FDA Approves Oral Testosterone Replacement Therapy Kyzatrex

Nelson Vergel · Aug 3, 2022

Another oral testosterone undecanoate.

FDA Approves Oral Testosterone Replacement Therapy Kyzatrex

The FDA has approved Kyzatrex (testosterone undecanoate) for the treatment of primary and secondary hypogonadism in adult males.

www.empr.com

SteveCleves · Aug 3, 2022

Is undecanoate expensive or complicated to synthesize?

madman · Aug 4, 2022

KYZATREX (testosterone undecanoate) capsules, for oral use, CIII, Initial U.S. approval: 1953

2.3 Recommended Dosage and Administration

Individualize the dosage of KYZATREX based on the patient’s serum testosterone concentration response to the drug. The recommended starting dose is 200 mg orally twice daily, once in the morning and once in the evening. Take KYZATREX with food.

Dosage Adjustment

Check serum testosterone concentrations 7 days after starting treatment or after dosage adjustment, 3 to 5 hours after the morning dose. Adjust the KYZATREX dose as necessary as shown in Table 1. Thereafter, periodically monitor serum testosterone concentrations.

The minimum recommended dose is 100 mg once daily in the morning. The maximum recommended dose is 400 mg twice daily. For total daily doses greater than 100 mg, administer the same dose in the morning and evening.

3 DOSAGE FORMS AND STRENGTHS

Capsules:

• 100 mg, oval, opaque, white, imprinted with “MP100” in red ink
• 150 mg, oblong, opaque, white, imprinted with “MP150” in red ink
• 200 mg, oblong, opaque, white, imprinted with “MP200” in red ink

11 DESCRIPTION

KYZATREX is provided as a gelatin capsule containing testosterone undecanoate, a fatty acid ester of testosterone. Testosterone undecanoate is a white to off-white yellow crystalline powder. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

Testosterone undecanoate is chemically described as 17β-hydroxyandrost-4-en-3-one undecanoate. It has the empirical formula of C30H48O3 and a molecular weight of 456.7 g/mol. The structural formula for testosterone undecanoate is presented in Figure 1.

KYZATREX (testosterone undecanoate) capsules for oral use are available in three dosage strengths- 100 mg, 150 mg, and 200 mg. The 100 mg strength is an opaque, white capsule imprinted with “MP100” in red ink. The 150 mg strength is an opaque white capsule imprinted with “MP150” in red ink. The 200 mg strength is an opaque white capsule imprinted with “MP200” in red ink. All capsule strengths also contain DL-alpha-tocopheryl acetate (Vitamin E), phytosterol esters, polyoxyl 40 hydrogenated castor oil, and propylene glycol monolaurate as inactive ingredients.

Gelatin capsule shells are composed of the following inactive ingredients: gelatin, glycerin, purified water, sorbitol, and titanium dioxide.

12.3 Pharmacokinetics

Absorption

KYZATREX was taken orally at a starting dose of 200 mg twice per day with meals in a multicenter, open-label trial in hypogonadal males. The dose was adjusted, as needed, on Days 28 and 56 from a minimum dose of 100 mg (morning-only) to a maximum dose of 400 mg twice per day based on the plasma testosterone concentration obtained by a single blood draw collected 3 to 5 hours after the morning dose. The average daily NaF/EDTA plasma testosterone concentration was 393.3 (±113.6) ng/dL after 90 days of treatment (normal eugonadal range in NaF/EDTA plasma: 222-800 ng/dL. Note that the titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)].

KYZATREX is expected to produce testosterone concentrations that approximate normal concentrations seen in healthy men.

Table 5 summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 90 days of KYZATREX treatment administered daily

Figure 2 summarizes the mean plasma total testosterone profile at the final PK visit.

When KYZATREX was given with breakfast containing 16%, 33%, and 45% fat, the exposure (AUC0-24 hr) of testosterone was increased by 37%, 87%, and 94%, respectively, compared to when given under fasted conditions. The primary efficacy and safety study was conducted under fed conditions regardless of the type of meals and the primary efficacy endpoint of achieving testosterone Cavg in normal testosterone range was met

There was no effect on testosterone PK when KYZATREX was administered with 20% alcohol along with a high-fat meal versus a high-fat meal alone.

madman · Aug 4, 2022

Novel oral testosterone replacement therapy headed to FDA

https://www.mdedge.com/familymedicine/article/235184/mens-health/novel-oral-testosterone-replacement-therapy-headed-fda?sso=true Marius Pharmaceuticals has submitted a new drug application (NDA) to the Food and Drug Administration for Kyzatrex, an oral testosterone replacement therapy (TRT)...

www.excelmale.com

Novel Oral T Formulation Improves Male Well Being Without Compromising IPSS

Abstract Introduction: Male hypogonadism results from insufficient secretion of testosterone (T) and is characterized by low serum T concentrations. Common symptoms of hypogonadism include decreased libido, impotence, weakness, low energy, depression and/or loss of motivation, memory and...

www.excelmale.com

Effects of the oral TU Kyzatrex™ on ambulatory blood pressure in HG men

Abstract Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5...

www.excelmale.com

madman · Aug 7, 2022

Unfortunately, most would not even want to waste their time with any of the available oral TU options (JATENZO®, TLANDO™, KYZATREX®) as they are dead set on running a TT 1000+ ng/dL, and this at f**king TROUGH!

