Essential Medicines List (EML) 2019

Application for the revision of first line treatment of primary

hyperthyroidism in the adult and children’s WHO EML:

methimazole (MMI)/carbimazole (CMZ) vs propylthiouracil (PTU)

Submitted by: Global Pediatric Endocrinology and Diabetes (GPED), Vancouver, Canada

To: 21st WHO Expert Committee on the Selection and Use of Essential Medicines

World Health Organization

Geneva

Authors: Dr Jean-Pierre Chanoine (GPED and British Columbia Children’s Hospital, Vancouver,

Canada)

Dr Jennifer Kendrick (Department of Pharmacy, British Columbia Children’s Hospital,

Vancouver, Canada)

Contact: Jean-Pierre Chanoine, MD, FRCPC (Academic)

Clinical Professor and Head

Endocrinology and Diabetes Unit K4-212

British Columbia Children’s Hospital

4480 Oak Street

Vancouver BC V6H 3V4

Canada

Email: jchanoine@cw.bc.ca; Phone: 1-604-8752624; Fax: 1-604-8753231

1. Summary statement of the proposal for inclusion, change or deletion

Graves’ disease (GD) is the most common cause of hyperthyroidism in both adults and

children. Management of Graves disease includes antithyroid drugs (ATDs), thyroidectomy

or radioactive iodine. In low resource settings, environmental conditions (lack of an

experienced surgeon or of a well-equipped nuclear medicine facility) may prevent performing

a thyroidectomy (which can be associated with severe complications such as permanent

hypoparathyroidism or laryngeal nerve damage) or radio ablation of the thyroid gland.

Medical treatment with ATDs remains the preferred first line treatment of hyperthyroidism

by most physicians. ATDs include propylthiouracil (PTU, since 1947) and methimazole

(MMI, since 1952)/carbimazole (CMZ, since 2005). The three ATDs belong to the

thionamide group. PTU which has long been included in the WHO essential list of medicines

(EML) and it remains, to this day, the only ATD included in both EML and EMLc.

In this document, MMI and CMZ will mostly be presented together as CMZ’s activity

depends on its transformation into MMI after absorption. Indeed, although most of the

medical information derives from studies performed with MMI, the profile of the two drugs

is considered virtually identical. Usually, only one of the two drugs (MMI or CMZ) is

available in a given country and this seems to simply reflect differences in the registration of

the drug. For instance, MMI is present in North America while CMZ is present in Europe,

Australia and New Zealand.

Historically, all three drugs have been widely used as first line therapy for Graves’

hyperthyroidism and given for extended periods at a time when the small perceived

differences between PTU and MMI/CMZ in terms of metabolism and safety did not justify

preferring one above the other in children and non-pregnant adults. However, a review of the

available information has identified rare but irreversible cases of liver failure with PTU,

while such severe side-effects have not been reported with MMI/CMZ with the exception of

one recent CMZ case (1). As a consequence, in 2010, the Federal Drug Administration

(FDA) added a Boxed Warning to the label for PTU, to include information about reports of

severe liver injury and acute liver failure, some of which have been fatal, in adult and

pediatric patients using this medication (2-4). Interestingly, in the United States, between

1996 and 2008, MMI use had increased by 800% while PTU use had only increased from

348,000 to 415,000. This trend showing a proportionally greater increased use of MMI

compared to PTU (in particular in children) was likely caused by the lowered cost of the

MMI in the 1990s and the number of serious hepatic side effects seen in patients on PTU

(prior to the official FDA agency warning) (5).

PTU is therefore not recommended anymore as a first line therapy in Graves

hyperthyroidism. Instead, MMI (or CMZ) should be used as first line therapy in all children

and non-pregnant adults.

Thus, the application proposes the inclusion on the core list of the EML and EMLc of

methimazole (INN thiamazole) with a square box, representative of the pharmacological class

of sulfur- containing imidazole derivatives (4thlevel ATC group H03BB) for the first line

medical management of Graves’ hyperthyroidism in children and non-pregnant adults. The

square box listing would incorporate carbimazole as a therapeutically equivalent alternative.

The application also proposes the current listing for propylthiouracil on the EML be

transferred to the complementary list, and the square box removed. PTU should remain the

drug of choice during the first trimester of pregnancy, during thyroid storm, for patients who

cannot tolerate MMI or for patients for whom radioactive iodine therapy or surgery is not

appropriate treatment. If MMI/CMZ is not available, the use of PTU is better than no

treatment and PTU can be used provided that the potential risks are discussed with the

patient.

No change is proposed to the current listing of PTU on the complementary list of the EMLc.

However, a note specifying that PTU be used only when alternative first-line treatments are

not appropriate or available is proposed for both the EML and EMLc to reinforce its use only

as a second-line therapy.

2. Name of relevant WHO department and focal point

This application was discussed with the following members at the Department of Essential

Medicines and Health Products in WHO.

