sign in sign up
<<
Home , Carbimazole, Propylthiouracil, Thiamazole

Essential Medicines List (EML) 2019

Application for the revision of first line treatment of primary in the adult and children’s WHO EML: methimazole (MMI)/ (CMZ) vs (PTU)

Submitted by: Global Pediatric Endocrinology and (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: [email protected]; 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 . 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 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 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 ) with a square box, representative of the pharmacological class of - containing 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 , during , 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: [email protected]

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: [email protected]

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 thyroperoxidase, which adds to residues on the thyroxine hormone precursor thyroglobuline. PTU also inhibits the enzyme tetraiodothyronine 5’, which converts thyroxine (T4) to (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 ( or liver failure) by the patient. Normalization of the 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. of PTU and MMI in the breastmilk has not been shown to be associated with neonatal 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 that were available at the time (20).

Table 2 Effectiveness of PTU, MMI and CMZ

Trial Patients Intervention Outcome Adults Sriussadaporn et al Thailand MMI 15 mg OD vs Serum FT3 and FT4 reductions, (2017) (21) 50 patients included MMI 15 mg (5 mg and cumulative rate of achieving RCT (44 analysed, 33F: TID) euthyroidism (28.6% versus 12 weeks 11M, mean age 38 34.8%, 71.4% versus 82.6%, and years) 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) Japan MMI 30 mg/d (15 Overall, MMI 30 mg/d (22) Mean age 40 years mg BID) vs normalized FT4 in more patients RCT 396 patients included PTU 300 mg/d (100 than PTU 300 mg/d and MMI 15 12 weeks (303 analysed) mg TID) vs mg/d at 12 wk (96.5 vs. 78.3%; P MMI 15 mg/d (OD) = 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) China (Taiwan) PTU 150 mg OD vs After 12 weeks, MMI OD was RCT 30 patients (21F: 9 M) MMI 15 mg OD better than PTU OD in decreasing 12 weeks Mean age 31.5 years FT4 and FT3 as well as TSH Abs. Mafauzy et al Malaysia CMZ 30 mg OD After 6 weeks, mean thyroid (2003) (24) 70 patients included (48 (30 mg OD vs 15 mg hormone concentrations were not patients analyzed) BID vs 10 mg TID different between the 3 groups. RCT More patients were hypothyroid 6 weeks when CMZ was taken OD, possibly reflecting better compliance with OD compared to TID. Homsanit et al Thailand PTU 150 mg OD vs Compared with PTU treatment, (2001) (25) MMI 15 mg OD FT3 concentrations were lower RCT 71 patients (62F: 9 M) after 4 weeks and FT4 lower after 12 weeks Mean age 35 years 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 USA PTU 300 mg (100 At 3 months, MMI once a day (1995) (26) 29 patients (22 patients mg TID) vs MMI 30 was as effective as PTU TID. RCT analyzed) mg OD Compliance was higher with MMI 12 weeks (83%) compared to PTU (53%). Children and adolescents

Sato et al (2011) Japan 4 groups: The mean duration for (27) Mean age 12 years M1 (< 0.75 mg/kg normalization of FT4 was Retrospective study 133 patients included MMI, n = 34) significantly longer in group P1 (MMI group: N = 64, M2 (≥ 0.75 mg/kg (3.1 ± 3.3 months) compared to 55F:9M) MMI, n = 30) the other subgroups (M1: 1.9 ± (PTU group: N = 69, P1 (< 7.5 mg/kg 1.2; M2: 1.4 ± 0.7; P2; 1.7 ± 1.3). 59F:10M) PTU, n = 24) P2 (≥ 7.5 mg/kg PTU, n = 45).