More T is better mentality.....LMFAO!

All bout DEM GAINZZZ BRUH!

eli · Aug 7, 2022

madman said:
Unfortunately, most would not even want to waste their time with any of the available oral TU options (JATENZO®, TLANDO™, KYZATREX®) as they are dead set on running a TT 1000+ ng/dL, and this at f**king TROUGH!

More T is better mentality.....LMFAO!

All bout DEM GAINZZZ BRUH!

Looks very similar to how long cream stays in the system.... If it works as well as cream on scrotum, I'd be alll over it

Systemlord · Aug 8, 2022

I'm only seeing this new oral T option hitting a peak at 600 ng/dL and I'm hitting as high as 715-650 ng/dL after 4 hours and 981 ng/dL at 2 hours.

@madman Can you explain why after the second or evening dosage the peak and trough levels are a little higher than after the first dosage?

The only thing I can come up with is a higher metabolism during the daylight hours versus the night time.

tareload · Aug 8, 2022

madman said:
they are dead set on running a TT 1000+ ng/dL, and this at f**king TROUGH!

1200+ ng/dl trough or you ain't trying Brother @madman . Come on now.

Starting TRT Over Soon

Yeah. Ok. Tell Keith I even have a special plot just for him now: Presenting the Rouzier/Nichols/Bossa Commemorative T Dose Response Chart. #SymptomRelief?..1200 ng/dl trough w/ E7D or E3.5D dosing What’s your problem Bro? I’m only “hitting” 1200 ng/dl. Also courtesy of...

forums.t-nation.com

madman · Aug 11, 2022

Systemlord said:
I'm only seeing this new oral T option hitting a peak at 600 ng/dL and I'm hitting as high as 715-650 ng/dL after 4 hours and 981 ng/dL at 2 hours.

@madman Can you explain why after the second or evening dosage the peak and trough levels are a little higher than after the first dosage?

The only thing I can come up with is a higher metabolism during the daylight hours versus the night time.

Look over the Cmax (Mean/SD) for KYZATREX® in Table 5.

The peak/trough between the two doses (AM/PM) in Figure 2. is nothing to brag about.

The peak between the two doses (AM/PM) for TLANDO™.

*The mean maximum (Cmax) serum testosterone concentrations observed were 979 ng/dL and 989 ng/dL following the morning and evening TLANDO doses, respectively. The average serum testosterone concentrations over 24 hours (Cavg0-24h) observed following TLANDO administration was 476 ng/dL.

Even then the peak/trough between the two doses (AM/PM) in Figure 1. for TLANDO™ and in Figure 2. for JATENZO® is not worth fretting over.

11 DESCRIPTION

KYZATREX is provided as a gelatin capsule containing testosterone undecanoate, a fatty acid ester of testosterone. Testosterone undecanoate is a white to off-white yellow crystalline powder. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

Testosterone undecanoate is chemically described as 17β-hydroxyandrost-4-en-3-one undecanoate. It has the empirical formula of C30H48O3 and a molecular weight of 456.7 g/mol. The structural formula for testosterone undecanoate is presented in Figure 1.

KYZATREX (testosterone undecanoate) capsules for oral use are available in three dosage strengths- 100 mg, 150 mg, and 200 mg. The 100 mg strength is an opaque, white capsule imprinted with “MP100” in red ink. The 150 mg strength is an opaque white capsule imprinted with “MP150” in red ink. The 200 mg strength is an opaque white capsule imprinted with “MP200” in red ink. All capsule strengths also contain DL-alpha-tocopheryl acetate (Vitamin E), phytosterol esters, polyoxyl 40 hydrogenated castor oil, and propylene glycol monolaurate as inactive ingredients.

Gelatin capsule shells are composed of the following inactive ingredients: gelatin, glycerin, purified water, sorbitol, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.3 Pharmacokinetics

Absorption

KYZATREX was taken orally at a starting dose of 200 mg twice per day with meals in a multicenter, open-label trial in hypogonadal males. The dose was adjusted, as needed, on Days 28 and 56 from a minimum dose of 100 mg (morning-only) to a maximum dose of 400 mg twice per day based on the plasma testosterone concentration obtained by single blood draw collected 3 to 5 hours after the morning dose. The average daily NaF/EDTA plasma testosterone concentration was 393.3 (±113.6) ng/dL after 90 days of treatment (normal eugonadal range in NaF/EDTA plasma: 222-800 ng/dL. Note that the titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)].

