medications {159}3 {159}2 {159}1 {159}0 {170}9 {170}8 {170}7 {170}6 {170}5 {170}4 {170}3 {170}2 {170}1.

Thyroid hormones are minimally transferred across the placenta and therefore have little protective effect on the fetus {170}0 {159}9 {159}8 {159}7 {159}6 {159}5 {159}4 {159}3 {159}2 {159}1 {159}0 {172}9. They may also mask signs of remission of hyperthyroidism, resulting in fetal and maternal exposure to unnecessarily high doses of antithyroid agents {172}8 {172}7 {172}6 {172}5 {172}4 {172}3 {172}2 {172}1 {172}0 {159}9 {159}8 {159}7. For these reasons, adjunctive treatment with thyroid hormones is not recommended during pregnancy {159}6 {159}5 {159}4 {159}3 {159}2 {159}1 {159}0 {172}9 {172}8 {172}7 {172}6.

Several case reports have been published in which antithyroid agents were given to a euthyroid mother of a hyperthyroid fetus {172}5 {172}4 {172}3 {172}2. Fetal heart rate monitoring and ultrasound examinations were used to monitor fetal response {172}1 {172}0 {172}9. Fetal tachycardia was reduced and the infants were euthyroid at delivery {172}8 {172}7 {172}6. However, further data are needed regarding this form of therapy for fetal hyperthyroidism {172}5 {172}4.

FDA Pregnancy Category D {172}3 {172}2 {172}1 {172}0.

Breast-feeding

Small amounts of methimazole and propylthiouracil are distributed into breast milk{172}9{172}8{172}7{172}6{172}5{172}4{172}3{172}2{172}1{172}0{172}9{172}8{172}7{172}6{172}5. Maternal serum and breast milk concentrations of methimazole are nearly equal{172}4{172}3{172}2{172}1{172}0{172}9{172}8{172}7{172}6. Methimazole is contraindicated in nursing mothers. Postpartum patients should not breast feed their infants while receiving methimazole.{172}5 Propylthiouracil is generally preferred over methimazole during lactation because methimazole is distributed into breast milk more readily (approximately ten-fold), presumably due to its insignificant level of protein binding and ionization{172}4{172}3{172}2{172}1{172}0{158}9{158}8{158}7{158}6{158}5{158}4{158}3{158}2{158}1{158}0{158}9{158}8{158}7{158}6. Serial monitoring of thyroid function (by measurement of serum thyrotropin and thyroxine concentrations) of the infant is advisable.{158}5{158}4{158}3{158}2{158}1{158}0{162}9{162}8{162}7 However, some clinicians feel that small doses of methimazole (e.g., £ 10–15 mg per day) do not pose a significant risk to the infant if thyroid function is monitored frequently {162}6 {162}5 {162}4 {162}3 {162}2 {162}1.

There is a theoretical risk of causing hypothyroidism and/or agranulocytosis in the infant with high maternal doses of antithyroid agents {162}0 {172}9 {172}8 {172}7 {172}6 {172}5 {172}4 {172}3 {172}2 {172}1 {172}0. Termination of breast-feeding may be necessary prior to initiation of high-dose therapy {158}9 {158}8 {158}7 {158}6 {158}5.

Pediatrics

Antithyroid agents are frequently used to treat hyperthyroidism in children {158}4 {158}3 {158}2 {158}1 {158}0 {162}9 {162}8. Children seem to respond to antithyroid agents as well as do adults {162}7 {162}6 {162}5 {162}4. Pharmacokinetic studies conducted in children also did not reveal any differences unique to the pediatric population {162}3 {162}2 {162}1.

Caution is necessary in interpreting results of thyroid function tests in neonates, because serum concentrations of thyroid hormones are higher at birth than those of healthy children or adults and begin to fall to normal in the first week of life.