Dr Suzanne Hill, B. Med (Hons), Grad Dip Epi, PhD, FAFPHM Director

Email: hills@who.int

Dr Nicola Magrini, MD

Secretary of the Expert Committee on the Selection and Use of Essential Medicines Policy,

Access and Use Team (Office M527),

Email: magrinin@who.int

World Health Organization

20, Avenue Appia - 1211 Geneva 27 - Switzerland

website: www.who.int

3. Name of the organization(s) consulted and/or supporting the application

Global Pediatric Endocrinology and Diabetes (GPED, www.globalpedendo.org)

4. International Non-proprietary Name (INN, generic name) and Anatomical

Therapeutic Chemical (ATC) code of the medicine.

PTU

INN: Propylthiouracil

ATC code: H03BA02

Methimazole

INN: Thiamazole

ATC: H03BB02

Carbimazole

INN: Carbimazole

ATC: H03BB01

5. Formulation(s) and strength(s) proposed for inclusion; including adult and

paediatric

Methimazole: Tablet 5 mg, 10 mg, 20 mg (EML) and tablet 5 mg, 10 mg (EMLc)

Carbimazole: Tablet 5 mg, 10 mg, 20 mg (EML) and tablet 5 mg, 10 mg (EMLc)

Propylthiouracil: Tablet 50 mg (EML and EMLc)

6. Whether listing is requested as an individual medicine or as representative of a

pharmacological class

Propylthiouracil is proposed as an individual medicine, with removal of the square box in the

current EML listing.

Methimazole is proposed to be listed with a square box as representative of anti-thyroid

preparations in the pharmacological class of sulfur- containing imidazole derivatives (4th

level ATC group H03BB). Carbimazole is a therapeutically equivalent alternative.

7. Treatment details (requirements for diagnosis, treatment and monitoring)

Recent guidelines from the European Thyroid Association (2018) (6) and from the American

Thyroid Association (2016) (7) are available and consider both children and adults. Japanese

pediatric consensus guidelines are also available (8). To our knowledge, there is no WHO

guidelines for the management of Graves disease.

Thyroid Stimulating Hormone (TSH) is the single most useful test in confirming the presence

of thyrotoxicosis. By sensitive assays, TSH should be undetectable or low in all patients with

thyrotoxicosis of thyroidal origin (6, 7, 9).

First line management of Graves disease, the most common form of primary

hyperthyroidism, primarily consists in ATDs. All recent adult and pediatric guidelines

recommend the use of MMI or CMZ as first line therapy.

PTU was introduced for clinical use in July 1947 (10). It acts by inhibiting the enzyme

thyroperoxidase, which adds iodide to tyrosine residues on the thyroxine hormone precursor

thyroglobuline. PTU also inhibits the enzyme tetraiodothyronine 5’deiodinase, which

converts thyroxine (T4) to triiodothyronine (T3). This effect may be important in very severe

hyperthyroidism (“thyroid storm”) as the inhibition of T4 to T3 conversion could lead to a

faster decrease in the hyperthyroid symptoms.

Methimazole was introduced in 1952. It also inhibits the enzyme thyroperoxidase but unlike

PTU, does not inhibit the enzyme tetraiodothyronine 5’deiodinase. It is marketed in North

America.

Carbimazole was developed in 2004. Its action is identical to the action of MMI. Indeed,

CMZ is metabolized into MMI after absorption. Mole for mole, it is equipotent to MMI (11),

but because of differences in the molecular weight, CMZ should be dosed at 140% of MMI

(12). It is marketed in Europe, the United Kingdom, Australia and New Zealand but not in

North America.

The equivalence between PTU and MMI is traditionally estimated at 10-20 to 1 (10-20 mg

PTU corresponds to 1 mg MMI/CMZ) (7). In adults, thionamide treatment is usually started

with high doses (20 to 40 mg/day of methimazole or 200 to 400 mg/day of propylthiouracil).

In children, the initial dose of MMI/CMZ ranges from 0.1-1.0 mg/kg/d with a maximum of

15-30 mg (8, 13, 14). MMI/CMZ is usually given OD or BID while PTU is given TID.

Prior to treatment initiation, baseline white blood cell count (WBC) and liver function tests

(LFTs) are recommended. During treatment, there is no consensus on the need to measure

WBC and LFTs regularly, and emphasis is put on the recognition of the severe side effects

(agranulocytosis or liver failure) by the patient.

Normalization of the thyroid function tests take place within 4-12 weeks. Follow up of the

patient consists in “titrating” the dose of ATDs by progressively decreasing the dose of

MMI/CMZ as the TSH increases, with the goal of keeping the TSH in the normal range. In

contrast to the “titrating” approach, a “block and replace” approach (consisting in “blocking”

the thyroid gland with a high dose of thionamides to make the patient hypothyroid and

“replace” the patient with L-thyroxine to restore euthyroidism) has not been associated with a

higher rate of remission and is associated with a higher risk of side effects (12).

