Medicines Safety Update

Summary

Cholinesterase inhibitors have been associated with syncope and fall-related injuries, including hip fracture. Caution should be used when patients are started on a cholinesterase inhibitor, and patients should only be maintained on these medicines if there is evidence of continuing benefit.

The cholinesterase inhibitors, donepezil (Aricept), rivastigmine (Exelon) and galantamine (Galantyl, Reminyl) are available on the Pharmaceutical Benefits Scheme (PBS) as authority items for patients with mild to moderately severe Alzheimer's disease. More than 2.5 million PBS prescriptions for cholinesterase inhibitors have been dispensed since 2001.

A recent Canadian population-based cohort study found that cholinesterase inhibitor use was associated with increased rates of syncope, bradycardia, pacemaker insertion and hip fracture in older adults with dementia.¹Hospital visits for syncope were more frequent in people receiving cholinesterase inhibitors than in controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio 1.76; 95% confidence interval 1.57 to 1.98). No comparison of event rates for individual cholinesterase inhibitors was conducted as it was assumed that donepezil, galantamine and rivastigmine have similar adverse-effect profiles. The authors noted that cholinesterase inhibitors generally augment vagal influences on the heart and promote bradycardia, which may result in neurocardiogenic syncope.

To June 2010, the TGA had received a total of 623 reports of suspected adverse reactions to cholinesterase inhibitors. Eighty-four (14%) of these reports describe syncope, syncope-related events or bradycardia.

While syncope and bradycardia are listed in the product information for each cholinesterase inhibitor as 'common' to 'very rare' adverse effects, the TGA reminds prescribers to use caution when starting patients on cholinesterase inhibitors, and that patients should only be maintained on these medicines if there is evidence of continuing benefit.

Summary

The combination of a macrolide antibiotic and a statin can increase the risk of myopathy and rhabdomyolysis. If a patient taking a statin is to be prescribed a macrolide, consider temporarily stopping the statin or choosing a different antibiotic.

Combining clarithromycin or erythromycin with simvastatin or atorvastatin increases the risk of statin-induced myopathy and rhabdomyolysis. The TGA receives several reports of rhabdomyolysis in patients taking an HMG-CoA reductase inhibitor (statin) and a macrolide antibiotic almost every year. We remind health professionals to use caution with this combination.

If a patient taking a statin is to be prescribed a macrolide antibiotic, consider temporarily stopping the statin or choosing a different antibiotic, if appropriate. Use particular caution in patients who are on higher statin doses, have comorbidities, are older, or are taking other medicines, because they are at higher risk of rhabdomyolysis (see box). Ask patients taking statins to promptly report muscle aches, pain or weakness, particularly if accompanied by malaise, fever or brown urine.

To July 2010, TGA had received 25 reports of rhabdomyolysis in patients prescribed a macrolide antibiotic and a statin. In 80% of cases, patients had at least one other risk factor for statininduced myopathy before they were prescribed clarithromycin or erythromycin. In almost 50% of cases, patients had two or more other risk factors. The most common risk factors were older age; high statin dose; concomitant diltiazem, cyclosporin or gemfibrozil; and hypothyroidism or diabetes. This is consistent with an earlier analysis of reports to the TGA.²

Either simvastatin or atorvastatin was involved in each case reported to the TGA. Both of these statins are metabolised by cytochrome P450 3A4, which is inhibited by clarithromycin and erythromycin. Interactions with other statins or other macrolides are less likely: CYP3A4 has little or no involvement in the metabolism of pravastatin, fluvastatin and rosuvastatin, and the macrolides azithromycin and roxithromycin are not inhibitors of CYP3A4.³

Summary

Uterine perforation is a known but rare complication associated with the levonorgestrelreleasing intrauterine system (Mirena). Observing correct insertion technique is important to minimise the risk of perforation.

