madman
Super Moderator
Efficacy and safety outcomes of a compounded testosterone pellet versus a branded testosterone pellet in men with testosterone deficiency: a single-center, open-label, randomized trial (2023)
Eliyahu Kresch, MD, Thiago Fernandes Negris Lima, MD, Manuel Molina, MD, Nicholas A. Deebel, MD, Rohit Reddy, BA, Mehul Patel, MD, Justin Loloi, MD, Chase Carto, BS, Sirpi Nackeeran, MD, Daniel C. Gonzalez, BA, Jesse Ory, MD, Ranjith Ramasamy, MD
Abstract
Background: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients.
Aim: To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively.
Methods: This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg).
Outcomes: We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 AM): serum testosterone, estradiol, hematocrit, and prostate-specific antigen.
Results: After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study.
Clinical Implications: Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD.
Strengths and Limitations: Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort.
Conclusion: E100 compounded testosterone pellets are a non-inferior option of TTh as compared with Testopel for men presenting with TD.
Introduction
Testosterone deficiency (TD) is characterized by a combination of low serum testosterone with symptoms such as low energy, fatigue, decreased muscle mass, reduced libido, and erectile dysfunction.1 TD prevalence can be as high as 6% in men aged 40 to 70 years.2 Testosterone therapy (TTh) in this setting has many benefits, such as increased lean body mass, bone formation, and libido and decreased total cholesterol, and it may even increase cognitive function.3,4
Multiple forms of TTh currently exist on the market and are available to patients, consisting of intramuscular, subdermal, transdermal, oral, and buccal formulations.5,6 These options have different dosing regimens, pharmacokinetic profiles, advantages, disadvantages, and monitoring requirements that the physician-patient team must consider. Subcutaneous testosterone pellets were first developed in the 1940s but did not gain popular adoption in the United States until Food and Drug Administration (FDA) approval for Testopel in 1972.5,7 Subcutaneous long-lasting testosterone pellets are placed in the subcutaneous hypovascular space and gradually dissolve to provide steady testosterone release.7,8
Testopel pellets (Endo International plc) are 3 × 8–mm pellets that each contains 75 mg of crystalline testosterone. Current FDA dosing guidelines recommend 150 to 450 mg every 3 to 6 months with appropriate titration required to induce pubertal changes in hypogonadal males if indicated.9 However, a large retrospective study of 380 men found that higher pellet numbers (10-12) making up 450 to >750 mg was associated with more consistent, higher, and longer maintenance of therapeutically ranged testosterone levels.8
Since FDA approval of market brand testosterone pellets, comparable pellet formulations of differing sizes and dosing regimens were studied but have not reached the market.10 In this trial, we sought to evaluate the safety profile of compounded pellets (E100) and to compare the efficacy between compounded and market-brand testosterone pellets. This trial evaluated the market brand testosterone pellet Testopel (75 mg) and compared it with compounded testosterone pellets (100 mg; E100) manufactured by Empower Pharmaceuticals, an FDA-registered facility. Maintaining FDA approval and regulation ensures adherence to the FDA’s current good manufacturing practice regulations. These outline the standards for the design, monitoring, and control of manufacturing processes and facilities to ensure that products are safe and effective and to hold the approved agency subject to state and local regulations.
Discussion
TD imposes a significant detrimental effect on men’s quality of life. The estimated prevalence of TD is 6% in the American male population. Since the life expectancy of a US male is 74.5 years, many men will require long-term TTh.13 Of the various forms of testosterone replacement, testosterone pellets represent an effective, long-term treatment strategy with sustained increases in serum testosterone for up to 6 months.14 The novel findings of this single-center, open-label, randomized trial suggest that market brand and E100 compounded testosterone pellets are similar in their ability to increase serum total testosterone to within reference levels without a significant difference in side effect profile at <10% of the price. In our study, the market brand Testopel and E100 compounded pellets produced by an FDA-registered facility yielded normalization of testosterone levels with similar rates of side effects, such as polycythemia and changes in estradiol and PSA. Testopel has been shown to normalize testosterone levels and improve symptoms for at least 3 months and up to 6 months in men with TD. Specifically, Kaminetsky et al conducted a phase IV, single-center, open-label study to assess the safety and efficacy of subcutaneous insertion of testosterone pellets during a single implantation procedure. The authors determined that mean testosterone significantly increased at weeks 1, 4, and 12 as compared with preimplantation levels and then returned to baseline by week 24. The normalization of serum testosterone coincided with objective improvement in TD symptoms, as demonstrated via objective measures such as patient questionnaires.15 These findings were corroborated in a large multicenter retrospective review assessing the clinical utility of testosterone pellets for TD. In the study, Testopel elicited sustained levels of testosterone for at least 4 months and up to 6 months in men with TD, regardless of pellet number (number of Testopel pellets employed varied, with patients receiving 6 or 7, 8 or 9, or ≥10 pellets). In our trial, a significant percentage of men from both arms exhibited low levels of serum testosterone at the 4-month follow-up. While the objective of our study was not to assess dosing, it may be worth taking a closer look at optimal dosing regimens to achieve eugonadal testosterone levels for the longest period. Another aspect of the trial that should be explored is the statistically significant increase in levels of estradiol in the E100 compounded testosterone pellets as compared with Testopel. We explored different aspects of the data to help illuminate the reason for this inconsistency. Higher testosterone levels and body mass index could explain increases in estradiol; however, both parameters were not statistically different in each group. Impurities within the compounded pellets can be another explanation for the difference, but more intensive studies must be done to clarify.
