The government is now operating in accordance with the Guidance on Caretaker Conventions, pending the outcome of the 2025 federal election.
Summary
Our investigation into the risk of myocardial infarction and stroke in patients taking romosozumab (Evenity) found that stronger warnings regarding these risks were needed in the Product Information (PI) - external site and Consumer Medicine Information (CMI) - external site. Romosozumab use is now also contraindicated in patients with a history of myocardial infarction or stroke.
The following sections of these documents have been updated to reflect an increased risk of myocardial infarction and stroke: Contraindications; Special warning and precautions for use; and Adverse events.
What health professionals should do
Health professionals should be alert to the updated warnings and new contraindications and should inform patients and carers of the potential cardiovascular risks associated with romosozumab use.
Background
Romosozumab is indicated:
- for the treatment of osteoporosis in postmenopausal women at high risk of fracture
- for treatment to increase bone mass in men with osteoporosis at high risk of fracture.
It is currently listed on the PBS for severe established osteoporosis - external site for initial and continuing treatment, with authority required for both treatments.
Our Pharmacovigilance Branch undertook a signal investigation in October 2023 to assess the risk of myocardial infarction and stroke with romosozumab.
Myocardial infarction and stroke are serious life-threatening conditions that require prompt diagnosis and management. They can both result in death, permanent disability and significant hospital stays.
The Australian, European Union and United States product information documents all describe the results of 2 pivotal studies providing data about the potential risk of major adverse cardiac events associated with romosozumab.1,2 There was a higher rate of major adverse cardiac events (a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) associated with romosozumab in one trial but not the other. The disparity between these 2 trials has been a focus for regulators assessing the safety of this medicine.
Additional risk minimisation measures already in place include:
1. a Prescriber Guide containing information about the cardiovascular risks of romosozumab and the appropriate prevention, early diagnosis, and adequate management of these events
2. a Patient Alert Card intended for distribution to patients and their caregivers by their healthcare professional with information about the cardiovascular risks of romosozumab.
We consider that the benefit-risk balance of romosozumab remains positive, and it continues to be a useful treatment for osteoporosis for some patients.
Additional warnings in the PI
The following text was added to the PI for romosozumab and the CMI was updated to align with the PI.
4.3 Contraindications
History of myocardial infarction or stroke (see section 4.4 Special warnings and precautions for use)
4.4 Special warnings and precautions for use:
Myocardial infarction and stroke
In randomised controlled studies, an increase in serious cardiovascular events (myocardial infarction and stroke) has been observed in patients treated with EVENITY, compared to controls (see section 4.8 Adverse effects (Undesirable effects), Myocardial infarction, stroke and mortality).
Evenity is contraindicated in patients with previous myocardial infarction or stroke (see section 4.3).
When determining whether to use EVENITY for an individual patient, consideration should be given to their fracture risk over the next year and their cardiovascular risk based on risk factors (e.g.,, established cardiovascular disease, hypertension, hyperlipidaemia, diabetes mellitus, smoking, severe renal impairment, age). EVENITY should only be used if the prescriber and patient agree that the benefit outweighs the risk. Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, EVENITY treatment should be discontinued.
4.8 Adverse effects
Adverse reactions
Cardiac disorders: myocardial infarction (frequency uncommon)
Myocardial infarction, stroke and mortality
In the active-controlled trial of romosozumab for the treatment of severe osteoporosis in postmenopausal women during the 12-month double-blind romosozumab treatment phase, 16 women (0.8%) had myocardial infarction in the romosozumab arm versus 5 women (0.2%) in the alendronate arm and 13 women (0.6%) had stroke in the romosozumab arm versus 7 women (0.3%) in the alendronate arm. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 women (0.8%) in the romosozumab group and 12 women (0.6%) in the alendronate group. The number of women with major adverse cardiac events (MACE = positively adjudicated cardiovascular death, myocardial infarction or stroke) was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for romosozumab compared to alendronate. All-cause death occurred in 30 women (1.5%) in the romosozumab group and 22 women (1.1%) in the alendronate group.
In the placebo-controlled trial of romosozumab for the treatment of osteoporosis in postmenopausal women (including women with severe and less severe osteoporosis) during the 12-month double-blind romosozumab treatment phase, there was no difference in positively adjudicated MACE; 30 (0.8%) occurred in the romosozumab group and 29 (0.8%) in the placebo group. All-cause death occurred in 29 women (0.8%) in the romosozumab group and 24 women (0.7%) in the placebo group.
Cases reported to us
A search of our Database of Adverse Event Notifications on 27 November 2023 identified 9 related distinct case reports (some including multiple adverse events): intraventricular haemorrhage (2), cerebrovascular accident (2), acute myocardial infarction (1), cerebral haemorrhage (1), embolic stroke (1), myocardial infarction (2), transient ischaemic attack (1). The outcomes of the reported adverse events were all serious with 2 leading to death.
References
- Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377:1417–27. https://doi.org/10.1056/nejmoa1708322 - external site
- Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016 20;375:1532–43. https://doi.org/10.1056/NEJMoa1607948 - external site
What to report? You don't need to be certain, just suspicious!
We encourage 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 (look for the Black Triangle ▼ in PI and CMI documents – this symbol identifies medicines that are new or being used differently)
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
To report a suspected side effect or for more information about reporting, go to our ‘Report problem or side effect’ webpage or contact our Pharmacovigilance Branch ADR.Reports@health.gov.au.
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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This Medicines Safety Update is written by staff from our Pharmacovigilance Branch.
Editor: Dr Sophie Russell
Deputy Editor: Aaron Hall
Contributors: Renae Mura