Testosterone therapy has recently skyrocketed as more men are being introduced to the idea of “low T” through an ever-increasing advertising push.
Manufacturers have drastically increased their advertising spending from $14.3 million in 2011 to $107.3 million in 2012.1 The US Food and Drug Administration (FDA) estimates that almost 2.3 million patients were on testosterone therapy in 2013, a 77% increase from 2010.2 This increase begs the question whether testosterone therapy has the data to support its use.
One study estimated that the crude prevalence of hypogonadism was 38.7% in men aged 45 years and older, and suggested that 13.8 million men in that age group visiting primary care physicians in the United States may have low testosterone.3
Although opinions vary and studies differ, the number of patients on testosterone therapy continues to grow and it is imperative for pharmacists to grasp this complex treatment.
Dosage Forms Available
The recent population spike in the testosterone market has enticed numerous manufacturers to enter the market with an array of testosterone dosage forms, ranging from oral tablets to surgically implanted pellets. Pharmacists need to understand the clinical pearls of each dosage form to provide optimal care to their patients.
The oral dosage form has been associated with hepatic adverse events, including cholestatic jaundice syndrome, neoplasm of the liver, and peliosis hepatis.4 For this reason, physicians often do not recommend the use of current oral testosterone dosage forms.
Intramuscular testosterone injections are used more routinely. The advantages of an intramuscular injection are the potential for improved adherence in relation to their infrequent administration and reduced cost. Depending on the specific testosterone product, intramuscular injections can be dosed once every 2 weeks, even as little as once every 10 weeks. There are some downsides as many patients may fear the idea of a slow, deep intramuscular injection into the gluteal muscle. One product even carries a black box warning due to the increased risk for pulmonary oil microembolism; and anaphylaxis is required for office or hospital administration.4
Transdermal and topical testosterone dosage forms provide a convenient, nonintrusive delivery method. The ease of application that these products offer the patient is apparent. Patches are applied every 24 hours (at night) to the back, abdomen, upper arms, or thighs; patients need to remove the old patch before applying a new one. Application sites should be rotated daily, and the same site should not be used for at least 7 days. In addition, patients should wait at least 3 hours before showering or bathing. Application site reactions can occur frequently with patches,5 underlying the important role of pharmacists to highlight adverse events.
Topical gels come in tubes, packets, and metered-dose pumps. Testosterone gel is applied every 24 hours (in the morning) to the shoulders, upper arms, or abdomen. Patients must wash their hands thoroughly with soap and water immediately after application, and wait at least 5 hours before showering or bathing. The gel should be allowed to dry completely before any covering is applied. Metered-dose pumps differ from the packet and tube form in that they require 3 priming pumps before the first use. The potential for skin transfer has led to testosterone gels carrying a black box warning. If an unknowing person comes into contact with the application site or an unwashed article of clothing, unintended testosterone exposure can occur. Pharmacists have an excellent opportunity to prevent secondary exposure with proper patient counseling.6
Topical testosterone solutions are almost identical to the gel, except that the solution is applied to each axilla every 24 hours (in the morning). The testosterone solution is dispensed through a metered-dose pump and should be primed using 3 pumps prior to first use. Apply deodorant or antiperspirant at least 2 minutes before using the testosterone solution in an effort to avoid cross-contamination. Allow the solution to dry before dressing to promote proper absorption, and do not shower or bathe for at least 2 hours after application. Analogous to the gel, pharmacists play a significant role in preventing secondary exposure through proper patient education.7
Unlike the topical dosage forms, the subcutaneous testosterone implant is an invasive alternative method of testosterone administration. Testosterone pellets are implanted into the buttocks, lower abdominal wall, or thigh and slowly dissolve while releasing the hormone. The procedure, which occurs in a physician’s office and lasts approximately 15 minutes, will have to be repeated every 3 to 6 months. Once implanted, adherence is a nonissue. That being said, testosterone implants are often not recommended because of their invasiveness, as well as risks for spontaneous pellet extrusion and infection.4,8
Direct absorption of testosterone through the oral mucosa, which avoids first-pass metabolism improving bioavailability, is available in the form of a buccal tablet. One buccal testosterone tablet is applied to the upper gum above the incisor tooth twice daily in the morning and evening, rotating the application site. The tablet is held in place for 30 seconds by pushing down on the outside of the upper lip. Buccal tablets should not be chewed or swallowed. Gum irritation can be a frequent occurrence with the use of buccal testosterone, providing pharmacists with an opportunity to intervene in a meaningful manner to limit this adverse event.9