8. Information supporting the public health relevance

Graves disease is by far the most common most common of hyperthyroidism. This

autoimmune condition is most frequent in women (8F:1M) between 20 and 40 years. A meta-

analysis of European studies estimated a mean prevalence rate of 0.75% for males and

females combined and an incidence rate of 51 cases per 100,000 per year with a significant

influence of ethnicity and iodine nutrition.

In iodine-replete geographical areas, such as the Unites States, Graves disease represents

more then 80% of the cases of hyperthyroidism, with an incidence of 20–30 annual cases per

100,000 individuals. The incidence varies according to ethnicity and was estimated at 7.5

(whites), 12 (Hispanics), 20 (African Americans) and 25/100,000/yr in Asian/Pacific

Islanders in men and at 40 (whites), 60 (Hispanics) and 80/100,000/yr (African Americans

and Pacific Islanders) in women (data from the US military personnel) (15).

In iodine-deficient areas, Graves disease represents 50-60% of the cases of hyperthyroidism.

Within the same country, differences are observed based on iodine nutrition. China reported a

higher prevalence of overt and subclinical hyperthyroidism in an iodine-sufficient area than

in an iodine-deficient area (1.2% versus 1.0%; P < 0.001) (16).

In the pediatric age-group, Graves’ disease represents more than 90% of the cases of

hyperthyroidism with an incidence ranging from 0.1 per 100,000 children and 3.0 per

100,000 adolescents per year (13).

Overall, Graves’ disease is a common condition and antithyroid drugs are the most common

first line management. Although there is no precise estimate of the number of patients who

have received PTU, MMI or CMZ since they became available, this number is in the

millions. Since the recognition of the risk of irreversible liver failure with the use of PTU,

there has been a progressive shift in the use of the thionamides with a decrease in the use of

TU and an increase in the use of MMI/CMZ.

The initial recommended treatment with antithyroid drugs is generally 2 years. Only ~30% of

adult (17) or pediatric (18) patients will ultimately achieve remission. If remission is not

achieved after 2 years, long term treatment includes antithyroid drugs, radioiodine or surgery,

with a large geographical variation that reflects the availability of each therapeutic approach

and the region’s medical tradition.

9. Review of benefits: summary of comparative effectiveness in a variety of clinical

settings

PTU and MMI/CMZ differ by their metabolism, duration of action and side effects. In

general, less information is available for CMZ which was introduced more recently.

However, because CMZ is metabolized into MMI after absorption, it is assumed that data that

apply to MMI also apply to CMZ. Importantly, MMI/CMZ have a better safety profile and

can be taken OD/BID compared to PTU.

a. Metabolism

Compared to PTU, MMI is characterized by a longer serum half-life and duration of action,

which makes it possible to prescribe as an OD or BID medicine, compared to TID with PTU

(Table 1).

Both MMI and PTU cross the placenta and are excreted in the breastmilk (Table 1). Because

MMI may cause more (severe) fetal malformations to the fetus than PTU (see below), PTU

remains the drug of choice during the first trimester of pregnancy. Excretion of PTU and

MMI in the breastmilk has not been shown to be associated with neonatal hypothyroidism for

doses up to 300 mg (PTU) or 20 mg (MMI) per day (19).

Table 1. Comparison of PTU and MMI metabolism (6)

b. Comparative effectiveness

We searched the English literature through Pubmed to identify all studies that either

compared 2 of the 3 ATDs or different doses of the same ATD in adults and in children. We

also looked at the references of the studies we identify to find additional additional studies.

Table 2 describes 4 adult studies that compare the effectiveness of PTU and MMI, 1 study

that assess the effect of MMI or CMZ taken once, twice or three times a day. We also found

one RCT comparing PTU and MMI in children and adolescents. All studies only include

patients with Graves disease at the initiation of treatment. We did not include a study from

1959 comparing CMZ and MMI because of the poor quality of the assays of thyroid

hormones that were available at the time (20).

Table 2 Effectiveness of PTU, MMI and CMZ

Trial Patients Intervention Outcome

Adults

Sriussadaporn et al

(2017) (21)

RCT

12 weeks

Thailand

50 patients included

(44 analysed, 33F:

11M, mean age 38

years)

MMI 15 mg OD vs

MMI 15 mg (5 mg

TID)

Serum FT3 and FT4 reductions,

and cumulative rate of achieving

euthyroidism (28.6% versus

34.8%, 71.4% versus 82.6%, and

85.7% versus 87.0%) were similar

at 2, 4, 8, and 12 weeks with both

regimen.

The authors suggest that in

clinically moderate Graves

disease, MMI OD and TID give

similar results.

