Treatment with testosterone undecanoate injections and pulmonary oil microembolism

September 2022

The safety and efficacy of hypogonadism treatment with testosterone undecanoate injection has been well established in both clinical trials,1,2 post-marketing surveillance studies3,4 and long-term real-world evidence (RWE) studies.5-8

Nevertheless, there have been occasional reports of pulmonary oil microembolism after administration of testosterone undecanoate injections.

Here we summarize the results of a recent literature review that aimed to evaluate the occurrence of pulmonary oil microembolism during treatment with intramuscular testosterone undecanoate injection, using data from peer-reviewed studies and post marketing reports.9

Key Points

  • Treatment with testosterone undecanoate injections has been linked to occasional reports of pulmonary oil microembolism.
  • Incidence of pulmonary oil microembolism is rare, and usually resolves itself within 30 min after injection.
  • Proper injection technique and proper product usage are key elements in the prevention of POME events.

What is known about testosterone undecanoate injections and pulmonary oil microembolism

The Electronic Medicines Compendium (EMA) states the following:

“As with all oily solutions, Nebido must be injected strictly intramuscularly and very slowly (over two minutes). Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnea, malaise, hyperhidrosis, chest pain, dizziness, paresthesia, or syncope. These reactions may occur during or immediately after the injection and are reversible. The patient should therefore be observed during and immediately after each injection in order to allow for early recognition of possible signs and symptoms of pulmonary oily microembolism. Treatment is usually supportive, e.g. by administration of supplemental oxygen. Suspected anaphylactic reactions after Nebido injection have been reported.”

However, the rate of pulmonary oil microembolism during routine treatment of hypogonadism with intramuscular testosterone undecanoate injection has, until recently, been unknown.
 

What this study adds

A peer-reviewed literature review investigated pulmonary oil microembolism incidence in the setting of testosterone undecanoate injections.9 A total of 48 articles were selected in the literature review, which included 29 studies that used testosterone undecanoate and reported its effects.

Relatively few pulmonary oil microembolism cases were reported across multiple published studies, including those that focused particularly on the occurrence rate of pulmonary oil microembolism while administrating intramuscular testosterone undecanoate. Of the 29 individual studies, which included 7,978 patients, eight studies reported a total of 88 cases of pulmonary oil microembolism or cough. These included episodes of cough that were not originally declared as pulmonary oil microembolism. One post-market review reported 223 cases per 3,107,652 injections. When pulmonary oil microembolism did occur, almost all cases resolved spontaneously within 60 min without intervention. Overall, pulmonary oil microembolism was observed to be rare.9

 

Commentary

This literature review confirms findings from a previous post-marketing safety analysis,10 which aimed to identify the annual rate and clinical features of spontaneously reported pulmonary oil microembolism cases. A Risk Evaluation and Mitigation Strategy (REMS) database was searched for pulmonary oil microembolism reports occurring with administration of testosterone undecanoate from March 5, 2014, through June 30, 2018. Each case was reviewed and adjudicated by a drug safety physician to confirm the reported event had predefined clinical characteristics consistent with pulmonary oil microembolism.10

 

Of 633 individual case safety reports, 28 spontaneously reported adverse events were classified as POME, for a yearly spontaneously reported adverse event per-injection rate of <0.1%. Most (21/22) events resolved, and of those with a resolution time reported, most (13/17) resolved within 30 minutes. More than 60% (13/21) of patients required no medical intervention (i.e. the pulmonary oil microembolism event resolved spontaneously). One fatality was reported 18 months after a documented pulmonary oil microembolism event and appeared unrelated to the reported testosterone undecanoate injection or subsequent injections after the pulmonary oil microembolism event. In 3 out of 4 pulmonary oil microembolism cases with symptoms serious enough to require an emergency room visit, issues with injection technique or dosing were identified as a potential contributing factor. It was concluded that pulmonary oil microembolism events appear to be rare, with resolution occurring quickly without medical intervention in most cases.10

The risk of pulmonary oil microembolism can be reduced by proper injection technique  and adhering to the recommended Nebido® injection interval;9 after the initial injection, the second injection 6 weeks later (loading phase), and subsequent injections every 10–14 weeks.