Adolescents

Antithyroid agents are frequently used to treat hyperthyroidism in adolescents {162}0 {172}9 {172}8 {172}7 {172}6 {172}5. Adolescents seem to respond to antithyroid agents as well as do adults {172}4 {172}3 {172}2. Pharmacokinetic studies conducted in adolescents did not reveal any differences unique to the adolescent population {172}1 {172}0.


Geriatrics


One study showed that agranulocytosis is more likely to occur in patients older than 40 years of age or in patients taking more than 40 mg of methimazole per day {14} {17} {29} {63} {132} {140} {147} {152}.

In one pharmacokinetic study, no significant differences were found for geriatric patients in certain pharmacokinetic parameters (e.g., Vd, Vd beta, Vd at steady state, area under the curve, and clearance) {140} {152}. Rate of absorption was decreased (approximately one-third that of younger subjects) though there are no data regarding the clinical significance of this finding {75} {140} {152}.

Geriatric patients with severe cardiac disease should be given antithyroid agents and/or beta-adrenergic blocking agents, such as propranolol, for 4 to 6 weeks prior to treatment with radioiodine to help reduce possible exacerbation of heart disease by radiation-induced thyroiditis {29} {49} {57} {58} {59} {60} {61} {62} {74} {152}. Antithyroid drugs must be discontinued at least 3 to 4 days prior to radioiodine treatment and should not be readministered until 1 week after treatment {57} {58} {59} {60} {61} {62} {152}. However, a beta-adrenergic blocking agent may be used throughout the treatment period if needed {57} {58} {59} {60} {61} {62} {152}.


Dental

The bone marrow depressant effects of antithyroid agents may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication {164}.

Aminophylline {130} {152} or
Oxtriphylline {130} {152} or
Theophylline {130} {152}    (hyperthyroid patients have exhibited increased metabolic clearance of aminophylline and theophylline, which returned to normal as the patients became euthyroid {130} {152}; decreased dose of aminophylline, oxtriphylline, or theophylline may be necessary as patients become euthyroid {130} {152})


» Amiodarone {153} {172} or
» Iodinated glycerol {147} {148} {152} or
» Iodine {140} {147} {148} {152} or
» Potassium iodide {106} {147} {148} {152}    (iodide or iodine excess may decrease response to antithyroid agents, requiring an increase in dosage or longer duration of therapy with antithyroid agents {140} {147} {148} {152} {153}; amiodarone contains 37% iodine by weight, and therefore its use significantly increases iodine intake {153}; iodine deficiency may increase response to antithyroid agents, requiring a decrease in dosage or shorter duration of therapy with antithyroid agents {140} {147} {148} {152})


» Anticoagulants, coumarin- or indandione-derivative {63} {64} {106} {130} {131} {152}    (as thyroid and metabolic status of patient decreases toward normal, response to oral anticoagulants may decrease {130} {131} {152}; however, if thioamide-induced hypoprothrombinemia occurs, anticoagulant effect may be enhanced {63} {130} {152}; adjustment of oral anticoagulant dosage on the basis of prothrombin time is recommended {106} {130} {131} {152})


» Beta-adrenergic blocking agents    (hyperthyroidism causes an increased clearance of beta blockers with a high extraction ratio; dose reduction may be necessary when patient becomes euthyroid. )

{174}
» Digitalis glycosides {130} {147} {152}    (serum concentrations of digoxin and digitoxin have been reported to increase as the thyroid and metabolic status of patients taking antithyroid agents decreased {130} {147} {152}; reduction in dosage of any digitalis glycoside may be necessary as patients become euthyroid {130} {147} {152})


