Safety Alerts
Risk of hypomagnesaemia associated with long-term use of proton pump inhibitors
22 August 2011
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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HSA would like to inform healthcare professionals that emerging data has shown that proton pump inhibitors (PPIs) may cause hypomagnesaemia if taken for prolonged periods of time. This applies especially to treatment duration with PPIs that exceed one year. Low serum magnesium levels can result in serious adverse events including tetany, arrhythmias and convulsions. This risk may be increased for patients on concomitant drugs known to deplete magnesium, such as digoxin and diuretics. Patients who develop hypomagnesaemia, besides requiring magnesium supplementation, may also need to discontinue their PPI therapy.
PPIs are indicated for a variety of conditions such as gastro-oesophageal reflux disease, acid-related dyspepsia, gastric and duodenal ulcers, and reflux oesophagitis. PPIs include omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
Regulatory actions taken by the US Food and Drug Administration (FDA)
In March 2011, the US FDA announced that it would be adding information about the potential risk of hypomagnesaemia with prolonged PPI use into the package inserts of all prescription PPIs.1 This warning arose from the FDA's review of this safety issue, which focused on 38 cases in the US Adverse Event Reporting System (AERS) and an additional 15 cases reported in the literature. The data reviewed by FDA suggested an association between hypomagnesaemia-related serious adverse events and prolonged PPI use. However, since hypomagnesaemia has not been formally known to be associated with the use of PPIs, this condition is likely under-recognised and under-reported. As such, the available data is insufficient to quantify an incidence rate for hypomagnesaemia with PPI therapy.
Most cases of hypomagnesaemia occurred after a year of treatment with PPIs, with some reported in adult patients after taking PPIs for three months. In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued. The median time required for magnesium to normalise was one week after discontinuing the PPI, whereas the median time to develop hypomagnesaemia again after re-challenging the PPI was two weeks.
Serious adverse events observed with hypomagnesaemia included tetany, seizures, tremors, carpo-pedal spasm, atrial fibrillation, supraventricular tachycardia, and abnormal QT interval. Hypomagnesaemia also produces impaired parathyroid hormone secretion which may lead to hypocalcaemia. The mechanism responsible for hypomagnesaemia associated with long-term PPI use is currently unknown. However, it may be related to changes in the intestinal absorption of magnesium.
HSA's advisory
To date, HSA has not received any local reports of hypomagnesaemia associated with PPI use, but this could likely be due to under-recognition of this adverse effect. HSA is working with the licence holders of PPI products to strengthen the local package insert for all PPIs to include warnings that reflect the above safety issue. In addition, HSA recommends that healthcare professionals may consider monitoring magnesium levels prior to the initiation of PPI treatment and periodically in patients expected to be on prolonged PPI treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (eg, diuretics).
For patients taking digoxin concomittantly, periodic monitoring of serum magnesium level is especially important because hypomagnesaemia can increase myocardial sensitivity to cardiac glycosides.
In most patients, treatment of hypomagnesaemia may require magnesium replacement and discontinuation of the PPI. Patients should be advised to seek immediate care from a healthcare professional if they experience arrhythmias, tetany, tremors, or seizures while on prolonged treatment.
Healthcare professionals are also strongly encouraged to report any adverse reactions suspected to be associated with PPIs to the Vigilance Branch of HSA.