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) Japan MMI 30 mg/d (15 The incidence of adverse events (22) Mean age 40 years mg BID) vs was higher in the PTU group, with RCT 396 patients included PTU 300 mg/d (100 54 of 104 patients) having some 12 weeks (303 analysed) mg TID) vs adverse effects. PTU was stopped MMI 15 mg/d (OD) 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) Taiwan PTU (24,941) and MMI/CBM vs. PTU users had a (28) 92% < 65 years of age; MMI/CMZ (46,438) higher hepatitis incidence rate 77-82% female (3.17/1000 vs. 1.19/1000 person- Retrospective years) but a lower incidence of cohort using acute liver failure (0.32/1000 vs. administrative 0.68/1000 person-years). database (2004-8) CMZ was not associated with the 71,379 ATD hepatitis risk (adjusted HR 1.04, initiators, with a 95% CI 0.50,2.16). median follow-up of 196 days

Pediatric cohort and RCT studies Sato et al (2011) Japan 4 groups: No serious adverse reaction such (27) Mean age 12 years M1 (< 0.75 mg/kg as agranulocytosis, severe liver Retrospective study 133 patients included MMI, n = 34) failure, or MPOANCA-associated (MMI group: N = 64, M2 (≥ 0.75 mg/kg nephritis or . 55F:9M) MMI, n = 30) Minor adverse effects occurred in (PTU group: N = 69, P1 (< 7.5 mg/kg 16 patients of group MMI (25.0 % 59F:10M) PTU, n = 24) ) and 22 in group PTU (31.9 % ) P2 (≥ 7.5 mg/kg (NS): skin eruption, liver PTU, n = 45). dysfunction, , 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) United States Dose: PTU (28 Adverse drug reactions occurred RCT Prepubertal, 7 patients patients, 70%), mean in 35% during the first 24 weeks 40 children (three boys, 43%), dose 6.4 mg/kg/day of the treatment: major in 5% mean age 6.4 yr; MMI (12 patients, patients and minor in 30% Median follow up: pubertal, 21 patients 30%), mean dose of patients. There was no difference 4 years (four boys, 19%) of 0.74 mg/kg/day) in side effects between patients mean age 12.5 yr; receiving PTU or MTZ within the Postpubertal, 12 same age group. patients (three boys, 25%), mean age 16.2 yr. Case reports CMZ/MMI Ferguson C et al 41-year-old woman CMZ (dose not Unilateral exudative effusion with (2018) (29) reported), beta- prominent eosinophils on pleural blockers and cytology 4 weeks after starting Case report CMZ. The patient received N=1 treatment for pleural empyema, including antibiotics and intercostal drain insertion. Pleural effusion did not reaccumulate after discontinuation of CMZ Gaspar-da-costa et 75-year-old man MMI (dose not Unilateral pleural effusion with al. (2017) (30) reported). Chronic eosinophils 6 days after starting medicines: enalapril, methimazole. Past history of Case report carvedilol, arterial hypertension, atrial N=1 nifedipine, aspirin, fibrillation, end-stage renal , disease on haemodialysis, omeprazole and peripheral artery disease and tansulosin prostatic hyperplasia. Cardona Attard et 42-year old man CMZ 10 mg OD for Bilateral exudative pleural al. (2016) (31) > 2 years effusions and liver toxicity. Resolved 5 months after Case report discontinuation of CMZ N=1 Lim et al (2013) 24-year old Chinese CMZ 40 mg for 2 Myositis, resolved with (32) woman months discontinuation of CMZ

Case report N=1 Haq et al. (2013) 50-year old woman CMZ 40 mg Systemic lupus erythematosus, (33) manifesting as serositis resulting in an exudative pleural effusion Case report and a proinflammatory/ N=1 prothrombotic state. Resolved with discontinuation of CMZ. Mavrakanas et al. 66 year old man CMZ 30 mg, Anti- cytoplasmic (2013) (34) decreased to 10 mg antibodies (ANCA)-associated OD vasculitis. Patient remained in Case report dialysis 6 months after N=1 discontinuation of the CMZ. Patient also had diabetes Raja et al (2010) 68 year-old male CMZ 20 mg OD Sensorineural deafness and (35) tinnitus. Resolved after discontinuation Case report N = 1 Jain et al (2010) 45 year-old female CMZ 30 mg OD Acute cholestatic hepatitis along (36) 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 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) China CMZ median dose Aplasia cutis (N = 3), 10 mg OD (Range ((N = 1). Embryopathy risk: 14.8% Retrospective cohort 2.5-40 mg) (2008-2010)