» Sodium iodide I 131 {49} {74} {106} {152}    (antithyroid agents may decrease thyroidal uptake of I 131 {74} {106} {152}; a rebound increase in uptake may occur up to 5 days after sudden withdrawal of the antithyroid agent {113} {114} {152})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results {07}
» Sodium iodide I 123 {106} {152} or
» Sodium iodide I 131 {49} {74} {152} or
» Sodium pertechnetate Tc 99m {112} {140} {152}    (antithyroid agents may decrease thyroidal uptake of I 123, I 131, or pertechnetate {74} {112} {140}; withdrawal of the antithyroid agent 5 days or more before radioactive iodine uptake tests is necessary to prevent interference {113} {114})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum concentrations {70} {128} {160} and
Alkaline phosphatase, serum concentrations {69} {70} {128} {160} and
Aspartate aminotransferase (AST [SGOT]), serum concentrations {69} {70} {128} {135} {160} and
Bilirubin, serum concentrations {69} {128} {135} {160} and
Lactate dehydrogenase (LDH), serum concentrations {70} {128} {160} and
Prothrombin time (PT) {63} {69} {135} {160}    (may be increased {69} {70} {128}; may indicate hepatotoxicity and be associated with splenomegaly {06} {64} {69} {128} {160})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Severe adverse reaction or severe allergic reaction to either methimazole or propylthiouracil, or history of {06} {29} {63} {64} {137} {152} {162} {165}
Risk-benefit should be considered when the following medical problem exists
» Hepatic function impairment {04} {52} {88} {128} {140} {142} {150} {152}    (elimination half-life may be prolonged, in proportion to the degree of hepatic insufficiency {04} {52} {88} {140} {142} {150} {152})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Leukocyte count, total and differential {12} {18} {44} {63} {64} {81} {86} {102} {110} {140} {168}    (determinations recommended prior to initiation of treatment and if infection occurs {44} {102} {110})


Prothrombin time (PT){174}    (should be monitored during treatment with methimazole, especially before surgical procedures{174})


» Free thyroxine (T 4), by direct assay {29} {31} {68} {111} {134} {156} {162} {169} {172} and/or
» Thyrotropin (TSH) by sensitive radioimmunoassay {09} {29} {51} {64} {68} {111} {132} {133} {137} {156} {165} {169} {172} and/or
Total thyroxine (T 4), either by competitive protein-binding assay or by radioimmunoassay {29} {31} {51} {66} {67} {71} {111} {132} {133} {137} {147} {172} and/or
Total triiodothyronine (T 3) by radioimmunoassay {31} {51} {66} {67} {68} {71} {84} {111} {133} {134} {172}    (determination of serum concentrations is recommended prior to initiation of therapy, at monthly intervals during initial therapy, then every 2 to 3 months {29} {51} {68} {70} {133} {137} {172}; some clinicians recommend at least yearly follow-up for life in patients successfully treated with antithyroid medications {26} {29} {49} {51} {52} {126} {137} {147} {165} {171} {172}; in patients treated with these agents who do not undergo thyroid ablation with sodium iodide I 131 or surgery, the risk of subsequent hypothyroidism is related to immunogenic thyroid disease itself, and not the medication {165} {171} {172}; recurrence of hyperthyroidism is common {165} {169} {171} {172})




Side/Adverse Effects

Note: Incidence of most adverse reactions is dose-related {13} {14} {29} {52} {68} {75} {81} {113} {132} {134} {140} {148}; most side effects occur within the first 4 to 8 weeks {17} {52} {137}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Fever, mild and transient {17}{52}{53}{63}{64}{126}{147}{160}
    
leukopenia (continuing or severe fever or chills, throat infection, cough, mouth sores, or hoarseness)—usually asymptomatic{13}{21}{23}{29}{52}{54}{63}{64}{140}{143}
    
skin rash or itching {12}{13}{14}{17}{19}{21}{27}{29}{43}{50}{52}{53}{54}{63}{64}{66}{68}{70}{81}{85}{86}{104}{126}{127}{132}{134}{137}{140}{143}{147}{160}

Note: Mild leukopenias occur more frequently in patients (12% of adults and 25% of children) treated with antithyroid agents {29} {52}. Also, approximately 10% of untreated hyperthyroid patients have leukocyte levels below 4000 per cubic millimeter {63} {64}.
Incidence of skin rash or itching is 3 to 5% {14} {22} {29} {48} {53}. Usually consists of maculopapular eruptions {22} {126} {140}. An allergic reaction occurs less frequently and may disappear spontaneously with continued treatment {19} {52}; appears to be dose-related. Skin rash may also be a sign of vasculitis {13} {20} {27} {29} {117} {140}.