KYZATREX is expected to produce testosterone concentrations that approximate normal concentrations seen in healthy men.

Table 5 summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 90 days of KYZATREX treatment administered daily.

Figure 2 summarizes the mean plasma total testosterone profile at the final PK visit.

When KYZATREX was given with breakfast containing 16%, 33%, and 45% fat, the exposure (AUC0-24 hr) of testosterone was increased by 37%, 87%, and 94%, respectively, compared to when given under fasted conditions. The primary efficacy and safety study was conducted under fed conditions regardless of the type of meals and the primary efficacy endpoint of achieving testosterone Cavg in normal testosterone range was met

There was no effect on testosterone PK when KYZATREX was administered with 20% alcohol along with a high-fat meal versus a high-fat meal alone.

14 CLINICAL STUDIES

The efficacy and safety of KYZATREX were evaluated in Study MRS-TU-2019EXT (NCT04467697) a multi-center, open-label study of approximately 6 months of duration in 155 hypogonadal males.

Patients received KYZATREX at a starting dose of 200 mg twice daily with meals. The dosage was adjusted on Days 28 and 56 between a minimum dose of 100 mg (single morning dose) and a maximum dose of 800 mg (400 mg twice daily) based on plasma testosterone concentration from a single blood draw between 3 to 5 hours after the morning dose.

The primary efficacy endpoint was the percentage of KYZATREX-treated patients with mean plasma total testosterone concentration (Cavg) over 24 hours within the normal range of 222-800 ng/dL on the final PK visit of the study on Day 90.

The efficacy population consisted of 139 hypogonadal, males with a median age of 50 years (range 22 to 66 years), 79% were White, 16% were Black, 3% were Asian, and 2% were American Indian, Alaskan Native, or Other.

Primary efficacy results are summarized in Table 6.

Table 6:

Secondary endpoints were the percentage of patients with a maximum total testosterone concentration (Cmax) meeting three predetermined limits: less than or equal to 1.5 times the upper limit of the normal range (ULN) (1200 ng/dL), between 1.8 and 2.5 times ULN (1440-2000 ng/dL), and greater than 2.5 times ULN (2000 ng/dL).

The percentage of patients who received KYZATREX and had testosterone Cmax threshold less than or equal to 1200 ng/dL, between 1440 and 2000 ng/dL, and greater than 2000 ng/dL at the final PK visit were 88%, 4%, and 0%, respectively.

11 DESCRIPTION

TLANDO (testosterone undecanoate) capsules contain 112.5 mg testosterone undecanoate, an ester of testosterone, for oral administration. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

The chemical name of testosterone undecanoate is 17β-undecanoyloxy-4-androsten-3-one. It has an empirical formula of C30H48O3 and a molecular weight of 456.7. The structural formula is:

Testosterone undecanoate is a white to off-white crystalline substance.

The inactive ingredients in TLANDO capsules are ascorbyl palmitate, glyceryl monolinoleate, polyethylene glycol 8000, and polyoxyl 40 hydrogenated castor oil. The capsule shell contains black iron oxide, gelatin, and titanium dioxide. The capsule is imprinted with black ink that contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

12 CLINICAL PHARMACOLOGY

12.3 Pharmacokinetics

Absorption Testosterone undecanoate is a lipophilic molecule that is primarily absorbed into the lymph system after oral administration and then released into the general blood circulation by the thoracic duct, avoiding absorption into the portal vein and thereby circumventing first-pass metabolism in the liver. Testosterone undecanoate is converted to testosterone following absorption.

Following administration of 225 mg of TLANDO in ninety-five hypogonadal males, maximum serum testosterone concentrations were observed at a median (Tmax) of about 5 hours. The mean maximum (Cmax) serum testosterone concentrations observed were 979 ng/dL and 989 ng/dL following the morning and evening TLANDO doses, respectively. The average serum testosterone concentrations over 24 hours (Cavg0-24h) observed following TLANDO administration was 476 ng/dL.

Figure 1 shows the mean serum total testosterone concentration-time profile for hypogonadal men (N=90) administered TLANDO.

14 CLINICAL STUDIES

The efficacy and safety of TLANDO was evaluated in Study 16-002 a multicenter, open-label, single-arm study in adult hypogonadal male patients (NCT03242590). Patients received TLANDO 225 mg, orally twice daily with food for approximately 24 days; no titration was performed to adjust the dosage.

