Background of Safety Issue

(i) Risk of birth defects and neonatal disorders in case of exposure during pregnancy

In December 2018, based on the assessment of epidemiological studies and case reports, the European Medicines Agency (EMA) has concluded that there is a strong association of carbimazole or methimazole (also known as thiamazole, the active form of carbimazole) with congenital malformation when administered during pregnancy, particularly at high doses and during the first trimester of pregnancy. Reported malformations include aplasia cutis congenita, craniofacial malformations (choanal atresia; facial dysmorphism), exomphalos, oesophageal atresia, omphalo-mesentric duct anomaly and ventricular septal defect¹.

EMA requested the product registration holders of carbimazole and methimazole to update the product information to include further advice for women of childbearing potential to use effective contraception during treatment. The use of these drugs in pregnant women should also be based on individual benefit/risk assessment. If it is to be used during pregnancy, the lowest effective dose without additional administration of thyroid hormones should be administered, and close maternal, foetal and neonatal monitoring is recommended.

(ii) Risk of pancreatitis

Recent data demonstrates the association of carbimazole and methimazole with pancreatitis. Based on all available evidence, EMA is requiring all product package inserts of carbimazole and methimazole to be updated with a new contraindication in patients with a history of acute pancreatitis after administration of carbimazole or methimazole.

Adverse Drug Reaction Reports

NPRA has received 332 reports with 593 adverse events suspected to be related to carbimazole and four (4) reports with five (5) adverse events with methimazole.  No report has been received regarding congenital malformation or pancreatitis suspected to be related to carbimazole or methimazole².

Advice for Healthcare Professionals

• Based on available evidence, carbimazole and methimazole may cause congenital malformations when administered during pregnancy, particularly in the first trimester of pregnancy and at high doses.
• Careful benefit/risk assessment should be carried out prior to treatment with carbimazole or methimazole during pregnancy. Use the lowest effective dose without any additional administration of thyroid hormone.
• Patients of child-bearing potential should be advised to use reliable contraception during treatment and inform their healthcare professionals if they become pregnant or are planning to have a baby.
• If a patient develops acute pancreatitis after the administration of carbimazole or methimazole, these drugs should be discontinued immediately. Re-exposure to patients with history of acute pancreatitis may result in recurrence of acute pancreatitis with decreased time to onset.
• Inform patients on the signs of acute pancreatitis such as fever or abdominal pain, and to seek immediate attention if it occurs.
• Report any adverse drug reactions related to carbimazole or methimazole to NPRA.

References:

1. European Medicine Agency (2019). PRAC recommendations on signals: Adopted at the 26 – 29 November 2018 PRAC meeting. EMA/PRAC/826440/2018.
2. The Malaysian Adverse Drug Reaction Database, NPRA [Accessed: February 2019].

DISCLAIMER
This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.