Incidence less frequent
    
Agranulocytosis {13}{14}{15}{17}{18}{21}{23}{24}{29}{44}{52}{53}{54}{63}{64}{68}{70}{81}{102}{126}{127}{128}{134}{137}{140}{147}{160}(continuing or severe fever or chills, throat infection, cough, mouth sores, or hoarseness){14}{15}{17}{18}{21}{23}{29}{44}{52}{63}{64}{147}{160}
    
arthralgias{13}{20}{27}{29}{50}{52}{53}{54}{63}{64}{68}{81}{126}{132}{137}{140}{147}{160} or arthritis{13}{20}{29}{52}{133}{137}{140} or vasculitis (pain, swelling, or redness in joints){03}—usually with propylthiouracil{13}{20}{27}{29}{52}{53}{110}{137}{147}{160}
    
lupus-like syndrome {13}{20}{29}{52}{53}{63}{64}{137}{147}{160}(fever or chills; general feeling of discomfort or illness or weakness)—usually with propylthiouracil{20}{160}
    
peripheral neuropathy (numbness or tingling of fingers, toes, or face){63}{64}

Note: Agranulocytosis (incidence 0.4%) usually occurs during the first 3 months of therapy {18} {23} {29} {52} {53} {70} {126} {127} {132} {147} {160} {162} {168}. May occur less predictably and with lower doses of propylthiouracil {29} {52} {53} {68} {126} {147}. Deaths due to agranulocytosis have been reported {52} {147}.


Incidence rare
    
Aplastic anemia (continuing or severe fever or chills, throat infection, cough, mouth sores, or hoarseness){13}{23}{29}{52}{63}{64}{126}{137}{140}
    
hypoprothrombinemia (for propylthiouracil) {29}{52}{63}{64}{126}{130}
or thrombocytopenia{06}{29}{52}{63}{64}{140}{143} (rarely, increase in bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
    
cholestatic jaundice (yellow eyes or skin){69}{135}—for methimazole{12}{16}{17}{29}{52}{53}{54}{63}{113}{128}{132}{140}{147}{160}
    
hepatic necrosis (yellow eyes or skin){69}{135}—primarily with propylthiouracil{12}{16}{17}{29}{50}{52}{53}{54}{64}{68}{69}{100}{113}{128}{132}{135}{140}{147}{160}{162}
    
interstitial pneumonitis (cough or shortness of breath)—with propylthiouracil{11}{13}{20}{64}
    
lymphadenopathy (swollen lymph nodes){63}{64}{69}{127}{140}
    
sialadenopathy (swollen salivary glands){63}{64}
    
nephritis (for methimazole){13}{29}{52}{63}{64}{102} or renal vasculitis (usually with propylthiouracil) {113}{140}(backache; increase or decrease in urination; swelling of feet or lower legs)

Note: Jaundice may persist for up to 10 weeks after drug discontinuance {160}. Fatal hepatic necrosis has been reported with both agents {29} {52} {53} {64} {69} {128} {135} {160} {162}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Dizziness {63}{64}
    
loss of taste —for methimazole{29}{52}{63}{64}
    
nausea or vomiting {54}{63}{64}{126}{132}{147}
    
stomach pain {54}{63}{64}{68}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose (hypothyroidism)
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Changes in menstrual periods
    
coldness
    
constipation
    
dry, puffy skin
    
goiter (swelling in the front of the neck){162}
    
headache {63}{64}
    
listlessness or sleepiness {64}
    
muscle aches
    
nausea or vomiting, severe {63}{64}
    
unusual tiredness or weakness
    
weight gain, unusual {63}

Note: Hypothyroidism may be an unavoidable long-term sequela to hyperthyroidism {26} {28} {29} {67} {70} {85} {105} {147} {148}.




