Jatenzo (Oral Testosterone Undecanoate) Safety in Adults 65 and Older

Why Geriatric Safety Deserves Separate Attention

Men aged 65 and older face a distinct risk-benefit equation when starting Jatenzo. Age-related declines in renal function, cardiovascular reserve, and hepatic metabolism change how oral testosterone undecanoate behaves in the body, and polypharmacy compounds those changes in ways younger patients rarely encounter.

The Endocrine Society's 2018 clinical practice guideline recommends testosterone therapy for men with symptomatic hypogonadism confirmed by morning serum testosterone measurements on at least two occasions 1. The guideline specifically notes that men over 65 should undergo individualized risk-benefit assessment because evidence of long-term safety in this age group was limited at the time of publication. Since then, the TRAVERSE trial has provided the largest cardiovascular safety dataset for testosterone therapy in older men 2.

Jatenzo's key trial enrolled men aged 18 to 75, with approximately 18% of the study population falling in the 65+ bracket 3. Subgroup analyses did not reveal a statistically different efficacy rate in older participants. 87% of the overall cohort reached eugonadal testosterone levels (300 to 1 to 100 ng/dL) by month three. The safety signals that did emerge, particularly blood pressure elevation and hematocrit increases, tracked with older age as a risk amplifier.

Blood Pressure Elevation: A Dose-Dependent Concern

Jatenzo raises systolic blood pressure by an average of 3 to 5 mmHg, and the FDA mandated a Risk Evaluation and Mitigation Strategy (REMS) program specifically because of this signal. For geriatric patients already managing hypertension, this increase can push readings above treatment targets.

The prescribing information reports that 7.6% of Jatenzo-treated patients experienced blood pressure increases meeting predefined safety thresholds during the key trial, compared to lower rates in younger subgroups 4. The American Heart Association defines stage 1 hypertension as systolic 130 to 139 mmHg 5. A 5 mmHg increase in a 68-year-old man with a baseline systolic of 132 mmHg could shift him from managed stage 1 into stage 2 territory.

Prescribers should check blood pressure at baseline, one month after initiation, and at every dose titration visit. Patients already on antihypertensives may need medication adjustment within the first 8 to 12 weeks of starting Jatenzo. The REMS program requires that prescribers be certified and that pharmacies verify enrollment before dispensing, a layer of oversight that exists for no other testosterone formulation on the U.S. market.

Cardiovascular Risk After TRAVERSE

The TRAVERSE trial settled a decades-long debate about testosterone and heart disease, but its findings demand careful interpretation for geriatric patients. The trial randomized 5,246 men aged 45 to 80 (mean age 63) with hypogonadism and preexisting cardiovascular disease or elevated cardiovascular risk to receive either transdermal testosterone gel or placebo 2.

At a mean follow-up of 33 months, testosterone was noninferior to placebo for the primary composite endpoint of major adverse cardiovascular events (MACE): cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The hazard ratio was 0.96 (95% CI: 0.78 to 1.17). Non-inferiority was met.

Several points matter for Jatenzo prescribers treating older men. TRAVERSE used transdermal gel, not oral testosterone undecanoate. Jatenzo's unique lymphatic absorption pathway avoids first-pass hepatic metabolism, which could theoretically produce different cardiovascular effects than transdermal delivery. No dedicated cardiovascular outcomes trial has been conducted with Jatenzo specifically. The FDA's 2015 class-wide label warning about cardiovascular risk applies to all testosterone products, including Jatenzo 6.

For men over 65 with established coronary artery disease or heart failure with reduced ejection fraction, the risk-benefit calculation tilts differently than for a 50-year-old with isolated hypogonadism. A shared decision-making conversation should document the patient's cardiovascular history, current ejection fraction if known, and statin or antiplatelet regimen before initiating therapy.

Hematocrit and Polycythemia Monitoring

Testosterone stimulates erythropoiesis. This is true across all formulations, but it creates particular hazards for geriatric patients who may already have elevated hematocrit from chronic hypoxia, sleep apnea, or dehydration.

The Jatenzo prescribing information recommends checking hematocrit at baseline, at 3 months, at 6 months, and annually thereafter 4. If hematocrit exceeds 54%, the label instructs prescribers to stop therapy until values normalize. In the key trial, hematocrit increases of greater than 2% occurred in roughly 5.5% of patients, with the highest rates among those receiving the 396 mg twice-daily dose.

