Risk of acute pancreatitis and congenital malformations associated with the use of carbimazole or thiamazole

HSA would like to bring the attention of healthcare professionals to overseas case reports of acute pancreatitis with the use of carbimazole or thiamazole and to update on the known risk of congenital malformations associated with these products.

Carbimazole and its active metabolite thiamazole (synonym: methimazole), are antithyroid agents that inhibit the activity of thyroid peroxidase, a key enzyme in thyroid hormone biosynthesis. Carbimazole and thiamazole have been registered in Singapore since 1990 and 1997, respectively. They are indicated for the treatment of hyperthyroidism, including preparation for thyroidectomy and treatment before and after radioiodine treatment.

Findings from published case reports and epidemiological studies

a) Risk of acute pancreatitis

Overseas cases of carbimazole- and thiamazole-induced acute pancreatitis have been reported in literature.^1-8 The majority of these cases involved females and patients aged 55 years and above, who developed acute pancreatitis within two to three weeks following initiation of carbimazole or thiamazole therapy (range: four days to three months). Known risk factors for pancreatitis (e.g. hypertriglyceridemia, chronic alcohol consumption, cholelithiasis, autoimmune diseases) were ruled out by the reporting physician or denied by the patient. Positive dechallenge was seen in all these patients, whose symptoms and examination findings improved following withdrawal of carbimazole or thiamazole and conservative treatment. Reintroduction of carbimazole or thiamazole to some patients led to recurrent acute pancreatitis with a decreased time-to-onset (TTO) (i.e. after the single or second dose of carbimazole or thiamazole in most of the cases), suggesting an immune-mediated mechanism. Although the sulfhydryl group of carbimazole and thiamazole has been postulated to be involved in the drug-induced autoimmunisation,^{1, 3} its exact role in the development of acute pancreatitis remains to be confirmed. 

b) Update on risk of congenital malformations

Carbimazole and thiamazole are known to cross the placenta and are suspected to cause congenital malformations. Recent studies have provided further evidence of an increased risk of congenital malformations with carbimazole or thiamazole use during pregnancy. A recent meta-analysis of 12 published case-control and cohort studies demonstrated that exposure to carbimazole or thiamazole during pregnancy increased the risk of congenital malformations compared to no antithyroid drug exposure (odds ratio [OR] 1.88; 95% confidence interval [CI] 1.33-2.65).⁹ In addition, a Korean nationwide cohort study using a prescription claims database observed a 1.3-fold (95% CI 1.06-1.63) increased congenital malformation risk with exposure to thiamazole during the first trimester compared with pregnancies without antithyroid drug prescriptions, corresponding to 17 additional congenital malformation cases (95% CI 1.94-32.15) per 1,000 live births.¹⁰ The authors also found that high cumulative thiamazole dose (> 495 mg) was associated with a 1.87-fold (95% CI 1.06-3.30) increased congenital malformation risk compared with low cumulative dose (up to 126 mg). The mechanism underlying carbimazole or thiamazole embryopathy remains unknown, and the contribution of maternal hyperthyroidism to the risk of congenital malformations is poorly understood.

Regulatory actions taken by EMA

In January 2019, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) issued its recommendations on the risk of acute pancreatitis and congenital malformations with carbimazole and thiamazole.¹¹ The committee’s review of the EudraVigilance (the European adverse event database) and literature identified post-marketing reports of acute pancreatitis with carbimazole or thiamazole. In the cases reporting recurrent acute pancreatitis, a decreased TTO after re-exposure to carbimazole or thiamazole was noted, suggesting a possible immunological mechanism. The committee considered that the available data demonstrated an association between both carbimazole and thiamazole with acute pancreatitis. As a result, the European product information (PI) for carbimazole- and thiamazole-containing products will be updated to include a warning on risk of acute pancreatitis and a contraindication for use in patients with a history of acute pancreatitis after administration of carbimazole or thiamazole.

The PRAC also concluded that data from case reports and epidemiological studies further strengthened the evidence for an increased risk of congenital malformations with carbimazole and thiamazole use, especially when administered in the first trimester of pregnancy and at high doses (15 mg or more of carbimazole daily).¹² Reported malformations included aplasia cutis congenita (absence of a portion of skin, often localised on the head), craniofacial malformations (choanal atresia; facial dysmorphism), defects of the abdominal wall and gastrointestinal tract (exomphalos, oesophageal atresia, omphalo-mesenteric duct anomaly), and ventricular septal defect. Consequently, the European PIs for carbimazole- and thiamazole-containing products will be updated with new advice on contraception and pregnancy, including use of effective contraception during treatment in women of childbearing potential during treatment, as well as close maternal, foetal and neonatal monitoring when carbimazole or thiamazole is used during pregnancy.

Local situation and HSA’s advisory

To date, HSA has received one local report of pancreatitis associated with carbimazole use in a 69-year-old female, with no further details provided. No local reports of congenital malformations associated with carbimazole or thiamazole use have been received. In March 2019, a Dear Healthcare Professional Letter was issued by the product registrant for Thyrozol^® (Merck Pte Ltd) to inform healthcare professionals about these safety concerns.¹³ The local package inserts for all carbimazole- and thiamazole-containing products will be updated to warn about these risks, including a new contraindication for use in patients with a history of acute pancreatitis after administration of carbimazole or thiamazole, and a new recommendation to use effective contraceptive measures during treatment.

Healthcare professionals are advised to take into consideration the above safety information when prescribing carbimazole and thiamazole. If acute pancreatitis is suspected, healthcare professionals are advised to consider immediate discontinuation of carbimazole and thiamazole. These drugs should also be avoided in patients with a history of acute pancreatitis following administration of carbimazole or thiamazole as re-exposure might result in recurrence of acute pancreatitis with a decreased TTO.

Healthcare professionals are also encouraged to counsel women of childbearing potential on the importance of using effective and reliable contraception during treatment with carbimazole or thiamazole. When carbimazole or thiamazole is prescribed during pregnancy following a positive benefit versus risk assessment, the lowest effective dose should be used together with close maternal, foetal and neonatal monitoring.

References

1. Clin Endorinol 1999; 51: 667-70.

2. Endocr J 2002; 49: 315-8.

3. Endocr Pract 2011; 17: 960-2.

4. Thyroid 2012; 22: 94–6.

5. Case Rep Gastroenterol 2012; 6: 223–31.

6. J Korean Med Sci 2014; 29: 1170–3.

7. J Investig Med High Impact Case Rep 2015; 3: 2324709615592229.

8. Clin J Gastroenterol 2018 Nov 24.

9. PLoS ONE 2017; 12: e0180108.

10. Ann Intern Med 2018; 168: 405-13.

11. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-26-29-november-2018-prac-meeting_en.pdf

12. https://www.gov.uk/drug-safety-update/carbimazole-increased-risk-of-congenital-malformations-strengthened-advice-on-contraception

13. https://www.hsa.gov.sg/announcements/thyrozol--thiamazole-synonym-methimazole--new-risk-of-acute-pancreatitis-and-update-on-risk-of-congenital-malformations/