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antithyroid Agents (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergies to any thioamide

Pregnancy—May be used but careful monitoring is necessary





Breast-feeding—Distributed into breast milk, although propylthiouracil is distributed in much lesser amounts; may continue breast-feeding with low doses and monitoring of infant
Other medications, especially iodides, coumarin- or indandione-derivative anticoagulants, amiodarone, beta-adrenergic blocking agents, digitalis glycosides, or radioiodide
Other medical problems, especially hepatic function impairment

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Importance of not missing doses and, if taking more than one dose per day, of taking at evenly spaced intervals

Taking methimazole at same time in relation to meals every day

» Proper dosing
Missed dose: Taking as soon as possible; taking both doses together if almost time for next dose; checking with physician if more than one dose is missed

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Checking with physician before discontinuing medication

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required, because of the risk of thyroid storm

» Checking with physician immediately if injury, infection, or other illness occurs, because of the risk of thyroid storm

Caution if any laboratory tests required; possible interference with test results


Side/adverse effects
Signs of potential side effects, especially fever, skin rash or itching, bone marrow depression, hepatic dysfunction, lupus-like syndrome, arthralgias, arthritis, nephritis (for methimazole), vasculitis, pneumonitis, lymphadenopathy, sialadenopathy, hypoprothrombinemia (for propylthiouracil), or peripheral neuropathy


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and results of thyroid function tests {51} {52}.

In some patients, once- or twice-a-day therapy may be associated with a decreased incidence of side effects and improved compliance, although divided daily doses may be more effective {29} {79} {81} {86} {113} {115} {133} {138} {140} {147} {148}. If divided daily doses are given, they should be administered at evenly spaced intervals throughout the day {29} {47} {63} {64} {68} {133} {139} {147}. Methimazole has a longer duration of action and therefore may frequently be more effective than propylthiouracil in once-daily dosing {29} {47} {50} {52} {53} {75} {114} {116} {118} {138} {140} {152} {162}.

Confirmation of remission may be by sensitive TSH assay, trial withdrawal of the medication, protirelin test, thyroid suppression test, or thyroid-stimulating immunogloglubin (TSI) titer {06} {09} {29} {51} {68} {111} {115} {121} {132} {133} {134} {137} {162}.

Duration of treatment necessary to produce a prolonged remission varies from 6 months to several years, with an average duration of 1 to 2 years {05} {29} {44} {51} {52} {66} {68} {70} {73} {75} {79} {81} {86} {111} {113} {115} {126} {132} {133} {137} {140} {147} {148} {169} {171}. Control of hyperthyroidism with medication is sometimes followed by a spontaneous remission {51} {52} {53} {63} {64} {66} {67} {68} {70} {73} {119} {120} {126} {132} {133} {134} {137} {140} {147} {148} {160} {169} {171}. Premature withdrawal may result in exacerbation of hyperthyroidism, although some clinicians feel that treatment may be withdrawn as soon as a euthyroid state is obtained (usually within 4 to 5 months), with no problems of rebound {70}.

Iodide is usually added to thioamide antithyroid therapy for 7 to 10 days prior to surgery to reduce the vascularity of the thyroid gland, thereby decreasing subsequent blood loss during surgery {13} {29} {49} {51} {110} {126} {147}.

If an antithyroid agent is being used in severely hyperthyroid patients to improve their thyroid state prior to radioactive iodine therapy, the antithyroid medication must be discontinued 2 to 4 days before treatment to prevent impairment of radioactive iodine uptake {74} {106} {113} {114}. Antithyroid treatment may be resumed, if desired, 3 to 7 days after radioactive iodine treatment to hasten return to euthyroidism, until effects of the iodine are apparent {05} {51} {74} {114}.