Nakamura (2007)

(22)

RCT

12 weeks

Japan

Mean age 40 years

396 patients included

(303 analysed)

MMI 30 mg/d (15

mg BID) vs

PTU 300 mg/d (100

mg TID) vs

MMI 15 mg/d (OD)

Overall, MMI 30 mg/d

normalized FT4 in more patients

than PTU 300 mg/d and MMI 15

mg/d at 12 wk (96.5 vs. 78.3%; P

= 0.001; and 86.2%, P = 0.023,

respectively).

In the group of patients with

severe hyperthyroidism (64

patients), MMI 30 mg/d

normalized FT4 more effectively

than PTU 300 mg/d at 8 and 12

wk and than MMI 15 mg/d at 8

wk, respectively (P < 0.05).

The authors conclude that MMI

15 mg/d is suitable for mild and

moderate Graves disease, whereas

MMI 30 mg/d is advisable for

severe cases. PTU is not

recommended for initial use.

He et al (2004) (23)

RCT

12 weeks

China (Taiwan)

30 patients (21F: 9 M)

Mean age 31.5 years

PTU 150 mg OD vs

MMI 15 mg OD

After 12 weeks, MMI OD was

better than PTU OD in decreasing

FT4 and FT3 as well as TSH

receptor Abs.

Mafauzy et al

(2003) (24)

RCT

6 weeks

Malaysia

70 patients included (48

patients analyzed)

CMZ 30 mg OD

(30 mg OD vs 15 mg

BID vs 10 mg TID

After 6 weeks, mean thyroid

hormone concentrations were not

different between the 3 groups.

More patients were hypothyroid

when CMZ was taken OD,

possibly reflecting better

compliance with OD compared to

TID.

Homsanit et al

(2001) (25)

RCT

12 weeks

Thailand

71 patients (62F: 9 M)

Mean age 35 years

PTU 150 mg OD vs

MMI 15 mg OD

Compared with PTU treatment,

FT3 concentrations were lower

after 4 weeks and FT4 lower after

8 weeks with MMI. After 12

weeks, 77% of MMI patients had

thyroid hormones concentrations

below the upper limit of normal

compared to 19% with PTU.

Nicholas et al

(1995) (26)

RCT

12 weeks

USA

29 patients (22 patients

analyzed)

PTU 300 mg (100

mg TID) vs MMI 30

mg OD

At 3 months, MMI once a day

was as effective as PTU TID.

Compliance was higher with MMI

(83%) compared to PTU (53%).

Children and adolescents

Sato et al (2011)

(27)

Retrospective study

Japan

Mean age 12 years

133 patients included

(MMI group: N = 64,

55F:9M)

(PTU group: N = 69,

59F:10M)

4 groups:

M1 (< 0.75 mg/kg

MMI, n = 34)

M2 (≥ 0.75 mg/kg

MMI, n = 30)

P1 (< 7.5 mg/kg

PTU, n = 24)

P2 (≥ 7.5 mg/kg

PTU, n = 45).

The mean duration for

normalization of FT4 was

significantly longer in group P1

(3.1 ± 3.3 months) compared to

the other subgroups (M1: 1.9 ±

1.2; M2: 1.4 ± 0.7; P2; 1.7 ± 1.3).

Overall, the literature suggests that MMI (21) or CMZ (24)given once a day is as effective as

when divided BID or TID.

Using the commonly accepted conversion of 10-20 mg of PTU for 1 mg of MMI, MMI is

similarly or more effective than PTU in decreasing thyroid hormones concentrations (22, 25,

26) and in children and adolescents (27). This effect may be partly due to MMI itself, to its

longer half-life compared to PTU or to a better compliance with MMI (taken once a day)

compared to PTU (taken 3 times a day).

In summary, existing ATDs (PTU, MMI and CMZ) are all effective in the management of

Graves hyperthyroidism. However, MMI/CMZ seem to be more effective than PTU and can

be taken once a day, in contrast to PTU that requires a BID or TID administration.

Data for CMZ are not always available. The activity of CMZ exclusively depends on its

metabolism into MMI and both drugs are therefore considered equivalent.

10. Review of harms and toxicity: summary of evidence of safety

Overall, both PTU and MMI/CMZ all present with minor and major side effects, both in

adults and in children (Tables 3 and 4). However, major side effects are much less common

with MMI/CMZ, making it a first line therapy for Graves hyperthyroidism.

Table 3 describes the safety of PTU, MMI and CMZ as reported in cohort studies. The Table

also includes case reports of side effects reported in the English literature found on Pubmed

for MMI and CMZ over the last 10 years.