Recently, the FDA approved a nasal testosterone dosage form supplied as a metered-dose pump known as Natesto. Natesto is not yet available and will be the first nasal dosage form on the market. Application is easy, but patients with adherence issues may struggle because it requires frequent administration (ie, 1 pump in each nostril 3 times daily). Nasal adverse events have been shown in clinical trials, which may further complicate potential adherence issues.4
As testosterone use soars, it becomes essential for the most accessible healthcare provider, the pharmacist, to not only understand the dosage forms, but also the risks associated with therapy to optimize patient care. Contraindications for testosterone therapy include breast or prostate cancer, and serious adverse events such as sleep apnea, erythrocytosis, benign prostatic hyperplasia, and venous thromboembolism.4 Of late, the FDA has required manufacturers to include a general warning for venous thromboembolism on testosterone medication labeling.10
Recently, evidence relating testosterone therapy to an increased risk for cardiovascular events has been thrust into the limelight. The FDA and the Endocrine Society have acknowledged the issue, alerted clinicians, and begun an investigation into the potential association.11
Two main observational studies, one of which was published in JAMA, brought about this newfound unease.12,13 The first study suggested that testosterone therapy increased the risk for stroke, myocardial infarction, and death by 30%.12 The second study found that men aged 65 years and older on testosterone therapy had a 2-fold increased risk for myocardial infarction, and men aged less than 65 years with a preexisting heart condition had almost a 3-fold increased risk of myocardial infarction.13
That being said, the FDA has made it clear that they have not concluded that testosterone therapy increases the risk of suffering a cardiometabolic event; it is only being investigated. As both studies had retrospective designs and a multitude of the study participants had prior cardiovascular disease, further large-scale, randomized controlled trials are needed to establish a true relationship between the exposure and outcome. In addition, the JAMA study has been the target of scrutiny over its credibility because of large data errors and mis-reporting of data.14 Twenty-nine medical societies and 160 of the leading testosterone researchers have called for the retraction of the study.
Pharmacists need to continually adapt to the ever-changing world of medicine and work to understand clinical research. New concerns are often raised, and it is the responsibility of pharmacists to stay current with these warnings.
An FDA panel recently voted 20-1 for a labeling change highlighting the lack of benefit associated with testosterone on the effects of aging. They also reiterated that evidence linking testosterone therapy to cardiometabolic events was “inconclusive,” but voted that manufacturers conduct long-term studies to further evaluate the existence of a relationship.15
Testosterone therapy has become a topic of heated discussion around its indications and risks. With all the uncertainty surrounding testosterone therapy, and its use being at an all-time high, pharmacists not only need to understand the various modes of administration, but they must be able to use their clinical knowledge when assessing indications and potentially life-threatening adverse events.
- Consumer Reports. Do you need to be treated for low testosterone? Drugmakers spent more than $100 million advertising the drugs last year, but our experts aren’t buying it. www.consumerreports.org/cro/magazine/2013/07/do-you-need-to-be-treated-for-low-testosterone/index.htm. Published July 2013. Accessed September 16, 2014.
- Perrone M. Associated Press. FDA: little evidence to support testosterone drugs. http://bigstory.ap.org/article/fda-little-evidence-support-testosterone-drugs. Published September 3, 2014. Accessed September 16, 2014.
- Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-769.
- Snyder PJ. Testosterone treatment of male hypogonadism. In: UpToDate, Post AM (Ed), UpToDate, Waltham, MA.
- Androderm [package insert]. Parsippany, NJ: Watson Pharmaceuticals Inc; 2013.
- Androgel [package insert]. Chicago, IL: AbbVie Inc; 2014.
- Axiron [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.
- Testopel [package insert]. Rye, NY: Bartor Pharmaceuticals; 2013.
- Striant [package insert]. Chesterbrook, PA: Actient Pharmaceuticals LLC; 2014.
- US Department of Health & Human Services. US Food and Drug Administration. FDA adding general warning to testosterone products about potential for venous blood clots. www.fda.gov/Drugs/DrugSafety/ucm401746.htm. Accessed September 17, 2014.
- US Department of Health & Human Services. US Food and Drug Administration. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. www.fda.gov/Drugs/DrugSafety/ucm383904.htm. Accessed September 17, 2014.
- Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829-1836.
- Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE. 2014;9:e85805.
- The Androgen Study Group. Complaint to the journal oversight committee at JAMA. www.androgenstudygroup.org/initiatives/complaint-to-journal-oversight-committee-at-jama. Accessed September 17, 2014.
- Perrone M. Associated Press. Experts want restrictions on testosterone drug use. http://bigstory.ap.org/article/91599e0bd98f4cc98b55ce51f2fcc87b/experts-skeptical-testosterone-drug-benefits. Published September 17, 2014. Accessed September 18, 2014.