Diet/Nutrition
Food may inconsistently alter the bioavailability of methimazole {04} {75}. It is recommended that methimazole be taken at the same time in relation to meals every day.

For treatment of adverse effects
Reduction in dosage or temporary withdrawal of antithyroid medication may be recommended if signs and symptoms of hypothyroidism occur {29} {44} {114}. Some clinicians recommend adjunctive thyroid therapy (except during pregnancy) to prevent development of hypothyroidism {51} {52} {66} {68} {70} {81} {121} {126} {132} {140}. However, hypothyroidism may be an unavoidable long-term sequela to hyperthyroidism {26} {28} {29} {67} {70} {85} {105} {147} {148} {171}.

It is recommended that antithyroid therapy be discontinued promptly and supportive measures initiated if signs and symptoms of agranulocytosis, aplastic anemia, hepatic dysfunction, lupus-like syndrome, severe skin rash, swelling of cervical lymph nodes, or vasculitis occur {29} {52} {63} {64} {69} {70} {128}. If laboratory examinations show only a mild leukopenia, periodic blood count monitoring without withdrawal or reduction in dosage may be sufficient {29} {52}. Mild reactions may not require withdrawal, although they may precede more serious reactions {29} {86}. Leukocyte production usually returns to normal within 1 to 2 weeks after withdrawal {86}.

METHIMAZOLE

Summary of Differences
General dosing information: May be more suitable for once-daily administration.


Oral Dosage Forms

METHIMAZOLE TABLETS USP

Usual adult and adolescent {08} dose
Hyperthyroidism


Initial:
Mild hyperthyroidism—Oral, 15 mg a day as three equal divided daily doses{05}{06}{14}{25}{51}{53}{63}{79}{105}{138}{147}{174}.

Moderately severe hyperthyroidism—Oral, 30 to 40 mg a day as three equal divided daily doses{05}{06}{24}{25}{26}{29}{49}{63}{66}{67}{68}{75}{105}{132}{133}{138}{147}{160}{174}.

Severe hyperthyroidism—Oral, 60 mg a day as three equal divided daily doses{05}{06}{21}{29}{50}{52}{54}{63}{75}{105}{138}{147}{174}.



Maintenance:
Oral, 5 to 15 mg a day as three equal divided daily doses {50}{63}{66}{68}{133}{134}{174}.



Thyrotoxic crisis:
Oral, 15 to 20 mg every four hours during the first day, as an adjunct to other measures {71} {79} {87} {105}.



Usual pediatric dose
Hyperthyroidism
Initial: Oral, 0.4 mg per kg of body weight a day as three equal divided daily doses{05}{06}{46}{63}{78}{174}.

Maintenance: Oral, 0.2 mg per kg of body weight a day as three equal divided daily doses{05}{06}{63}{174}.


Strength(s) usually available
U.S.—


5 mg (Rx) [Tapazole (scored) (lactose )]{63}


10 mg (Rx) [Tapazole (scored) (lactose )]{63}

Canada—


5 mg (Rx) [Tapazole (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • Take at the same time in relation to meals every day.



Rectal Dosage Forms

METHIMAZOLE SUPPOSITORIES

Usual adult and adolescent dose
Hyperthyroidism
Initial: Thyrotoxic crisis—Rectal, 15 to 20 mg every four hours during the first day, as an adjunct to other measures, with the dosage being adjusted according to patient response {71} {79} {87} {105} {162} {163} {172}.


Usual pediatric dose
Hyperthyroidism
Initial: Thyrotoxic crisis—Rectal, 400 mcg (0.4 mg) per kg of body weight a day as one daily dose or as two divided daily doses {05} {06} {46} {63} {78} {162} {163} {172}.


Strength(s) usually available
U.S.—
Not commercially available. Compounding required for prescription.

Canada—
Not commercially available. Compounding required for prescription.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Store in a well-closed container. Protect from freezing.

