June 18, 2020



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The Latest in Testosterone Replacement Therapy (TRT): JATENZO® (testosterone undecanoate) Capsules CIII, an Oral Option for Patients with Hypogonadism

Introduction

There has been an explosion in treatment options for men with hypogonadism in the last 2 decades. The latest innovation in Testosterone Replacement Therapy (TRT) is JATENZO®, an oral softgel formulation of testosterone undecanoate (TU).1 Prior to the availability of JATENZO, treatment options in the United States (U.S.) included TRT injections, implantable pellets and several topical formulations.2,3 Even with so many dosing options available, many patients abandoned these kinds of treatments due to administration challenges (e.g., skin irritation for topicals, injection site pain for injectables).2,4

JATENZO is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) due to structural or genetic etiologies.

What took so long to develop an oral TRT?

After the discovery of testosterone and its synthesis in the 1930s, it was quickly realized that oral testosterone does not have sufficient bioavailability to be effective as a replacement therapy due to rapid metabolism in the liver.3 A number of strategies have been explored to overcome this, including chemical modification of testosterone, which eventually led to the FDA-approval of 17 α-methyl-testosterone.3 However, long-term use of 17 α-methyl-testosterone, especially at higher doses, can cause potentially serious liver toxicity, so this compound is rarely used as a TRT currently.3

Testosterone esters were also developed, both as intramuscular injections (testosterone enthanate, cypionate, and TU)3,5 and for oral use (TU only).2,3 In fact, a formulation of oral TU has been widely available and used outside the U.S. since the 1970s.2,3 It was not approved for use in the U.S. because of its pharmacokinetic profile; it is often a struggle to maintain testosterone in the eugonadal range with this formulation.2 In contrast, JATENZO met the US FDA regulatory standards for pharmacokinetics, and safety and efficacy, and is the first oral TU to be approved for use in the U.S.1 It became available for prescription in February 2020.6

What is different about JATENZO?

The key innovation to the formulation is the self- emulsifying drug delivery system,2,7,8 which allows for the formation of TU-containing lipoprotein particles in the gut as the contents of the capsules disperse. (Figure) This allows TU to be absorbed via the intestinal lymphatics, bypassing the liver, and avoiding hepatic first-pass metabolism of testosterone.7,8

Once in the systemic circulation, TU is released from the lipoprotein particle, and endogenous esterases cleave active testosterone (T) from TU. The fatty acid (undecanoate) is then metabolized like dietary fat.8 (Figure) The selection of the undecanoate ester is important, as other fatty acids are less lipophilic and can be diverted to the liver instead of being taken up by the intestinal lymphatic system.2

The result is consistently sustained therapeutic levels; in clinical trials of JATENZO, Cmax was reached at about 2 hours after the morning dose, with the Cmin around 12 hours. The Cavg of serum T over 24 hours was 489 ± 158 ng/dL (mean ± SD) when expressed as approximate serum T equivalents based on assay of plasma T.1,9

The most common adverse events of JATENZO (incidence ≥2%) are headache (5%), increased hematocrit (5%), hypertension (4%), decreased HDL (3%), and nausea (2%). No clinically significant changes in liver function tests have been observed in clinical trials.1,8

How is the formulation dosed and titrated?

JATENZO capsules are available in 3 different strengths, allowing physicians to prescribe 5 dose levels to ensure each patient achieves serum testosterone in the eugonadal range.1

JATENZO is taken twice daily (BID) with food, once in the morning and once in the evening.1 The starting dose is 237 mg TU BID, and serum T should be measured to check for response to therapy after at least 7 days on treatment, about 6 hours after the morning dose is taken.1

With the addition of JATENZO to the treatment paradigm for hypogonadism, patients and physicians finally have an oral softgel option for this chronic condition. For more information, visit JATENZO.com/hcp/.

Peer-reviewed publications of Phase 3 studies of JATENZO have been published and are available in Therapeutic Advances in Urology and The Journal of Clinical Endocrinology & Metabolism.