Table 3: Safety of PTU, MMI and CMZ as reported in cohort studies and case reports

Trial Patients Intervention Adverse Events

Adults cohort/RCT studies

Nakamura (2007)

(22)

RCT

12 weeks

Japan

Mean age 40 years

396 patients included

(303 analysed)

MMI 30 mg/d (15

mg BID) vs

PTU 300 mg/d (100

mg TID) vs

MMI 15 mg/d (OD)

The incidence of adverse events

was higher in the PTU group, with

54 of 104 patients) having some

adverse effects. PTU was stopped

or changed to MMI for 39

patients. In the MMI 30-mg

group, adverse effects occurred in

39 of 130 patients (30%), and the

drug was stopped or changed for

28 patients.

The percentage of patients who

showed AST and ALT higher than

double the upper range of the

normal standard was 26.9% on

PTU 300 mg/d, compared with

6.6% on MMI 30 mg/d (P <

0.001). Skin eruption or urticaria

similarly occurred in about 22%

in either group, but

leukocytopenia (less than

1000/mm3) was observed in five

patients in the PTU group only.

MMI 15 mg/d caused

significantly fewer adverse events

than MMI 30 mg/d. The total

incidence in the MMI 15 mg

group was about half that of the

MMI 30-mg group. Although the

frequency of mild hepatotoxicity

was similar, skin eruption/

urticaria induced by MMI 15 mg

was only about one third that of

MMI 30 mg

Wang et al. (2014)

(28)

Retrospective

cohort using

administrative

database (2004-8)

71,379 ATD

initiators, with a

median follow-up

of 196 days

Taiwan

92% < 65 years of age;

77-82% female

PTU (24,941) and

MMI/CMZ (46,438)

MMI/CBM vs. PTU users had a

higher hepatitis incidence rate

(3.17/1000 vs. 1.19/1000 person-

years) but a lower incidence of

acute liver failure (0.32/1000 vs.

0.68/1000 person-years).

CMZ was not associated with the

hepatitis risk (adjusted HR 1.04,

95% CI 0.50,2.16).

Pediatric cohort and RCT studies

Sato et al (2011)

(27)

Retrospective study

Japan

Mean age 12 years

133 patients included

(MMI group: N = 64,

55F:9M)

(PTU group: N = 69,

59F:10M)

4 groups:

M1 (< 0.75 mg/kg

MMI, n = 34)

M2 (≥ 0.75 mg/kg

MMI, n = 30)

P1 (< 7.5 mg/kg

PTU, n = 24)

P2 (≥ 7.5 mg/kg

PTU, n = 45).

No serious adverse reaction such

as agranulocytosis, severe liver

failure, or MPOANCA-associated

nephritis or vasculitis.

Minor adverse effects occurred in

16 patients of group MMI (25.0 %

) and 22 in group PTU (31.9 % )

(NS): skin eruption, liver

dysfunction, neutropenia, arthritis,

mild fever, urticaria, itching,

nausea.

The incidence of liver dysfunction

in group PTU (18.8 % ) was

significantly higher than that in

group MMI (6.3 %) (p < 0.05)

Lazar (2000)

RCT

40 children

Median follow up:

4 years

United States

Prepubertal, 7 patients

(three boys, 43%),

mean age 6.4 yr;

pubertal, 21 patients

(four boys, 19%) of

mean age 12.5 yr;

Postpubertal, 12

patients (three boys,

25%), mean age 16.2

yr.

Dose: PTU (28

patients, 70%), mean

dose 6.4 mg/kg/day

MMI (12 patients,

30%), mean dose of

0.74 mg/kg/day)

Adverse drug reactions occurred

in 35% during the first 24 weeks

of the treatment: major in 5%

patients and minor in 30%

patients. There was no difference

in side effects between patients

receiving PTU or MTZ within the

same age group.

Case reports CMZ/MMI

Ferguson C et al

(2018) (29)

Case report

N=1

41-year-old woman CMZ (dose not

reported), beta-

blockers and

selenium

Unilateral exudative effusion with

prominent eosinophils on pleural

cytology 4 weeks after starting

CMZ. The patient received

treatment for pleural empyema,

including antibiotics and

intercostal drain insertion. Pleural

effusion did not reaccumulate

after discontinuation of CMZ

Gaspar-da-costa et

al. (2017) (30)

Case report

N=1

75-year-old man MMI (dose not

reported). Chronic

medicines: enalapril,

carvedilol,

nifedipine, aspirin,

warfarin,

omeprazole and

tansulosin

Unilateral pleural effusion with

eosinophils 6 days after starting

methimazole. Past history of

arterial hypertension, atrial

fibrillation, end-stage renal

disease on haemodialysis,

peripheral artery disease and

prostatic hyperplasia.

Cardona Attard et

al. (2016) (31)

Case report

N=1

42-year old man CMZ 10 mg OD for

> 2 years

Bilateral exudative pleural

effusions and liver toxicity.