N = 29 treated mothers treated (27 infants examined) Andersen et al (2013) Denmark High prevalence of birth defects in (45) First trimester of children exposed to ATD in early Registry study (1996- pregnancy pregnancy (PTU, 8.0%; 2008) MMI/CMZ, 9.1%; MMI/CMZ and PTU, 10.1%; no ATD, 5.4%; PTU (N = 564); nonexposed, 5.7%; P<.001). Both MMI/CMZ (N = maternal use of MMI/CMZ 1097); (adjusted OR = 1.66 [95% CI MMI/CMZ and PTU 1.35–2.04]) and PTU (1.41 [1.03– (shifted in early 1.92]) and maternal shift between pregnancy (N = 159); MMI/CMZ and PTU in early no ATD during pregnancy (1.82 [1.08 –3.07]) were pregnancy (N = 3543); associated with an increased risk of never ATD use (N = birth defects. MMI/CMZ and PTU 811 730) 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) United States MMI or PTU The rates of congenital defects (per (46) 1000 infants) associated with ATD Retrospective use were 55.6 for MMI, 72.1 for administrative database PTU, and 65.8 for untreated analysis women with Graves disease N = 8050 treated compared to 58.8 among women N = 801,551 untreated without Graves disease. Wing (1994) (47) USA MMI: N = 36 Incidence of major congenital Retrospective cohort Graves disease (Median dose 40 anomalies in infants of PTU- 1974-1990 Mean age 40 years mg OD) treated mothers was 3.0% (three of N = 185 pregnant PTU: N = 99 99 with heart defects, although all mothers (Median dose: 450 3 mothers were treated with PTU mg OD) after 15 weeks of gestation). The Untreated: N = 43 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) Australia, 2 siblings CMZ 30 mg Minor dental anomalies (N = 2) N= 2 decreased to 15 Right sided choanal atresia, mg (N = 1) and 15 hypoplastic alae nasi, upslanting mg (N =1) 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) France CMZ 20 mg BID Esophageal atresia, small N = 1 22 year-old pregnant (first 4 weeks of omphalocele, and ileal prolapse woman gestation) through a patent omphalomesenteric duct Bowman (2012) (50) United Kingdom CMZ 40mg and L- Atypical umbilical stump, patent N = 1 T4 100 mcg OD vitellointestinal duct and aplasia cutis Rodriguez-Garcia Spain MMI 10 mg OD Aplasia Cutis and choanal atresia (2011) (51) (N= 1) N = 2 Aplasia Cutis and bilateral terminal reduction of toes 2 to 5 with absence of nails (N = 1) Douchement et al Treatment during the CMZ 25 mg bid Bilateral choanal atresia, (2010) (52) first 7 weeks of tracheoesophageal fistula, and N=1 pregnancy bilateral fifth-finger clinodactyly Gripp et al (2011) (53) MMI use in early Variable doses Microtia (N=5), trachea esophageal N=5 pregnancy 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) Exposure during the CMZ 5-60 mg OD Abdominal wall defect (N = 2, (42) first trimester of including one associated with N = 6 pregnancy 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