Polycythemia increases blood viscosity, raising the risk of venous thromboembolism (VTE). A 2019 meta-analysis published in JAMA Internal Medicine covering 15 placebo-controlled trials found a statistically significant increase in VTE events with testosterone use (OR 1.59 to 95% CI: 1.04 to 2.44) 7. Geriatric patients with reduced mobility, recent surgery, or active malignancy already carry elevated VTE risk independent of testosterone therapy.

Practical monitoring in older men should tighten the schedule. Checking hematocrit at baseline, 1 month, 3 months, 6 months, and every 6 months thereafter (rather than annually) provides earlier detection. Patients with baseline hematocrit above 50% should be counseled that Jatenzo may push them past the 54% threshold quickly, and alternative interventions for hypogonadal symptoms should be discussed.

Drug-Drug Interactions in Polypharmacy Settings

Men aged 65 and older take a median of five prescription medications according to CDC National Health and Nutrition Examination Survey data 8. Jatenzo's metabolic pathway creates interaction potential that multiplies with each added drug.

Oral testosterone undecanoate is absorbed through the intestinal lymphatic system, bypassing extensive first-pass hepatic metabolism. This pathway reduces (but does not eliminate) CYP3A4-mediated interactions compared to older oral testosterone formulations like methyltestosterone. Strong CYP3A4 inhibitors such as ketoconazole and ritonavir can still increase testosterone exposure. Strong CYP3A4 inducers like rifampin, carbamazepine, and phenytoin may reduce it.

Three interaction categories require specific attention in geriatric prescribing:

Anticoagulants. Testosterone can potentiate warfarin's effect by increasing sensitivity to vitamin K antagonism. Patients on warfarin should have INR checked within 1 to 2 weeks of starting Jatenzo. Direct oral anticoagulants (DOACs) like apixaban and rivarelbaan are CYP3A4 substrates. Concurrent use with Jatenzo has not been formally studied but warrants monitoring 4.

Diabetes medications. Testosterone may improve insulin sensitivity, potentially causing hypoglycemia in patients on sulfonylureas or insulin. Blood glucose monitoring frequency should increase during the first 3 months of testosterone therapy. The American Diabetes Association Standards of Care acknowledge testosterone's metabolic effects but do not provide specific dose-adjustment protocols 9.

Corticosteroids. Chronic corticosteroid use in conditions like COPD or rheumatoid arthritis compounds fluid retention risk when combined with testosterone. Peripheral edema occurred in 2.4% of Jatenzo-treated patients in the key trial 3. In older men already on prednisone, this percentage may be higher, though no formal subgroup data exists.

Renal Function and Dosing Considerations

Age-related glomerular filtration rate (GFR) decline affects most men over 65. The average 70-year-old male has an estimated GFR of approximately 75 mL/min/1.73m², compared to 120 mL/min/1.73m² in a healthy 25-year-old. Jatenzo's labeling does not include formal renal dosing adjustments because the drug's lymphatic absorption pathway theoretically bypasses renal elimination.

This does not mean renal function is irrelevant. Reduced GFR changes the clearance of testosterone metabolites, including dihydrotestosterone (DHT) and estradiol. Fluid retention, a known testosterone class effect, worsens more readily in patients with compromised renal function. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines do not specifically address testosterone therapy in CKD, but they recommend caution with any agent that promotes fluid retention in patients with stage 3b or worse CKD 10.

Prescribers should order a baseline comprehensive metabolic panel including creatinine and calculate eGFR before starting Jatenzo. For patients with eGFR below 45 mL/min/1.73m², monitoring visits should occur monthly for the first 3 months, with attention to weight gain, peripheral edema, and serum potassium.

Prostate Safety in Older Men

Prostate safety generates more patient anxiety than perhaps any other aspect of testosterone therapy. The data is more reassuring than many clinicians expect, but nuance exists for the 65+ population.

The Endocrine Society guideline contraindicates testosterone therapy in men with metastatic prostate cancer 1. For men without known prostate cancer, the 2023 AUA/Endocrine Society consensus position holds that testosterone therapy does not increase the incidence of prostate cancer based on available randomized trial data 11. The TRAVERSE trial's prostate substudy specifically examined this question in 5,204 men followed for a mean of 33 months: testosterone did not significantly increase the rate of high-grade prostate cancer events compared to placebo 2.