This study is not without limitations. Results from a randomized controlled trial may not always emulate situations encountered in real practice and thus may not be widely applicable, especially considering our strict exclusion criteria. The lack of external validity and the single-blinded design are also potential sources of inaccuracy and bias. One limitation specific to our trial includes the minor dosage difference between the pellets. We suffered a logistical dilemma between equalizing the dosages given to each group and studying their effects at or near the most common dosage. Although the difference in dose is relatively small (50 mg), it does introduce a potential confounding bias. Additionally, this study focused on the safety and noninferiority of E100 as compared with Testopel, and sexual dysfunction represents an important entity in the constellation of symptoms that patients with TD may experience. As such, an important consideration is a comparison of the effect of E100 vs Testopel on sexual symptoms after treatment. Finally, in this study, laboratory endpoints were assessed at 2, 4, and 6 months. Prior work on crystalline pellets has shown that peak testosterone was observed at the 1-month time frame.16 While our work did not capture this endpoint, we were able to capture therapeutic testosterone levels at 2 months for each arm. Future work could consider laboratory assessment at 1 month to ascertain the peak of each therapy. Finally, the relatively low power in each arm that qualified for analysis at the 6-month mark represents a limitation in long-term follow-up. Future work should examine patient- and dosing-based factors that optimize testosterone levels up to the 6-month period. This may include more frequent laboratory assessment as well as more frequent dosing (every 3 months) to better titrate treatment response and maintenance of stable testosterone levels. Nonetheless, despite these limitations, these data highlight the noninferiority and safety profile of E100 compounded testosterone pellets as compared with the more expensive Testopel in the treatment of men with TD. This is especially the case in patients who may not be able to afford the market brand or whose insurance does not cover the treatment, as the E100 compounded pellets are almost 1/10th the price.17,18 With these findings, urologists can better serve as advocates for their patients by offering an effective modality for treating the potentially debilitating effects of TD.
Conclusion
The findings of this study highlight the noninferiority of E100 compounded testosterone pellets in the treatment of male TD Thus, E100 compounded pellets represent an alternative to Testopel. With these data, urologists can more reasonably and comfortably offer men with TD E100 compounded testosterone pellets.
Eliyahu Kresch, MD, Thiago Fernandes Negris Lima, MD, Manuel Molina, MD, Nicholas A. Deebel, MD, Rohit Reddy, BA, Mehul Patel, MD, Justin Loloi, MD, Chase Carto, BS, Sirpi Nackeeran, MD, Daniel C. Gonzalez, BA, Jesse Ory, MD, Ranjith Ramasamy, MD
Abstract
Background: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients.
Aim: To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively.
Methods: This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg).
Outcomes: We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 AM): serum testosterone, estradiol, hematocrit, and prostate-specific antigen.
Results: After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study.
Clinical Implications: Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD.
Strengths and Limitations: Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort.
Conclusion: E100 compounded testosterone pellets are a non-inferior option of TTh as compared with Testopel for men presenting with TD.
Introduction
Testosterone deficiency (TD) is characterized by a combination of low serum testosterone with symptoms such as low energy, fatigue, decreased muscle mass, reduced libido, and erectile dysfunction.1 TD prevalence can be as high as 6% in men aged 40 to 70 years.2 Testosterone therapy (TTh) in this setting has many benefits, such as increased lean body mass, bone formation, and libido and decreased total cholesterol, and it may even increase cognitive function.3,4
Multiple forms of TTh currently exist on the market and are available to patients, consisting of intramuscular, subdermal, transdermal, oral, and buccal formulations.5,6 These options have different dosing regimens, pharmacokinetic profiles, advantages, disadvantages, and monitoring requirements that the physician-patient team must consider. Subcutaneous testosterone pellets were first developed in the 1940s but did not gain popular adoption in the United States until Food and Drug Administration (FDA) approval for Testopel in 1972.5,7 Subcutaneous long-lasting testosterone pellets are placed in the subcutaneous hypovascular space and gradually dissolve to provide steady testosterone release.7,8
Testopel pellets (Endo International plc) are 3 × 8–mm pellets that each contains 75 mg of crystalline testosterone. Current FDA dosing guidelines recommend 150 to 450 mg every 3 to 6 months with appropriate titration required to induce pubertal changes in hypogonadal males if indicated.9 However, a large retrospective study of 380 men found that higher pellet numbers (10-12) making up 450 to >750 mg was associated with more consistent, higher, and longer maintenance of therapeutically ranged testosterone levels.8
Since FDA approval of market brand testosterone pellets, comparable pellet formulations of differing sizes and dosing regimens were studied but have not reached the market.10 In this trial, we sought to evaluate the safety profile of compounded pellets (E100) and to compare the efficacy between compounded and market-brand testosterone pellets. This trial evaluated the market brand testosterone pellet Testopel (75 mg) and compared it with compounded testosterone pellets (100 mg; E100) manufactured by Empower Pharmaceuticals, an FDA-registered facility. Maintaining FDA approval and regulation ensures adherence to the FDA’s current good manufacturing practice regulations. These outline the standards for the design, monitoring, and control of manufacturing processes and facilities to ensure that products are safe and effective and to hold the approved agency subject to state and local regulations.