References 1. Khan S, Galliford T. A rare case of carbimazole-induced acute liver failure. Endocrine Abstracts. 2017:50 P415. 2. FDA Drug Safety Communication: New Boxed Warning on severe liver injury with propylthiouracil [cited (Accessed Nov 18, 2018). Available from: https://www.fda.gov/Drugs/DrugSafety/ucm209023.htm 3. Rivkees SA. 63 years and 715 days to the "boxed warning": unmasking of the propylthiouracil problem. Int J Pediatr Endocrinol. 2010;2010. 4. Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med. 2009;360(15):1574-5. 5. Emiliano AB, Governale L, Parks M, Cooper DS. Shifts in propylthiouracil and methimazole prescribing practices: antithyroid drug use in the United States from 1991 to 2008. J Clin Endocrinol Metab. 2010;95(5):2227-33. 6. Kahaly GJ, Bartalena L, Hegedus L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J. 2018;7(4):167-86. 7. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-421. 8. Committee on Pharmaceutical Affairs JSfPE, the Pediatric Committee JTA, Minamitani K, Sato H, Ohye H, Harada S, et al. Guidelines for the treatment of childhood-onset Graves' disease in Japan, 2016. Clin Pediatr Endocrinol. 2017;26(2):29- 62. 9. Dufour DR. Laboratory tests of thyroid function: uses and limitations. Endocrinol Metab Clin North Am. 2007;36(3):579-94, v. 10. Akmal A, Kung J. Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity. Expert Opin Drug Saf. 2014;13(10):1397-406. 11. Jansson R, Dahlberg PA, Lindstrom B. Comparative of carbimazole and methimazole. Int J Clin Pharmacol Ther Toxicol. 1983;21(10):505-10. 12. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906- 18. 13. Lee HS, Hwang JS. The treatment of Graves' disease in children and adolescents. Ann Pediatr Endocrinol Metab. 2014;19(3):122-6. 14. Cappa M, Bizzarri C, Crea F. Autoimmune thyroid diseases in children. J Thyroid Res. 2010;2011:675703. 15. McLeod DS, Caturegli P, Cooper DS, Matos PG, Hutfless S. Variation in rates of autoimmune thyroid disease by race/ethnicity in US military personnel. JAMA. 2014;311(15):1563-5. 16. Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14(5):301-16. 17. Reinwein D, Benker G, Lazarus JH, Alexander WD. A prospective randomized trial of antithyroid drug dose in Graves' disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab. 1993;76(6):1516-21. 18. Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab. 2000;85(10):3678-82. 19. Nguyen CT, Sasso EB, Barton L, Mestman JH. Graves' hyperthyroidism in pregnancy: a clinical review. Clin Diabetes Endocrinol. 2018;4:4. 20. McGavack. Methimazole and carbimazole in hyperthyroidism: a comparison by a double blind technique. Am J Med Sci. 1959;238(1):1-12. 21. Sriussadaporn S, Pumchumpol W, Lertwattanarak R, Kunavisarut T. Efficacy of Once Daily versus Divided Daily Administration of Low Daily Dosage (15 mg/Day) of Methimazole in the Induction of Euthyroidism in Graves' Hyperthyroidism: A Randomized Controlled Study. Int J Endocrinol. 2017;2017:2619695. 22. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab. 2007;92(6):2157-62. 23. He CT, Hsieh AT, Pei D, Hung YJ, Wu LY, Yang TC, et al. Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves' hyperthyroidism. Clin Endocrinol (Oxf). 2004;60(6):676-81. 24. Mafauzy M, Wan Mohamad WB, Zahary MK, Mustafa BE. Comparison of the efficacy of single and multiple regimens of carbimazole in the treatment of thyrotoxicosis. Med J Malaysia. 1993;48(1):71-5. 25. Homsanit M, Sriussadaporn S, Vannasaeng S, Peerapatdit T, Nitiyanant W, Vichayanrat A. Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism. Clin Endocrinol (Oxf). 2001;54(3):385-90. 26. Nicholas WC, Fischer RG, Stevenson RA, Bass JD. Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J. 1995;88(9):973-6. 27. Sato H, Minagawa M, Sasaki N, Sugihara S, Kazukawa I, Minamitani K, et al. Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome. J Pediatr Endocrinol Metab. 2011;24(5-6):257-63. 28. Wang MT, Lee WJ, Huang TY, Chu CL, Hsieh CH. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol. 2014;78(3):619-29. 29. Ferguson C, Bradley C, J. Carbimazole-induced eosinophilic pleural effusion. BMJ Case Rep. 2018;2018. 30. Gaspar-da-Costa P, Duarte Silva F, Henriques J, do Vale S, Braz S, Meneses Santos J, et al. Methimazole associated eosinophilic pleural effusion: a case report. BMC Pharmacol Toxicol. 