Preparation of dosage form:
A formulation that has been used for the extemporaneous compounding of methimazole suppositories is as follows: {149} {162} {163}

   • 1200 mg methimazole dissolved in 12 mL of distilled water
   • 2 drops of Span 80
   • Cocoa butter (warmed to 37 °C [98.6 °F]) of sufficient quantity to make 20 suppositories containing 60 mg methimazole each.

Auxiliary labeling:
   • Refrigerate.
   • For rectal use only.

Note: Use of methimazole suppositories is generally reserved for treatment of thyrotoxic emergencies, in patients who are unable to tolerate oral medications {162} {172}. The efficacy of chronic rectal dosing with extemporaneously compounded formulations has not been established {162} {172}.



PROPYLTHIOURACIL

Summary of Differences


Precautions:
Pregnancy—May be preferred to methimazole, due to lower rate of placental transfer.

Breast-feeding—May be preferred to methimazole, due to a lower rate of distribution into breast milk.



Side/adverse effects:
Agranulocytosis may be less predictable, because it is usually not dose-related.



Oral Dosage Forms

PROPYLTHIOURACIL TABLETS USP

Usual adult and adolescent dose
Hyperthyroidism


Initial:
Oral, 300 to 900 mg a day as one to four divided daily doses until the patient becomes euthyroid {05} {08} {26} {29} {47} {50} {51} {52} {54} {55} {64} {68} {69} {70} {74} {77} {78} {79} {126} {127} {132} {133} {135} {147} {160}.

Note: Patients with severe hyperthyroidism may occasionally require up to 1.2 grams a day {18} {47} {52} {53} {74} {147}.




Maintenance:
Oral, 50 to 600 mg a day as one to four divided daily doses {05} {20} {27} {47} {49} {50} {55} {64} {68} {110} {113} {127} {133} {135} {160}.



Thyrotoxic crisis:
Oral, 200 to 400 mg every four hours during the first day, as an adjunct to other measures, the dosage then being decreased as the crisis subsides {29} {52} {71} {79} {87} {110}.



Usual pediatric dose
Hyperthyroidism


Initial:
Children 6 to 10 years of age—Oral, 50 to 150 mg a day as one to four divided daily doses.

Children 10 years of age and over—Oral, 50 to 300 mg a day as one to four divided daily doses {05} {06} {12} {13} {18} {64} {77} {78} {96}.



Maintenance:
Oral, determined by response {64}.



Neonatal thyrotoxicosis:
Oral, 10 mg per kg of body weight a day in divided daily doses {81}.



Strength(s) usually available
U.S.—


50 mg (Rx)[Generic]{64}

Canada—


50 mg (Rx) [Propyl-Thyracil (scored)]


100 mg (Rx) [Propyl-Thyracil (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take at the same time in relation to meals every day.



Rectal Dosage Forms

PROPYLTHIOURACIL ENEMA

Usual adult and adolescent dose
Hyperthyroidism
Initial: Thyrotoxic crisis—Rectal, 200 to 400 mg every four hours during the first day, as an adjunct to other measures, with the dosage being adjusted according to patient response {172}.


Usual pediatric dose
Hyperthyroidism—Initial: Thyrotoxic crisis
Children 6 to 10 years of age: Rectal, 50 to 150 mg a day as one to four divided daily doses, with the dosage being adjusted according to patient response {172}.

Children 10 years of age and over: Rectal, 50 to 300 mg a day as one to four divided daily doses, with the dosage being adjusted according to patient response {172}.

Neonatal thyrotoxicosis: Rectal, 10 mg per kg of body weight a day in divided daily doses, with the dosage being adjusted according to patient response {172}.


Strength(s) usually available
U.S.—
Not commercially available. Compounding required for prescription.

Canada—
Not commercially available. Compounding required for prescription.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Store in a well-closed container. Protect from freezing.