Resolved 5 months after

discontinuation of CMZ

Lim et al (2013)

(32)

Case report

N=1

24-year old Chinese

woman

CMZ 40 mg for 2

months

Myositis, resolved with

discontinuation of CMZ

Haq et al. (2013)

(33)

Case report

N=1

50-year old woman CMZ 40 mg

Systemic lupus erythematosus,

manifesting as serositis resulting

in an exudative pleural effusion

and a proinflammatory/

prothrombotic state. Resolved

with discontinuation of CMZ.

Mavrakanas et al.

(2013) (34)

Case report

N=1

66 year old man CMZ 30 mg,

decreased to 10 mg

OD

Anti-neutrophil cytoplasmic

antibodies (ANCA)-associated

vasculitis. Patient remained in

dialysis 6 months after

discontinuation of the CMZ.

Patient also had diabetes

Raja et al (2010)

(35)

Case report N = 1

68 year-old male CMZ 20 mg OD Sensorineural deafness and

tinnitus. Resolved after

discontinuation

Jain et al (2010)

(36)

45 year-old female CMZ 30 mg OD Acute cholestatic hepatitis along

with agranulocytosis resolved

with discontinuation of CMZ

Khan (1) 75 year-old female CMZ Cholestasis and progressive liver

failure

- Minor side-effects

Pruritus, skin rash, urticaria and arthralgias are the most common minor side-effects. These

side effects frequently resolve spontaneously despite continued therapy (Table 4). Reversible

hepatic toxicity (hepatitis with PTU and cholestasis with MMI) is not uncommon but is

usually reversible upon discontinuation of the treatment.

Table 4: Comparison of the safety of PTU and MMI (6)

Table 5: Adverse events reported to the FDA from 1970 to 1997 in individuals ≤18 years of

age (37).

- Major side-effects

a. Agranulocytosis

Agranulocytosis (Neutrophil WBC count <500/mm3) may be observed with both MMI/CMZ

and PTU. It is dose-dependent with PTU but not with MMI. It has been reported more

frequently in older adult patients, but it can occur at any age. It is most often detected within

the first 3 to 4 months after starting therapy. Following prompt discontinuation of the

antithyroid drug, patients usually recover within 2 to 3 weeks (38).

b. Liver failure

Whereas countless individuals have benefited from PTU therapy, over the 70 years that this

medication has been used, recent reports of PTU-related liver failure and death in children

and adults have accumulated (Tables 6 and 7). These observations have raised major

concerns about the safety of this medication, especially in children, who have a risk that is 5

times higher than in adults (Table 6). In contrast, no cases of irreversible liver failure were

reported with MMI between 1990 and 2008 (37). To our knowledge, only one case of

irreversible liver failure was reported in an elderly patient following treatment with CMZ (1).

Table 6: Comparison of PTU and MMI hepatotoxicity in adults and children at a glance (10)

Table 7. Number of recipients who received a liver transplant from 01/01/90–06/30/08 due to

PTU-induced liver failure. Over the same period, there were no MMI-related transplants (4,

37)

c. Vasculitis

Cases of blood vessel inflammation (vasculitis) associated with antineutrophil cytoplasmic

antibodies (ANCA) have been described, more often related to PTU than MMI use (39, 40).

ANCA-associated vasculitis affects the small vessels in different organs, frequently the

kidneys, lungs and skin, thus resulting in various clinical manifestations.

Balavoine et al (41) identified a total of 261 reports of hyperthyroid patients who developed

ANCA-associated vasculitis while taking ATDs between 1993 and 2015. ANCA antibodies

were present in the blood in a higher percentage of patients taking PTU (4% to 64%, average

30%) compared to those taking MMI (0% to 16%, average 6%). A high percentage (64%) of

children with Graves’ disease had ANCA antibodies in a Japanese study. An average of 15%

of patients with ANCA corresponding to 3% of all patients taking ATDs developed vasculitis

related to ANCA, 75% of these patients being on PTU, while 25% were on MMI. Patients

with high blood ANCA levels and those taking ADT treatment for a long period of time had a

higher risk to develop vasculitis. Based on the cases reported to the FDA, the risk of

vasculitis related to PTU use in children was 50 times higher compared to the risk expected

for adults. Following discontinuation of treatment, a rapid clinical improvement is observed

in the majority of the cases.

d. Fetal outcome

Table 8 summarizes key cohort studies that assess the outcome of pregnancies following

treatment with PTU, MMI or CMZ during pregnancy. They focus on the use of anti thyroid

drugs during the first trimester of pregnancy (organogenesis). Table 9 also reports case

reports of malformations observed in neonates from mothers treated with either CMZ or

MMI for the last 10 years. Because the reported malformations are similar for MMI and

CMZ, the risk associated with both drugs is considered as identical.

The literature is presently unclear on whether MMI and CMZ lead to a higher prevalence of

fetal malformations compared to PTU. Some studies have shown similar rates of fetal defects

with both drugs (2–3% with PTU and 2–4% with MMI) (28). This percentage may not be

higher than the percentage of malformations in the control population (42). In contrast, a

recent metanalysis showed an increased risk of neonatal congenital malformations associated

with MMI, but not PTU when compared to no ATD exposure (43). However, the fetal

malformations associated with PTU seem less severe than with MMI and CMZ and are easier

to correct.