2017;18(1):16. 31. Cardona Attard CD, Gruppetta M, Vassallo J, Vella S. Carbimazole-induced exudative pleural effusions. BMJ Case Rep. 2016;2016. 32. Lim AY, Kek PC, Soh AW. Carbimazole-induced myositis in the treatment of Graves' disease: a complication in genetically susceptible individuals? Singapore Med J. 2013;54(7):e133-6. 33. Haq I, Sosin MD, Wharton S, Gupta A. Carbimazole-induced lupus. BMJ Case Rep. 2013;2013. 34. Mavrakanas TA, Bouatou Y, Samer C, de Seigneux S, Meyer P. Carbimazole- induced, ANCA-associated, crescentic glomerulonephritis: case report and literature review. Ren Fail. 2013;35(3):414-7. 35. Raja UY, Kumar A, Possamai V, Warner D, Barton D. Drug-induced sensorineural deafness caused by antithyroid drugs: a rare side effect. J R Coll Physicians Edinb. 2010;40(3):219-20. 36. Jain K, Chakrapani M, Smitha K. Acute cholestatic hepatitis along with agranulocytosis: a rare side effect of carbimazole. Ann Afr Med. 2010;9(2):102-4. 37. Rivkees SA, Mattison DR. Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use. Int J Pediatr Endocrinol. 2009;2009:132041. 38. Marino M, Vitti P, Chiovato L. Graves’ Disease. In: Jameson JL, editor. Endocrinology: Adult and Pediatric. Philadelphia, PA: Elsevier Saunders; 2016. p. 1437-64. 39. Gao Y, Zhao MH, Guo XH, Xin G, Gao Y, Wang HY. The prevalence and target antigens of antithyroid drugs induced antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with hyperthyroidism. Endocr Res. 2004;30(2):205-13. 40. Huang CN, Hsu TC, Chou HH, Tsay GJ. Prevalence of perinuclear antineutrophil cytoplasmic antibody in patients with Graves' disease treated with propylthiouracil or methimazole in Taiwan. J Formos Med Assoc. 2004;103(4):274-9. 41. Balavoine AS, Glinoer D, Dubucquoi S, Wemeau JL. Antineutrophil Cytoplasmic Antibody-Positive Small-Vessel Vasculitis Associated with Antithyroid Drug Therapy: How Significant Is the Clinical Problem? Thyroid. 2015;25(12):1273-81. 42. Koenig D, Spreux A, Hieronimus S, Chichmanian RM, Bastiani F, Fenichel P, et al. Birth defects observed with maternal carbimazole treatment: Six cases reported to Nice's Pharmacovigilance Center. Ann Endocrinol (Paris). 2010;71(6):535-42. 43. Song R, Lin H, Chen Y, Zhang X, Feng W. Effects of methimazole and propylthiouracil exposure during pregnancy on the risk of neonatal congenital malformations: A meta-analysis. PLoS One. 2017;12(7):e0180108. 44. Ting YH, Zhou Y, Lao TT. Carbimazole embryopathy in a Chinese population: case series and literature review. Birth Defects Res A Clin Mol Teratol. 2013;97(4):225-9. 45. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab. 2013;98(11):4373- 81. 46. Korelitz JJ, McNally DL, Masters MN, Li SX, Xu Y, Rivkees SA. Prevalence of thyrotoxicosis, antithyroid medication use, and complications among pregnant women in the United States. Thyroid. 2013;23(6):758-65. 47. Wing DA, Millar LK, Koonings PP, Montoro MN, Mestman JH. A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol. 1994;170(1 Pt 1):90-5. 48. Goel H, Dudding T. Carbimazole/methimazole embryopathy in siblings: a possible genetic susceptibility. Birth Defects Res A Clin Mol Teratol. 2013;97(11):755-8. 49. Panait N, Michel F, D'Ercole C, Merrot T. Esophageal atresia, small omphalocele and ileal prolapse through a patent omphalomesenteric duct: a methimazole embryopathy? [Corrected]. J Pediatr Surg. 2013;48(6):E9-11. 50. Bowman P, Osborne NJ, Sturley R, Vaidya B. Carbimazole embryopathy: implications for the choice of antithyroid drugs in pregnancy. QJM. 2012;105(2):189-93. 51. Rodriguez-Garcia C, Gonzalez-Hernandez S, Hernandez-Martin A, Perez-Robayna N, Sanchez R, Torrelo A. Aplasia cutis congenita and other anomalies associated with methimazole exposure during pregnancy. Pediatr Dermatol. 2011;28(6):743-5. 52. Douchement D, Rakza T, Holder M, Bonne NX, Fayoux P. Choanal atresia associated with tracheoesophageal fistula: the spectrum of carbimazole embryopathy. Pediatrics. 2011;128(3):e703-6. 53. Gripp KW, Kuryan R, Schnur RE, Kothawala M, Davey LR, Antunes MJ, et al. Grade 1 microtia, wide anterior fontanel and novel type tracheo-esophageal fistula in methimazole embryopathy. Am J Med Genet A. 2011;155A(3):526-33.