Testosterone and risk of cardiovascular events

HSA would like to bring to the attention of healthcare professionals, the overseas signals of cardiovascular (CV) events that have been associated with the use of testosterone-containing products. Safety reviews conducted by international regulatory agencies have concluded that the signal of CV risk remains weak and further investigations by the manufacturers, such as the conduct of a well-designed clinical trial and close monitoring of these safety events, are necessary to confirm this risk.

Testosterone is a steroid hormone that plays a role in the development of androgenic and anabolic processes. It is mainly indicated for replacement therapy in males with primary and secondary hypogonadal disorders. Some of the testosterone-containing products are also indicated for osteoporosis caused by androgen deficiency, or for masculinisation in female to male transsexuals. Testosterone was first licensed locally in 1990, and there are currently seven testosterone-containing products in different dosage forms, ranging from oral capsules to subcutaneous implants: Andriol Testocaps® (MSD Pharma (Singapore) Pte Ltd), Androgel® (Orient Europharma Pte Ltd), Depo-Testosterone® (Pfizer Pte Ltd), HOM® (Blendforte Trading Co), Nebido® (Bayer (South East Asia) Pte Ltd), Sustanon® (A Menarini Singapore Pte Ltd), and Testosterone Implant® (MSD Pharma (Singapore) Pte Ltd).

International regulatory actions

a) US Food and Drug Administration (FDA)

In February 2014, the US FDA initiated a review on the CV risk in testosterone-treated men. This review was in response to findings from two published observational studies^1,2 that suggested an increased risk of CV events (namely stroke, myocardial infarction [MI], and death) in men who were prescribed testosterone therapy. In September 2014, a joint meeting between the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was convened to discuss the CV findings associated with testosterone available from published observational and meta-analysis studies. The advisory committee members generally agreed that the signal of CV risk is weak due to conflicting evidence from the studies. However, in view that some studies had observed this signal, the US FDA concluded that there is a possible increased CV risk associated with testosterone use. Manufacturers of testosterone-containing products were required to update the US package insert (PI) on the possible increased risk of MI and stroke, and to conduct a well-designed clinical trial to confirm if this risk exists with testosterone use.³

In June 2014, the US FDA issued a separate communication informing that the US PI of all testosterone-containing products would need to be updated on general warnings regarding the risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). This PI update followed the identification of VTE events associated with testosterone use from the FDA Adverse Event Reporting System (FAERS) database.⁴

b) European Medicines Agency (EMA)

In October 2014, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) conducted a similar review on the risk of CV events associated with testosterone, which concluded that based on current available data, the evidence for this risk remains weak and inconclusive.⁵ However, the PI for all testosterone-containing medicines should be updated on the current available safety information, including warnings on the population that might be at increased risk of CV events. In addition, the manufacturers of testosterone-containing products were required to closely monitor the CV safety concerns, including VTE events, and to submit the discussion of these findings to EMA by March 2016.

c) Health Canada

Health Canada completed its review on the CV risk of testosterone in July 2014. Based on the current available evidence, Health Canada concluded that there is a possibility of CV risk with the use of testoterone.⁶ Accordingly, the Canadian PIs of testosterone-containing products were updated to include a warning on possible CV events, including MI, stroke, VTE, tachycardia and atrial fibrillation.

d) New Zealand Medsafe

Medsafe’s Medicines Adverse Reactions Committee (MARC) convened a meeting in September 2014 to discuss the CV risk associated with testosterone use. The committee concluded that based on the current evidence, there is no significant statistical evidence to support an association between testosterone and MI, VTE, or stroke, and that longer-term, adequately powered, placebo-controlled clinical trials are required to investigate the risk of CV events with testosterone.⁷

HSA’s actions and advisory

HSA has received one local ADR report of MI associated with the use of testosterone. No local ADR reports of VTE associated with the use of testosterone have been received.

HSA has also consulted local experts (urologists and cardiologists) regarding the signal of CV risk with testosterone. Some of the experts were of the opinion that methodological limitations and biases may have impacted the findings of the observational studies mentioned above. HSA is working with the companies to ensure that the warnings and precautions relating to CV events are adequately highlighted across the PIs of testosterone-containing products.

HSA will continue to monitor international and local developments regarding the CV risk of testosterone-containing products and will update healthcare professionals of any new safety findings.

Healthcare professionals are advised to take into consideration the above safety issues when prescribing testosterone-containing products to their patients.

References

Healthcare professional, Industry member, Therapeutic Products

Published: 30 Sep 2015

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