Jatenzo-specific data from the key trial showed a mean PSA increase of 0.4 ng/mL over 12 months 3. This is consistent with the physiologic effect of restoring normal testosterone on prostatic tissue. PSA should be measured at baseline and at 3 to 6 month intervals during the first year. A PSA velocity exceeding 0.75 ng/mL per year or any absolute value above 4.0 ng/mL warrants urology referral, regardless of testosterone use.

Men with benign prostatic hyperplasia (BPH) may experience worsening lower urinary tract symptoms (LUTS) during testosterone therapy. An International Prostate Symptom Score (IPSS) questionnaire at baseline and at 3-month intervals helps quantify changes. The Jatenzo key trial did not specifically report IPSS outcomes, which represents a gap in the geriatric safety data.

Falls, Frailty, and Functional Outcomes

Testosterone therapy in older men is sometimes initiated to combat sarcopenia and reduce fall risk. The Testosterone Trials (TTrials), a coordinated set of seven placebo-controlled trials in 790 men aged 65 and older, demonstrated improvements in bone mineral density and sexual function but showed only modest gains in physical function 12.

Walking distance improved in the TTrials physical function trial, but the improvement (roughly 6 meters on the 6-minute walk test) did not meet the threshold considered clinically meaningful for fall prevention. Bone mineral density in the spine increased by 7.5% over 12 months in testosterone-treated men versus 0.8% in the placebo group, a statistically significant finding.

These results came from transdermal testosterone gel, not oral testosterone undecanoate. No dedicated functional outcomes trial exists for Jatenzo in the 65+ population. Extrapolation from TTrials data is reasonable given the shared pharmacodynamic endpoint (serum T normalization), but clinicians should not promise fall reduction as a treatment benefit of Jatenzo without stronger evidence.

Deprescribing and Discontinuation

Starting testosterone is simpler than stopping it. In geriatric medicine, every medication should face periodic deprescribing review. Jatenzo is no exception.

The American Geriatrics Society Beers Criteria does not list testosterone as a potentially inappropriate medication for older adults, but it does flag the need for reassessment of any drug that increases fall risk, fluid retention, or cardiovascular burden. Testosterone suppresses endogenous gonadotropin production. Abrupt discontinuation can produce a period of profound hypogonadism lasting weeks to months while the hypothalamic-pituitary-gonadal axis recovers.

No formal Jatenzo taper protocol exists in the prescribing information. A reasonable approach based on clinical experience involves reducing the dose to 158 mg twice daily for 4 to 6 weeks before discontinuation, then checking total testosterone and gonadotropins (LH, FSH) at 4 and 8 weeks after the final dose. If symptoms of hypogonadism return and the patient's cardiovascular and hematologic status permits, therapy can be resumed at the lowest effective dose.

For men aged 75 and older, the question of whether to continue testosterone therapy should be revisited annually. The Endocrine Society guideline does not define an upper age cutoff, but it recommends weighing symptoms, comorbidity burden, and life expectancy when deciding to continue 1. A geriatrician or endocrinologist should co-manage these decisions whenever possible.

Monitoring Schedule for Geriatric Patients on Jatenzo

A standardized monitoring protocol reduces the risk of missed safety signals. The following schedule is adapted from Endocrine Society recommendations and the Jatenzo REMS requirements, with tighter intervals for the 65+ population.

Baseline (before first dose): Total testosterone (AM draw), PSA, CBC with hematocrit, comprehensive metabolic panel, lipid panel, blood pressure, IPSS questionnaire, DXA scan if osteoporosis risk factors are present.

Month 1: Blood pressure, serum testosterone trough (drawn before morning dose).

Month 3: Total testosterone, CBC with hematocrit, PSA, blood pressure, hepatic function panel. Dose titration decision point.

Month 6: Total testosterone, CBC with hematocrit, PSA, blood pressure, lipid panel, comprehensive metabolic panel.

Every 6 months thereafter: CBC with hematocrit, blood pressure, serum testosterone. Annual: PSA, lipid panel, comprehensive metabolic panel, IPSS. DXA scan every 2 years if baseline osteopenia or osteoporosis was present.

The target serum testosterone range during Jatenzo therapy is 300 to 1 to 100 ng/dL measured at trough. Levels consistently above 1 to 100 ng/dL require dose reduction. Levels below 300 ng/dL at the 237 mg twice-daily maximum dose may indicate poor absorption, and clinicians should confirm the patient is taking capsules with a meal containing at least 30 grams of fat.