Overview

Acetazolamide is a carbonic anhydrous inhibitor. By acting on renal tubules, it increases excretion of bicarbonate, sodium and potassium resulting in alkaline diuresis¹. It is commonly used to decrease ocular aqueous humor secretion in glaucoma². It is also used as an adjunct in the treatment of certain types of epilepsy, or alkalinizing urine in cases of salicylate overdose and to treat abnormal retention of fluids^2,3.

Acetazolamide is known to be teratogenic or embryotoxic (oral or parenteral dosing) in mice, rats, rabbits and hamsters for doses exceeding ten times the recommended in man^1,2,3.

Background of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received information from the French National Agency for Medicines and Health Products Safety (ANSM), on the new contraindication of acetazolamide during the first trimester of pregnancy⁴. In the 2^nd and 3^rd trimesters of pregnancy, its use is restricted to situations of absolute necessity (for example in the emergency treatment of glaucoma and absence of safer alternatives) and requires special monitoring⁴.

Despite limited data, ANSM confirmed the signal of malformative effects and toxicity in the fetus since acetazolamide is a known animal teratogen, and the malformation is consistent with its mechanism of action⁴.

In case of exposure during pregnancy, the ANSM is requiring healthcare professionals to carry out specialised prenatal follow-up for malformations, including surveillance of the volume of the amniotic fluid and hydroelectrolytic assessment in the newborn⁴.

Local Scenario

In Malaysia, there are three (3) acetazolamide-containing products registered currently⁵.

Although there is currently no evidence of teratogenic or embryotoxic effects in human beings, and no adequate and well-controlled studies in pregnant women, the acetazolamide package insert (including Malaysia) already states that acetazolamide should not be used in pregnancy, especially during the first trimester, or should only used in pregnancy if the potential benefit justifies the potential risk^1,2,3.

Adverse Drug Reaction Reports⁶

Since year 2000, the NPRA has received a total of 28 reports with 51 adverse events suspected to be related to acetazolamide-containing products. Among the reports, the most reported adverse reactions were hypoaesthesia (3), rash (3) and rash maculo-papular (3). To date, no ADR related to teratogenicity or malformation following the use of acetazolamide has been reported to the NPRA.

Advice for Healthcare Professionals

• Acetazolamide should not be used in pregnancy, especially during the first trimester.
• Acetazolamide may only be used in pregnancy if the potential benefit justifies the potential risk. Consider other available alternatives before using acetazolamide in pregnancy.
• Carry out specialised prenatal follow up and assessment in the newborn in case of exposure during pregnancy (ultrasound, monitoring of amniotic fluid volume, hydro-electrolytic assessment, etc.).
• Please report all adverse events, especially pregnancy exposure suspected to be related to acetazolamide to the NPRA.

References:

1. Malaysian Acetomid Tablet package insert. (Version: February 2017)
2. Malaysian Apo-Acetazolamide package insert. (Version: May 2008)
3. Malaysian Acetazolamide 500mg Powder for Solution for Injection package insert. (Version: Nov 2010)
4. The French National Agency for the Safety of Medicines and Health Products (2018). Acetazolamide (Diamox and Defiltran): a new contraindication during pregnancy - Information point.
5. The NPRA QUEST 3+ database [Accessed: 12/11/2018]
6. The Malaysian Adverse Drug Reaction database, NPRA [Accessed: 12/11/2018]

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.