Greater Glasgow and Clyde Medicines

Proton Pump Inhibitors (PPIs): Adverse Effects Reported by the MHRA

This is last in a series of PPI blogs

Key points:

  • Increased risk of fracture, hypomagnesaemia and subacute cutaneous lupus erythematosus (SCLE) are significant adverse effects associated with PPI use that have been reported by the MHRA

  • Due to the risk of fractures in patients taking PPIs, assess osteoporosis risk and dietary intake of calcium / vitamin D

  • Consider checking serum magnesium before and periodically throughout PPI therapy, especially in patients with additional risk factors for hypomagnesaemia

  • Consider possible SCLE diagnosis in patients on a PPI who present with new-onset photosensitive rash

  • Report suspected side effects via the MHRA Yellow Card scheme. Refer to Yellow Card Reporting – An update for healthcare professionals for further information on reporting

 

Fractures

  • It is thought that long-term PPI use impairs dietary calcium absorption, which may increase the risk of fractures due to reduced bone density. Risk is associated with prolonged use (i.e. >1 year) and high doses. Elderly patients are the most affected.

  • Several meta-analyses have demonstrated a ‘modest’ increase in the risk of wrist, hip, and spinal fractures (10-40% from baseline). Whilst studies vary in their adjustment for other risk factors and calcium / vitamin D intake, the role of PPIs cannot be excluded.

  • In all patients prescribed a long-term PPI, assess the risk of osteoporosis / fractures, ensure adequate calcium and vitamin D intake, and treat patients at risk of osteoporosis in accordance with the current guidance.

 

Hypomagnesaemia

  • It is unclear how PPIs affect serum magnesium levels; it is thought that they may impair intestinal magnesium absorption or reduce intestinal transport. Most evidence for the association between PPIs and hypomagnesaemia is based on case reports, with a very variable time to onset (weeks to years).

  • Symptoms include muscle twitches, tremor, vomiting, fatigue, delirium, arrhythmias and convulsions. These can develop gradually and be overlooked; it is important to also consider over-the-counter use of PPIs.

  • The MHRA have advised to consider checking serum magnesium levels before and periodically throughout PPI treatment, especially in those taking other medicines that may contribute to hypomagnesaemia (e.g. diuretics, ciclosporin, aminoglycoside antibiotics, insulin, and cetuximab).

  • NHSGGC Biochemistry have also recommended that serum magnesium levels be checked for patients who:

    • Have symptoms of hypomagnesaemia

    • Have hypokalaemia or hypocalcaemia

    • Are taking digoxin

    • Have other causes of magnesium deficiency (e.g. prescribed diuretics, malabsorption syndromes, stoma losses etc.)

 

Subacute cutaneous lupus erythematosus (SCLE)

  • SCLE is characterised by a widespread photosensitive rash. This usually takes the appearance of erythematous ring-shaped regions containing scaly plaques and raised papules. Arthralgia may also be present. There have been very rare reports of SCLE with PPIs.
  • A small number of studies and case reports have indicated a possible association with the use of PPIs. Notably, there have been instances of symptom resolution after stopping a PPI, plus less-frequent reports of symptoms returning on restarting a different PPI.
  • The evidence, whilst limited, indicates a class effect, and that onset varies from weeks to years. It usually resolves on cessation of the PPI without scarring. In patients who develop these signs / symptoms:

    • Consider SCLE as a possible diagnosis

    • Consider whether the PPI can be stopped, depending on the severity of the condition and need; note symptoms may recur even if the patient is changed to another PPI
    • Advise covering the skin and using broad-spectrum sunscreen on exposed areas

 

Patient Scenarios - Hypomagnesaemia

Scenario 1

A 56-year-old woman developed vomiting and diarrhoea, most likely due to infection with norovirus. Her usual medication was omeprazole 20 mg daily and amlodipine 5 mg daily. She had a history of excessive alcohol consumption. Two days after the vomiting and diarrhoea had settled, her GP referred her for admission to hospital due to ongoing weakness and anorexia. On admission there were no abnormal physical findings. Her serum magnesium was low at 0.4mmol/L and her serum potassium was low at 3mmol/L. The rest of her results were unremarkable.

What are the issues?

  • Consider that certain patient groups may be more at risk of hypomagnesaemia if nutrition status is poor, e.g. alcohol misuse.

  • When additional risk factors for hypomagnesaemia are present alongside PPI use, the cause may be undetermined / multifactorial. However, the PPI should still be reviewed on a case-by-case basis as it may be contributing to the patient’s condition.

  • Symptoms of hypomagnesaemia may begin insidiously and so the cause may be overlooked.

What could be done in this patient?

  • Magnesium and potassium should be replaced as per local guidelines. Refer to the NHSGGC Adult Therapeutics Handbook.

  • The indication for the PPI should be noted and it should be stopped if possible. Alternatives to the PPI should be considered if necessary.

  • Her symptoms of weakness and her dietary intake should be monitored.

  • The patient should be encouraged to reduce her excessive alcohol consumption (a referral to the Addictions team could be considered if appropriate).

 

Scenario 2

An elderly patient on long-term PPI treatment presented to the GP with dizziness and falls. There were no abnormal neurological findings. Electrolyte imbalance was considered as a possible cause. Their magnesium level was found to be low.

What are the issues?

  • Many patients present in primary care with non-specific issues which can be difficult to explain.

  • This case highlights the potential to consider adverse drug reactions as a cause of vague presentations.

  • Ruling out possible causes is an important part of the diagnostic process. If electrolyte imbalance had not been identified, this patient may have been given unnecessary drug therapy to treat the symptoms rather than the cause. Accurate diagnosis helps to avoid polypharmacy.

What could be done in this patient?

  • Magnesium should be replaced and monitored as per local guidance. Refer to the NHSGGC Adult Therapeutics Handbook.
  • Her urea and electrolytes (U+Es) and symptoms should be monitored for any improvement in her condition.
  • The indication for the PPI should be noted and it should be stopped if possible. Alternatives to the PPI should be considered if clinically appropriate.
  • If the PPI cannot be stopped, magnesium supplementation could be considered, based on clinical judgement and local guidance.

 

For further information, refer to the other blogs in the PPI series:

General overview of oral Proton Pump Inhibitors (PPIs)

Proton pump inhibitors (PPIs): potential link with Clostridioides difficile infection and pneumonia

 

Published: 01/02/2023. Medicines Update blogs are correct at the time of publishing