The cause of pulmonary oil microembolism appears to involve accidental delivery of the oil vehicle into the venous circulation, where it subsequently moves to the lungs and results in coughing.10 It should be noted that POME is not specific for testosterone undecanoate injections, and can also occur after injection of short-acting injections in oily vehicle (incidence 1.5%).11 For instance, the cough occurring after trenbolone injection, popularly known as “tren cough”  is likely due to oil particles that have been delivered to the lungs (prostaglandins may partly contribute to the cough, albeit probably to a lesser extent than oil particles). It should be pointed out that the same research group that showed an incidence of POME after short-acting testosterone injections of 1.5%, found the incidence of POME with Reandron®/Nebido® to be 19 per 1000 injections (0.019%).12 A possible explanation for the warnings about POME on labels for testosterone undecanoate injection products is that these are relatively new drugs, and side effects are a lot more likely to be reported with a new drug than with older drugs (such as short-acting injections) that may receive less scrutiny.

 

Summary

Most studies investigating hypogonadism treatment with testosterone undecanoate injection did not report cases of pulmonary oil microembolism. When cases of pulmonary oil microembolism have been reported, they are more commonly seen in studies that focused specifically on the occurrence of pulmonary oil microembolism, but the rate in those studies still remained low.

Data from clinical trials, post-marketing surveillance studies and long-term RWE studies show that treatment of hypogonadism with testosterone undecanoate inection is safe and effective. While pulmonary oil microembolism may occur after injection of testosterone undecanoate on rare occasions, it typically resolves spontaneously, and is not considered a common side effect.

The clinical implication of available data is that proper injection technique and proper product usage are key elements in the prevention of pulmonary oil microembolism events.

References

  • Wittert G, Bracken K, Robledo KP, et al. Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial. The lancet Diabetes & endocrinology. Jan 2021;9(1):32-45. Return to content
  • Minnemann T, Schubert M, Hubler D, et al. A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate. The aging male : the official journal of the International Society for the Study of the Aging Male. Sep 2007;10(3):155-8. Return to content
  • Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. The journal of sexual medicine. Feb 2013;10(2):579-88. Return to content
  • Wolf J, Keipert D, Motazedi H, Ernst M, Nettleship J, Gooren L. Effectiveness and tolerability of parenteral testosterone undecanoate: a post-marketing surveillance study. The aging male : the official journal of the International Society for the Study of the Aging Male. Dec 2017;20(4):225-234. Return to content
  • Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study. Int J Obes (Lond). Jun 2020;44(6):1264-1278. Return to content
  • Saad F, Caliber M, Doros G, Haider KS, Haider A. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. The aging male : the official journal of the International Society for the Study of the Aging Male. Feb 20 2020;23(1):81-92. Return to content
  • Haider KS, Haider A, Saad F, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes, obesity & metabolism. Nov 2020;22(11):2055-2068. Return to content
  • Yassin A, Haider A, Haider KS, et al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Jun 2019;6(42):1104-1111. Return to content
  • Adam JA, Pastuszak AW, Christensen MB, et al. Occurrence of pulmonary oil microembolism (POME) with intramuscular testosterone undecanoate injection: literature review. Int J Impot Res. May 24 2022; Return to content
  • Pastuszak AW, Hu Y, Freid JD. Occurrence of Pulmonary Oil Microembolism After Testosterone Undecanoate Injection: A Postmarketing Safety Analysis. Sex Med. Jun 2020;8(2):237-242. Return to content
  • Mackey MA, Conway AJ, Handelsman DJ. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod. Apr 1995;10(4):862-5. Return to content
  • Middleton T, Turner L, Fennell C, et al. Complications of injectable testosterone undecanoate in routine clinical practice. Eur J Endocrinol. May 2015;172(5):511-7. Return to content