Discussion
TD imposes a significant detrimental effect on men’s quality of life. The estimated prevalence of TD is 6% in the American male population. Since the life expectancy of a US male is 74.5 years, many men will require long-term TTh.13 Of the various forms of testosterone replacement, testosterone pellets represent an effective, long-term treatment strategy with sustained increases in serum testosterone for up to 6 months.14 The novel findings of this single-center, open-label, randomized trial suggest that market brand and E100 compounded testosterone pellets are similar in their ability to increase serum total testosterone to within reference levels without a significant difference in side effect profile at <10% of the price. In our study, the market brand Testopel and E100 compounded pellets produced by an FDA-registered facility yielded normalization of testosterone levels with similar rates of side effects, such as polycythemia and changes in estradiol and PSA. Testopel has been shown to normalize testosterone levels and improve symptoms for at least 3 months and up to 6 months in men with TD. Specifically, Kaminetsky et al conducted a phase IV, single-center, open-label study to assess the safety and efficacy of subcutaneous insertion of testosterone pellets during a single implantation procedure. The authors determined that mean testosterone significantly increased at weeks 1, 4, and 12 as compared with preimplantation levels and then returned to baseline by week 24. The normalization of serum testosterone coincided with objective improvement in TD symptoms, as demonstrated via objective measures such as patient questionnaires.15 These findings were corroborated in a large multicenter retrospective review assessing the clinical utility of testosterone pellets for TD. In the study, Testopel elicited sustained levels of testosterone for at least 4 months and up to 6 months in men with TD, regardless of pellet number (number of Testopel pellets employed varied, with patients receiving 6 or 7, 8 or 9, or ≥10 pellets). In our trial, a significant percentage of men from both arms exhibited low levels of serum testosterone at the 4-month follow-up. While the objective of our study was not to assess dosing, it may be worth taking a closer look at optimal dosing regimens to achieve eugonadal testosterone levels for the longest period. Another aspect of the trial that should be explored is the statistically significant increase in levels of estradiol in the E100 compounded testosterone pellets as compared with Testopel. We explored different aspects of the data to help illuminate the reason for this inconsistency. Higher testosterone levels and body mass index could explain increases in estradiol; however, both parameters were not statistically different in each group. Impurities within the compounded pellets can be another explanation for the difference, but more intensive studies must be done to clarify.
This study is not without limitations. Results from a randomized controlled trial may not always emulate situations encountered in real practice and thus may not be widely applicable, especially considering our strict exclusion criteria. The lack of external validity and the single-blinded design are also potential sources of inaccuracy and bias. One limitation specific to our trial includes the minor dosage difference between the pellets. We suffered a logistical dilemma between equalizing the dosages given to each group and studying their effects at or near the most common dosage. Although the difference in dose is relatively small (50 mg), it does introduce a potential confounding bias. Additionally, this study focused on the safety and noninferiority of E100 as compared with Testopel, and sexual dysfunction represents an important entity in the constellation of symptoms that patients with TD may experience. As such, an important consideration is a comparison of the effect of E100 vs Testopel on sexual symptoms after treatment. Finally, in this study, laboratory endpoints were assessed at 2, 4, and 6 months. Prior work on crystalline pellets has shown that peak testosterone was observed at the 1-month time frame.16 While our work did not capture this endpoint, we were able to capture therapeutic testosterone levels at 2 months for each arm. Future work could consider laboratory assessment at 1 month to ascertain the peak of each therapy. Finally, the relatively low power in each arm that qualified for analysis at the 6-month mark represents a limitation in long-term follow-up. Future work should examine patient- and dosing-based factors that optimize testosterone levels up to the 6-month period. This may include more frequent laboratory assessment as well as more frequent dosing (every 3 months) to better titrate treatment response and maintenance of stable testosterone levels. Nonetheless, despite these limitations, these data highlight the noninferiority and safety profile of E100 compounded testosterone pellets as compared with the more expensive Testopel in the treatment of men with TD. This is especially the case in patients who may not be able to afford the market brand or whose insurance does not cover the treatment, as the E100 compounded pellets are almost 1/10th the price.17,18 With these findings, urologists can better serve as advocates for their patients by offering an effective modality for treating the potentially debilitating effects of TD.
Conclusion
The findings of this study highlight the noninferiority of E100 compounded testosterone pellets in the treatment of male TD Thus, E100 compounded pellets represent an alternative to Testopel. With these data, urologists can more reasonably and comfortably offer men with TD E100 compounded testosterone pellets.
