Medicines Safety Update Volume 6, Number 6, December 2015

1 December 2015

Medicines Safety Update is the medicines safety bulletin of the Therapeutic Goods Administration (TGA).

In this issue

TGA investigates proton pump inhibitors and increased cardiovascular risk

A TGA review of two recent studies linking proton pump inhibitor use with an increased risk of myocardial infarction has found that neither adequately demonstrated an increased risk that is independent of the patient population in which they are being used. As a result, no further action is required at this time.

Proton pump inhibitors (PPIs), including esome-prazole, lansoprazole, omeprazole, pantoprazole and rabeprazole, are a class of drugs that reduce production of gastric acid.

A 2010 study by Charlot and colleagues found that PPI use in a high-risk (post-myocardial infarction) population was associated with an increased risk of adverse cardiovascular outcomes.1

A subsequent study in 2015 by Shah et al found that PPI use was associated with an increased risk of acute myocardial infarction in the general population.2

The TGA review assessed the information in both of these studies.

Charlot et al 2010 study

Charlot and colleagues published a nationwide cohort study based on linked Danish data sets.1

Subjects were all patients (N=56,406) discharged after first-time myocardial infarction.

The primary outcome was a composite of cardiovascular death or rehospitalisation for stroke or myocardial infarction at 30 days post-discharge. The primary result was a 29% increase in the primary outcome for patients taking a PPI.

The study found no significant differences between different types of PPI.

In their discussion, Charlot and colleagues state that they 'suspect that the increased cardiovascular risk in all patients who received a PPI can be explained by differences in baseline comorbid conditions that were unmeasured or measured imperfectly'.

Significant missing information included smoking status, lipid levels and body mass index (BMI) of patients.

Shah et al 2015 study

Shah and colleagues published a data-mining study based on US patient clinical records.2

The study used data from two sources of electronic health records. Additionally, the authors examined the association between PPI use and cardiovascular mortality in a cohort of 1503 patients undergoing elective coronary angiogram at one of two hospitals.

The data-mining study included patients 18 or over with a documented diagnosis of gastro-oesophageal reflux disease. Drug exposures of interest were PPIs (N=104,860), with H2 antagonists (N=12,796) as a comparison group. The primary outcome of interest was myocardial infarction.

The study found an increased odds ratio for myocardial infarction in patients taking PPIs (odds ratios 1.16 [95% CI 1.09-1.24] and 1.19 [95% CI 1.09-1.24] in the two datasets).

The cohort study accumulated 58 cardiovascular mortality events, including myocardial infarction, cardiac arrest, stroke, heart failure or aneurysm rupture, over a median 5.2 years of follow-up.

Adjusted analysis (adjusted for age, gender, race, cholesterol level, systolic blood pressure, use of antihypertensives, and smoking status) using a Cox proportional hazard model yielded a hazard ratio of 2.00 [95% CI 1.07-3.78, p=0.031] for cardiovascular mortality among PPI users compared to non-users.

The data-mining approach described in the publication did not take into account important confounding factors such as BMI, socioeconomic status, or laboratory test results. Although concomitant medications and diseases were used as an overall proxy for health status, individual medications and diseases were not examined.

The authors stated that they regarded their findings as 'hypothesis generating' only.

TGA review findings

The TGA found that neither study was designed to address the possibility that PPI use was itself a marker of increased cardiovascular risk, as information on significant baseline risk factors was not collected. Additionally, PPIs may have been used when anginal pain was mistaken for pain due to gastro-oesophageal reflux.

Because of these limitations, these two studies did not demonstrate an increased cardiovascular risk for PPIs that was independent of the patient population in which they were being used.

It was determined that no further action was required at this time.

The TGA will continue to monitor this issue and encourages health professionals to report cardiovascular adverse events associated with use of PPIs.


  1. 1. Charlot M et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use. Ann Intern Med 2010; 153: 378-386.
  2. 2. Shah NH et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLOS ONE 2015; 10(6): e0124653.

Potential interaction – allopurinol and 6-mercaptopurine/azathioprine

Health professionals are reminded that the concomitant use of allopurinol with 6-mercaptopurine or azathioprine should be avoided because of a potentially dangerous interaction. If these medicines must be given together, the dose of 6-mercaptopurine or azathioprine should be reduced.

Allopurinol is an anti-uricaemic agent used to treat gout, uric acid nephrolithiasis and states of hyperuricaemia, including the prevention of tumour-lysis syndrome.

Azathioprine is an imidazole derivative of 6-mercaptopurine that is used as an immunosuppressant, while 6-mercaptopurine is used as a cytotoxic agent.

There are warnings regarding the potential interactions between allopurinol and 6-mercaptopurine/azathioprine in the respective Product Information (PI). Also, the Consumer Medicine Information leaflets for these medicines advise patients to tell their doctor if they are taking the other medicines linked to this interaction.

Details of interaction

Allopurinol reduces metabolism of 6-mercaptopurine and azathioprine, significantly increasing the risk of potentially fatal bone marrow toxicities and blood dyscrasias, including leukopenia, thrombocytopenia and pancytopenia.

Information for health professionals

Health professionals are reminded that the concomitant use of allopurinol and 6-mercaptopurine/azathioprine should be avoided if possible. However, if co-administration of these medicines is necessary, the dose of 6-mercaptopurine or azathioprine should be reduced to only one quarter of the normal dose and the patient's complete blood count should be closely monitored in accordance with the PI.