Mirena is an intrauterine delivery system that releases levonorgestrel 20 microgram/day. It is approved for use as a contraceptive for up to five years, for the treatment of idiopathic menorrhagia, and for the prevention of endometrial hyperplasia during oestrogen replacement therapy. As with copper intrauterine devices, Mirena is associated with uterine perforation at an incidence of less than 0.1%.⁵

In June 2010 in Canada, a reminder was issued to health professionals about the possibility of uterine perforation with Mirena, after it was noted that the number of perforations reported was rising alongside increased use of Mirena.⁶

In Australia, a total of 161 adverse reactions to Mirena had been reported to the TGA to June 2010. Of these, 22 were reports of uterine perforation. In at least seven cases, patients had known risk factors for uterine perforation. Perforation was reported to have occurred during insertion in three cases.

The presentation of uterine perforation may be subtle. Patients should regularly check for the threads attached to Mirena to ensure that the device has remained in the uterus. Health professionals should instruct women on how to check for the threads, and inform them of the efficacy, risks and side effects of Mirena.

Minimising the risk of uterine perforation

Correct insertion technique is important for reducing the risk of perforation (see box). Women who are postpartum, lactating or have atypical uterine anatomy (such as a fixed retroverted uterus) are at greatest risk of perforation.

Training in inserting intrauterine devices and Mirena is available through the Royal Australian and New Zealand College of Obstetricians and Gynaecologists and state and territory sexual health and family planning organisations. An education DVD is available from Bayer (ph 1800 673 270) and a leaflet explaining insertion is included in the packaging.

Summary

Most adverse event reports involving rivaroxaban received by the TGA describe thrombotic or haemorrhagic events, consistent with international experience and the known safety profile of rivaroxaban.The TGA will continue to routinely monitor reports of adverse reactions to rivaroxaban. We encourage health professionals to report suspected adverse reactions promptly.

Rivaroxaban is an oral anticoagulant that acts through direct inhibition of coagulation factor Xa. It was first registered in Australia in November 2008 and is approved for prevention of venous thromboembolism following elective total hip replacement or total knee replacement. Approximately 6800 PBS prescriptions have been dispensed since the drug was listed in August 2009.

At 15 July 2010, the TGA had received 44 adverse event reports involving rivaroxaban. Of these, 22 (50%) described thrombotic events and 17 (39%) haemorrhagic events (see Table). This is consistent with the known adverse effects of rivaroxaban (the Product Information lists haemorrhage, anaemia and deep vein thrombosis as adverse events⁷). It is also similar to reports submitted to the World Health Organization's Programme for International Drug Monitoring,^* to which more than 90 countries contribute spontaneous adverse drug reaction reports.^8,9

Reports received by the TGA do not indicate any new safety signals for rivaroxaban, but report numbers to date are small. Routine monitoring of adverse events with rivaroxaban will continue and as with all new drugs, health professionals are encouraged to report adverse events to the TGA (seeWhat to reportbelow).

There were several reports to the TGA in which rivaroxaban was apparently not used according to the dosing and administration instructions. These involved use of rivaroxaban sequentially with postoperative enoxaparin (3 cases: one haemarthrosis, two thrombotic events); double dosing with rivaroxaban for 3 days (one case: haemarthrosis); and starting rivaroxaban therapy one day after surgery (one case: thrombotic event). A causal link between these administration errors and the adverse events reported has not been established. Nevertheless, note that rivaroxaban should be started 6–10 hours after surgery, providing that haemostasis has been established, and a single 10 mg tablet taken daily for up to 14 days (knee replacement) or 35 days (hip replacement).⁷

In two cases, haemorrhagic events were associated with concomitant use of meloxicam or clopidogrel. Rivaroxaban should be used with caution in patients taking clopidogrel or non-steroidal anti-inflammatory drugs because of an increased risk of bleeding.⁷

*The information in adverse event reports in the WHO database is not homogeneous with respect to the sources of the information or the likelihood that the pharmaceutical product caused the suspected adverse reaction. The information in this article does not represent the opinion of the WHO.

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

DISCLAIMER

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.

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