In agreement with the guidelines from the European Thyroid Association and the American

Thyroid Association, we propose that PTU, if available, is recommended as the first-line drug

for treatment of hyperthyroidism during the first trimester of pregnancy because of the

possible association of methimazole (MMI) with specific congenital abnormalities that occur

during first trimester organogenesis. MMI may also be prescribed if PTU is not available or if

a patient cannot tolerate or has an adverse response to PTU (6, 7).

Table 8: Summary of birth defects associated with MMI and PTU (19)

Table 9: Outcome of infants born to mothers treated with antithyroid medications during

pregnancy (cohort studies and case reports)

Trial Patients Intervention Adverse Events

Cohort Studies

Ting et al (2013) (44)

Retrospective cohort

(2008-2010)

N = 29 treated mothers

treated (27 infants

examined)

China

CMZ median dose

10 mg OD (Range

2.5-40 mg)

Aplasia cutis (N = 3), omphalocele

((N = 1). Embryopathy risk: 14.8%

Andersen et al (2013)

(45)

Registry study (1996-

2008)

PTU (N = 564);

MMI/CMZ (N =

1097);

MMI/CMZ and PTU

(shifted in early

pregnancy (N = 159);

no ATD during

pregnancy (N = 3543);

never ATD use (N =

811 730)

Denmark

First trimester of

pregnancy

High prevalence of birth defects in

children exposed to ATD in early

pregnancy (PTU, 8.0%;

MMI/CMZ, 9.1%; MMI/CMZ and

PTU, 10.1%; no ATD, 5.4%;

nonexposed, 5.7%; P<.001). Both

maternal use of MMI/CMZ

(adjusted OR = 1.66 [95% CI

1.35–2.04]) and PTU (1.41 [1.03–

1.92]) and maternal shift between

MMI/CMZ and PTU in early

pregnancy (1.82 [1.08 –3.07]) were

associated with an increased risk of

birth defects. MMI/CMZ and PTU

were associated with urinary

system malformation, and PTU

with malformations in the face and

neck region. Choanal atresia,

esophageal atresia, omphalocele,

omphalomesenteric duct

anomalies, and aplasia cutis were

common in MMI/CMZ-exposed

children (combined, adjusted OR =

21.8 [13.4 –35.4]).

Korelitz et al (2013)

(46)

Retrospective

administrative database

analysis

N = 8050 treated

N = 801,551 untreated

United States MMI or PTU The rates of congenital defects (per

1000 infants) associated with ATD

use were 55.6 for MMI, 72.1 for

PTU, and 65.8 for untreated

women with Graves disease

compared to 58.8 among women

without Graves disease.

Wing (1994) (47)

Retrospective cohort

1974-1990

N = 185 pregnant

mothers

USA

Graves disease

Mean age 40 years

MMI: N = 36

(Median dose 40

mg OD)

PTU: N = 99

(Median dose: 450

mg OD)

Untreated: N = 43

Incidence of major congenital

anomalies in infants of PTU-

treated mothers was 3.0% (three of

99 with heart defects, although all

3 mothers were treated with PTU

after 15 weeks of gestation). The

incidence of anomalies in infants

of MMI-treated mothers was 2. 7%

(1 of 36 with bilateral inguinal

hernia). No case of aplasia cutis

were reported among neonates of

mothers receiving either

medication. These % ar similar to

the incidence of anomalies in the

normal population

Case reports Carbimazole/Methimazole (last 10 years)

Goel et al (2013) (48)

N= 2

Australia, 2 siblings CMZ 30 mg

decreased to 15

Minor dental anomalies (N = 2)

Right sided choanal atresia,

mg (N = 1) and 15

mg (N =1)

hypoplastic alae nasi, upslanting

palpebral fissures, arched

eyebrows, broad nasal bridge,

bulbous nose, telecanthus and a

small left ear (N = 1); hypoplastic

alae nasi, upslanting palpebral

fissures, arched eyebrows, broad

nasal bridge, bulbous nose,

telecanthus, and small ears (N = 1).