Please see Important Safety Information, including BOXED WARNING on increases in blood pressure, below.

References:

  1. JATENZO® (testosterone undecanoate) [prescribing information]. Northbrook, IL: Clarus Therapeutics, Inc.; March 2019.
  2. Yin AY, et al. J Androl. 2012;33:190-201.
  3. Nieschlag E, Nieschlag S. Eur J Endocrinol. 2019;180:R201-R212.
  4. Schoenfeld MJ, et al. J Sex Med. 2013;10:1401-1409.
  5. FDA website. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=085635. Accessed April 30, 2020.
  6. Clarus Therapeutics announces commercial launch and availability of JATENZO (testosterone undecanoate) capsules, CIII for the treatment of hypogonadism [press release]. Northbrook, IL: GlobeNewswire; February 10, 2020.
  7. Gupta S, et al. ISRN Pharmaceutics. 2013 Dec 26;2013:848043. doi:10.1155/2013/848043.
  8. Data on file. Clinical Study Report: CLAR-15012. Clarus Therapeutics, Inc.
  9. Data on file. Clinical Study Report: CLAR-18019. Clarus Therapeutics, Inc.

SEE MORE
INDICATION JATENZO® (testosterone undecanoate) capsules, CIII, is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone:
  • Primary hypogonadism (congenital or acquired): testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) above the normal range.
  • Hypogonadotropic hypogonadism (congenital or acquired): gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.
Limitation of useSafety and efficacy of JATENZO in males less than 18 years old have not been established.IMPORTANT SAFETY INFORMATION WARNING: INCREASES IN BLOOD PRESSURE
  • JATENZO can cause blood pressure (BP) increases that can increase the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke and cardiovascular death.
  • Before initiating JATENZO, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled.
  • Periodically monitor for and treat new-onset hypertension or exacerbations of pre-existing hypertension and re-evaluate whether the benefits of JATENZO outweigh its risks in patients who develop cardiovascular risk factors or cardiovascular disease on treatment.
  • Due to this risk, use JATENZO only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies.
CONTRAINDICATIONSJATENZO is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, in women who are pregnant, in men with a known hypersensitivity to JATENZO or its ingredients, or in men with hypogonadal conditions that are not associated with structural or genetic etiologies as JATENZO has not been established for these conditions and there is a risk of increased blood pressure with JATENZO that can increase the risk of MACE.WARNINGS AND PRECAUTIONS
  • JATENZO can increase blood pressure, which can increase the risk of MACE, with greater risk in patients with established cardiovascular disease or risk factors for cardiovascular disease. Before initiating JATENZO, consider the patient's baseline cardiovascular risk and ensure blood pressure is adequately controlled. Monitor blood pressure approximately 3 weeks after initiating, increasing the dose, and periodically while on JATENZO, and treat any new or exacerbations of hypertension. Re-evaluate benefits and risks of continued treatment with JATENZO in patients who develop cardiovascular risk factors or disease. JATENZO is contraindicated in men with hypogonadal conditions such as "age-related hypogonadism" because the efficacy of JATENZO has not been established for these conditions and the increases in BP can increase the risk of MACE.
  • Polycythemia may require a lower dose or discontinuation of JATENZO. Check hematocrit prior to initiation and every 3 months while a patient is on JATENZO and if hematocrit becomes elevated, stop JATENZO until hematocrit decreases to an acceptable level. If hematocrit increases after JATENZO is restarted, stop permanently.
  • Some studies, but not all, have reported an increased risk of major adverse cardiovascular events (MACE) in association with use of testosterone replacement therapy in men. Long-term clinical safety trials have not been conducted to assess the cardiovascular outcomes of testosterone replacement therapy in men. Patients should be informed of this possible risk when deciding whether to use or to continue to use JATENZO. JATENZO can increase blood pressure, which can increase the risk of MACE.
  • Monitor patients with benign prostatic hyperplasia (BPH) treated with androgens due to an increased risk for worsening signs and symptoms of BPH. Patients treated with androgens may be at increased risk for prostate cancer and should be evaluated prior to initiating and during treatment with androgens. Monitor prostate-specific antigen (PSA) levels periodically.