Preparation of dosage form:
A formulation that has been used for the extemporaneous compounding of propylthiouracil enemas is as follows: {159}

   • 400 mg propylthiouracil (8-50 mg tablets)
   • 60 mL aqueous sodium phosphates solution ( Fleet"s Phospho-Soda, pH 4.4 to 5.4). {170}

Auxiliary labeling:
   • For rectal use only.

Note: Use of propylthiouracil enema is generally reserved for treatment of thyrotoxic emergencies, in patients who are unable to tolerate oral medications {159} {172}. The efficacy of chronic rectal dosing with extemporaneously compounded formulations has not been established {159} {172}.



PROPYLTHIOURACIL SUPPOSITORIES

Usual adult and adolescent dose
Hyperthyroidism
Initial: Thyrotoxic crisis—Rectal, 200 to 400 mg every four hours during the first day, as an adjunct to other measures, with the dosage being adjusted according to patient response {172}.


Usual pediatric dose
Hyperthyroidism—Initial: Thyrotoxic crisis
Children 6 to 10 years of age: Rectal, 50 to 150 mg a day as one to four divided daily doses, with the dosage being adjusted according to patient response {172}.

Children 10 years of age and over: Rectal, 50 to 300 mg a day as one to four divided daily doses, with the dosage being adjusted according to patient response {172}.

Neonatal thyrotoxicosis: Rectal, 10 mg per kg of body weight a day in divided daily doses, with the dosage being adjusted according to patient response {172}.


Strength(s) usually available
U.S.—
Not commercially available. Compounding required for prescription.

Canada—
Not commercially available. Compounding required for prescription.

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Store in a well-closed container. Protect from freezing.

Preparation of dosage form:
A formulation that has been used for the extemporaneous compounding of propylthiouracil suppositories is as follows: {158}

   • 400 mg propylthiouracil (8-50 mg tablets) in
   • Hardfat (Witepsol H15), of sufficient quantity to make 4 suppositories containing 100 mg each.

Auxiliary labeling:
   • For rectal use only.

Note: Use of propylthiouracil suppositories is generally reserved for treatment of thyrotoxic emergencies, in patients who are unable to tolerate oral medications {158} {162} {172}. The efficacy of chronic rectal dosing with extemporaneously compounded formulations has not been established {158} {162} {172}.




Revised: 07/19/2001



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    1. Reviewers" consensus on monograph revision of 6/16/83.
    1. Panel comment, 1/84.
    1. Reviewers" consensus on monograph revision of 9/10/86.
    1. Panel comment, 9/10/86.
    1. Panel comment, 9/10/86.
    1. Panel comment, 9/10/86.
    1. Panel comment, 9/10/86.
    1. USP-DI Review 1986 7(4): 882. Comment received 11/14/88.
    1. Reviewers" consensus on monograph revision of 8/3/87.
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    1. Panel comment, 8/3/87.
    1. Panel comment, 8/3/87.
    1. Panel comment, 8/3/87.
    1. Panel comment, 8/3/87.
    1. Panel comment, 8/3/87.
    1. Panel comment, 8/3/87.
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    1. Reviewers" consensus on monograph revision of 5/3/91.
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    1. Panel comment, 5/3/91.
    1. Panel comment, 5/3/91.
    1. Panel comment, 5/3/91.
    1. Panel comment, 5/3/91.
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    1. Panel comment, 5/3/91.
    1. Panel comment, 5/3/91.
    1. Reviewers" consensus on monograph revision of 5/3/91.
    1. Panel comment, 5/3/91.
    1. Reviewers" consensus on monograph revision of 5/3/91.
    1. Panel comment, 5/3/91.
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    1. Telephone call to C.B. Fleets Company, 11/13/91.
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    1. Reviewers" consensus on monograph revision of 2/14/92.
    1. Panel comment, 2/14/92.
    1. Product Information: Tapazole®, methimazole. Jones Pharma Inc., St. Louis, Missouri (PI revised 07/14/1999) PI reviewed 06/2001.
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