It is recommended that, when prescribing azathioprine or 6-mercaptopurine, you should check that the patient is not being treated with allopurinol and educate them about this medicine interaction.

Intrauterine contraceptive devices and uterine perforation

While it is known that uterine perforation is a rare adverse event associated with the use of intrauterine contraceptive devices, a recent European study has found the that risk is increased for lactating women and during the first 36 weeks postpartum.

The European Active Surveillance Study was a large prospective, comparative, non-interventional cohort study assessing users of intrauterine contraceptive device (IUCD), including levonorgestrel IUCDs and copper IUCDs, who had a primary outcome of uterine perforation.1

Mirena is a 20 microgram per 24 hours IUCD containing 52 mg of levonorgestrel.

As Mirena contains an active pharmacological agent, it is regulated by the TGA as a medicine.

Copper IUCDs are regulated by the TGA as medical devices.

While the risk of uterine perforation associated with all types of IUCDs is low, the European Active Surveillance Study identified an increased risk of uterine perforation in lactating women and during the first 36 weeks postpartum for all such devices.

European Active Surveillance Study

Patients for the European Active Surveillance Study were recruited from 2006 to 2013 with a sample size of 61,448 IUCD users – 46% of women used a levonorgestrel IUCD and 54% were copper IUCD users.

The study included women who were postpartum and who were breastfeeding at the time of IUCD insertion; these groups of women have largely been excluded from previous studies.

There were 61 perforations with a levonorgestrel IUCD and 20 with a copper IUCD. First time-users of levonorgestrel IUCDs had a slightly higher rate of perforation than first-time copper IUCD users.

Both breastfeeding at the time of insertion and insertion up to 36 weeks after delivery were independently associated with an increased risk of uterine perforation.

While the background rate of uterine perforation associated with IUCDs was low, there was a six-fold increase in perforation risk (relative risk 6.1; 95% confidence interval 3.6 - 10.1) with breastfeeding regardless of the interval since the last delivery.

There was no statistically significant difference between the levonorgestrel and copper IUCDs.

Changes to Product Information and Instructions for Use

The Mirena Product Information (PI) previously included information about uterine perforation and device failure as potential adverse events.

However, the updated PI includes information regarding the increased uterine perforation risk for lactating women and during the first 36 weeks postpartum.

Additionally, the PI now advises that there is also an increased risk for women with a fixed, retroverted uterus.

For copper IUCDs, the TT380 and LOAD 375 devices, both sponsored by Medical Industries Australia, are in the process of having their Instructions for Use updated to include the relevant information from the European study.

Another copper IUCD, Multiload sponsored by Merck Sharp & Dohme (Australia), has recently been withdrawn from the market, with the last device supplied in April 2015.


  1. Heinemann K, Reed S, Moehner S, Minh TD. Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices. Contraception; 2015.

Peginterferon alfa-2a and facial palsy

Health professionals are advised that the Product Information for peginterferon alfa-2a has been updated to state that facial palsy has been reported during the post-marketing period for this medicine.

Peginterferon alfa-2a is a recombinant interferon alfa-2a protein conjugated with a single branched polyethylene glycol chain. It is marketed in Australia as Pegasys and in combination with ribavirin as Pegasys-RBV.

Peginterferon alfa-2a is indicated for use, under specific circumstances, in treatment of chronic hepatitis C and chronic hepatitis B.

Consult the Product Information (PI) for these medicines for full details of the approved indications.

TGA post-marketing monitoring of the Australian and international adverse event reports identified a potential link between treatment with peginterferon alfa-2a and VIIth nerve paralysis (also known as Bell's palsy).

To 19 August 2015, the TGA had received five reports of VIIth nerve paralysis associated with peginterferon alfa-2a, including three cases in which it was the sole suspected medicine.

Based on the identified safety concern and to align with information provided for these medicines in other international jurisdictions, the TGA has worked with the sponsor to update the peginterferon alfa-2a PI to state that facial palsy has been reported during the post-marketing period.

Facial palsy is also listed in the peginterferon alfa-2b PI as an adverse effect observed in the post-marketing setting.

At this stage there have been no reports of facial palsy for Pegasys-RBV or the other six pegylated and non-pegylated interferon products available in Australia.

The TGA will continue to monitor this issue.

Medicine shortages information

The Medicine Shortages Information Initiative provides information about a temporary or permanent disruption to the supply of a prescription medicine. Health professionals and consumers are invited to subscribe to the Medicine Shortages email list to receive an alert when there is new or updated medicine shortage information reported to the TGA.

What to report? You don't need to be certain, just suspicious!

The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.

We particularly request reports of:

  • all suspected reactions to new medicines
  • all suspected medicines interactions
  • suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.

Reports may be submitted:

For more information about reporting, visit or contact the TGA's Pharmacovigilance and Special Access Branch on 1800 044 114.


Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.

© Commonwealth of Australia 2015

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For correspondence or further information about Medicines Safety Update, contact the TGA's Pharmacovigilance and Special Access Branch at or 1800 044 114.

Medicines Safety Update is written by staff from the Pharmacovigilance and Special Access Branch.

Editor: Dr Jane Cook

Deputy Editor: Mr Michael Pittman

Acting TGA Principal Medical Adviser: Dr Tony Gill

Contributors include: Dr Richard Hill, Mr Zain Hussain and Dr Pamela Whalan