  • Postmarketing reports of venous thromboembolic events (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), have been reported in patients using testosterone replacement products like JATENZO. Evaluate patients with signs or symptoms consistent with DVT or PE and, if a VTE is suspected, discontinue JATENZO and initiate appropriate workup and management.
  • Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions. If abuse is suspected, check testosterone levels to ensure they are in therapeutic range. Counsel patients concerning the serious adverse reactions associated with abuse of testosterone and anabolic androgenic steroids. Conversely, consider the possibility of testosterone and anabolic androgenic steroid abuse in suspected patients who present with serious cardiovascular or psychiatric adverse events.
  • JATENZO is not indicated for use in women.
  • Large doses of androgens can suppress spermatogenesis by feedback inhibition of pituitary FSH. Inform patients of this risk before prescribing JATENZO.
  • Prolonged use of high doses of methyltestosterone has been associated with serious hepatic adverse events. JATENZO is not known to cause these adverse events; however, patients should be instructed to report any signs of hepatic dysfunction and JATENZO should be discontinued while the cause is evaluated.
  • Androgens, including JATENZO, may promote retention of sodium and water. Edema, with or without congestive heart failure, may be a serious complication in patients with pre-existing cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.
  • Gynecomastia may develop and persist in patients being treated for hypogonadism.
  • The treatment of hypogonadal men with testosterone may potentiate sleep apnea in some patients, especially those with risk factors such as obesity or chronic lung disease.
  • Changes in the serum lipid profile may require dose adjustment of lipid-lowering drugs or discontinuation of testosterone therapy. Monitor the lipid profile periodically, particularly after starting testosterone therapy.
  • Use JATENZO with caution in cancer patients at risk of hypercalcemia. Monitor serum calcium concentration regularly during treatment with JATENZO in these patients.
  • Androgens, including JATENZO, may decrease concentrations of thyroxine-binding globulin, resulting in decreased total T4 serum concentrations and increased resin uptake of T3 and T4. Free thyroid hormone concentrations remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.
  • Depression and suicidal ideation have been reported in patients treated with JATENZO in clinical trials. Advise patients and caregivers to seek medical attention for manifestations of new-onset or worsening depression, suicidal ideation or behavior, anxiety, or other mood changes.
ADVERSE EVENTSThe most common adverse events of JATENZO (incidence ≥2%) are headache (5%), increased hematocrit (5%), hypertension (4%), decreased HDL (3%), and nausea (2%).DRUG INTERACTIONS
  • JATENZO can cause changes in insulin sensitivity or glycemic control. Androgens may decrease blood glucose and may require a decrease in the dose of antidiabetic medications.
  • Anticoagulant activity may be affected by androgens. More frequent monitoring of international normalized ratio (INR) and prothrombin time are recommended in patients taking warfarin, especially at initiation and termination of androgen therapy.
  • Use of testosterone and corticosteroids concurrently may increase fluid retention and requires monitoring in patients with cardiac, renal, or hepatic disease.
  • Some prescription and nonprescription analgesic cold medications contain drugs known to increase blood pressure and concomitant use of these medications with JATENZO may lead to additional increases in blood pressure.
USE IN SPECIFIC POPULATIONSThe safety and efficacy of JATENZO in pediatric patients less than 18 years old have not been established. Improper use may result in acceleration of bone age and premature closure of epiphyses.There have not been sufficient numbers of geriatric patients involved in controlled clinical studies utilizing JATENZO to determine whether efficacy or safety in those over 65 years of age differs from younger subjects. There is insufficient long-term safety data in geriatric patients utilizing JATENZO to assess the potentially increased risk of cardiovascular disease and prostate cancer.Please click here for full Prescribing Information, including BOXED WARNING on increases in blood pressure.JATENZO® is a registered trademark of Clarus Therapeutics, Inc. © 2020 Clarus Therapeutics, Inc. All rights reserved. COR-US-0076 07/2020