Panait (2013) (49)

N = 1

France

22 year-old pregnant

woman

CMZ 20 mg BID

(first 4 weeks of

gestation)

Esophageal atresia, small

omphalocele, and ileal prolapse

through a patent

omphalomesenteric duct

Bowman (2012) (50)

N = 1

United Kingdom CMZ 40mg and L-

T4 100 mcg OD

Atypical umbilical stump, patent

vitellointestinal duct and aplasia

cutis

Rodriguez-Garcia

(2011) (51)

N = 2

Spain

MMI 10 mg OD Aplasia Cutis and choanal atresia

(N= 1)

Aplasia Cutis and bilateral terminal

reduction of toes 2 to 5 with

absence of nails (N = 1)

Douchement et al

(2010) (52)

N=1

Treatment during the

first 7 weeks of

pregnancy

CMZ 25 mg bid Bilateral choanal atresia,

tracheoesophageal fistula, and

bilateral fifth-finger clinodactyly

Gripp et al (2011) (53)

N=5

MMI use in early

pregnancy

Variable doses Microtia (N=5), trachea esophageal

fistula (N=1), absence of the gall

bladder (N = 1), enlarged anterior

fontanel was seen (N = 3),

clinodactyly of the fifth finger (N

= 3).

Koenig et al (2010)

(42)

N = 6

Exposure during the

first trimester of

pregnancy

CMZ 5-60 mg OD Abdominal wall defect (N = 2,

including one associated with

facial dysmorphia); patent

omphalomesenteric duct (N = 1);

Aplasia cutis (N = 2, including one

with facial dysmorphism); bilateral

choanal atresia with aorta

coarctation (N = 1, mother had

poorly controlled insulin

dependent diabetes)

11. Summary of available data on comparative cost and cost-effectiveness of the medicine

Based on pooled European data, the average prevalence of Graves disease is estimated at

0.75%. The cost of PTU, MMI and CMZ markedly varies from country to country. We

assume the following average equivalence between MMI, CMZ and PTU: MMI 10 mg=

CMZ 15 mg (assuming an equivalence of 140% CMZ compared to MMI and rounding to the

nearest tablet strength) = PTU 100-200 mg (assuming an equivalence of 10-20 mg PTU for 1

mg MMI).

The cost per mg for the ATDs to the government is shown for 5 countries in 4 continents.

Significant differences can be seen:

Botswana: CMZ 5 mg only (PTU not available): cost for 100 tablets = 10 USD (Source: Dr J

Dipesalema, Pediatric Endocrinologist, University of Botswana/Princess Marina Hospital,

Gaborone)

Canada: MMI 5 mg: cost for 100 tablets = 36 USD; MMI 10 mg: cost for 100 tablets = 62

USD; PTU 50 mg: cost for 100 tablets = 32 USD (Source: Roxane Carr, Pharmacist, BC

Children’s Hospital, Vancouver).

Chile: MMI 5 mg: cost for 100 tablets = 22 USD; MMI 10 mg: cost for 100 tablets = 34 USD

(Dr A Martinez, Pediatric Endocrinologist, Universidad Católica, Santiago)

Ghana: CMZ 5mg: cost for 100 tablets = 20 USD; CMZ 10 mg: cost for 100 tablets = 30

USD; PTU 50 mg: cost for 100 tablets = 38 USD (Source: Dr E Ameyaw, Pediatric

Endocrinologist, KATH, Kumasi)

Indonesia: MMI 5 mg: cost for 100 tablets= 7.19 USD; MMI 10 mg: cost for 100 tablets =

11.17 USD; CMZ 5 mg: cost for 100 tablets = 14 USD; PTU 100 mg. Cost for 100 tablets =

3.9 USD (Dr Aman Pulungan, Pediatric Endocrinologist, Jakarta, Indonesia)

Based on the following assumptions, cost per patient per month can be calculated:

- Average induction daily dose for 3 months: 20 mg MMI, 30 mg CMZ and 200-400

mg PTU

- Average daily dose during core treatment for 2 years: 10 mg MMI, 15 mg CMZ and

100-200 mg PTU

Table 10: Comparison of the costs of 1 mo of treatment during the induction period and the

core treatment period in the 5 countries listed above.

Botswana Canada Chile Ghana Indonesia

Induction (USD/mo)

MMI 10 mg 37 20 7

CMZ 5 or 10 mg 18 27

PTU 50 or 100 mg 58 68 3.5

Core (USD/mo)

MMI 10 mg 18.5 10 3.5

CMZ 5 or 10 mg 9 13.5

PTU 50 or 100 mg 29 34 1.8

In addition, an average 65% of patients will NOT achieve remission after 2 years. Depending

on availability of radioiodine, of surgery and depending on personal preferences of the patient

and of the physician, some patients will continue on antithyroid drugs indefinitely at an

estimated maintenance dose of 5-10 mg MMI, 7.5-15 mg CMZ and 50-100 mg PTU.

12. Summary of the regulatory status and market availability of the medicine

One of the 3 ATDs is registered or available in most countries. Very often, countries will

make available PTU (preferred in pregnant mothers during the first trimester of pregnancy)

and either MMI or CMZ.

13. Availability of pharmacopoeial standards – International, British, US and European

pharmacopoeias

International Pharmacopoeia: PTU

European Pharmacopoeia (EuP): CMZ and PTU

British Pharmacopoeia: CMZ and PTU

US Pharmacopoeia: MMI and PTU

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