A total of 95 hypogonadal men received a dose of TLANDO and were included in the efficacy evaluation. Patients had a median age of 56 years (range 29-74 years), 81% were White, 16% were Black, 2% were mixed race, and 1% were Asian; 26% were Hispanic.

The primary endpoint was the percentage of patients who achieved a 24-hour average serum testosterone concentration (Cavg0-24h) within the normal range of 300-1080 ng/dL on the final visit of the study.

Table 3 shows the proportion of subjects, Study 16-002, with an average serum total testosterone concentration in the normal range (300-1080 ng/dL).

Table 3:

Secondary endpoints were the percentage of patients with maximum total testosterone concentration (Cmax) meeting three predetermined limits: less than or equal to 1.5 times the upper limit of the normal range (ULN) (1620 ng/dL), between 1.8 and 2.5 times ULN (1944 - 2700 ng/dL), and greater than 2.5 times ULN (2700 ng/dL).

The percentage of patients who received TLANDO and had a T Cmax threshold less than or equal to 1620 ng/dL, between 1944 ng/dL and 2700 ng/dL, and greater than 2700 ng/dL at the PK visit were 82%, 5%, and 0%, respectively.

11 DESCRIPTION

JATENZO for oral use is provided as a gelatin capsule containing testosterone undecanoate, a fatty acid ester of testosterone. Testosterone undecanoate is a white to off-white yellow crystalline powder. Testosterone, an androgen, is formed by cleavage of the ester side chain of testosterone undecanoate.

Testosterone undecanoate is chemically described as 17β-hydroxyandrost-4-en-3-one undecanoate. It has the empirical formula of C30H48O3 and a molecular weight of 456.7. The structural formula for testosterone undecanoate is presented in Figure 1.

JATENZO capsules are available in three strengths 158 mg, 198 mg, and 237 mg.

The 158 mg strength is an opaque red capsule that contains 158 mg of testosterone undecanoate and is imprinted with “158” in white ink. The 198 mg strength is an opaque white capsule that contains 198 mg of testosterone undecanoate and is imprinted with “198” in red ink. The 237 mg strength is an opaque orange capsule that contains 237 mg of testosterone undecanoate and is imprinted with “237” in white ink. All capsule strengths also contain oleic acid, polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), borage seed oil, peppermint oil, and butylated hydroxytoluene as inactive ingredients.

Gelatin capsule shells are composed of the following inactive ingredients: Gelatin, sorbitol, glycerin, purified water, iron oxide red, FD&C Yellow #6, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.3 Pharmacokinetics

Absorption

JATENZO delivers physiologic amounts of testosterone, producing testosterone concentrations that approximate normal concentrations seen in healthy men.

JATENZO was taken orally at a starting dose of 237 mg twice per day with meals in a multicenter, open-label, randomized, 2-arm, active-controlled trial in hypogonadal males. The dose was adjusted, as needed, on Days 14 and 56 between a minimum of 158 mg twice per day and a maximum of 396 mg twice per day based on the average plasma testosterone concentration obtained over 24 hours after the morning dose. The average daily NaF-EDTA plasma testosterone concentration was 403 (± 128) ng/dL at the end of treatment, whereas the normal eugonadal range in NaF-EDTA plasma was 252-907 ng/dL in this study. Note that the titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)].

Table 3 summarizes the pharmacokinetic (PK) parameters for plasma total testosterone in patients completing at least 105 days of JATENZO treatment administered twice daily.

Figure 2 summarizes the mean plasma total testosterone profile for the patients at the final PK visit

When JATENZO was dosed with different breakfasts containing various amounts of fat, the bioavailability with the 30 g fat, 45 g fat, and high-calorie high-fat breakfasts was comparable, but there was a food effect with the 15 g fat breakfast compared to the 30 g fat breakfast. The 15 g fat breakfast had a 25% decrease in testosterone exposure compared to the 30 g fat breakfast.

14 CLINICAL STUDIES

14.1 Clinical Trials in Hypogonadal Males

The efficacy and safety of JATENZO were evaluated in 166 adult hypogonadal males in an open-label study of approximately 4 months duration (NCT02722278). The study included a Screening Phase, a Treatment Titration Phase, and a Treatment Maintenance Phase. JATENZO was taken orally at a starting dose of 237 mg twice per day with meals. The dose was adjusted on Days 21 and 56 between a minimum of 158 mg twice per day and a maximum of 396 mg twice per day on the basis of the average testosterone concentration obtained over 24 hours post-morning dose.

The primary endpoint was the percentage of patients with mean plasma total testosterone concentration (Cavg) over 24 hours within the normal eugonadal range on the final PK visit of the study.

Secondary endpoints were the percentage of patients with a maximum total testosterone concentration (Cmax) above three predetermined limits: less than or equal to 1500 ng/dL, between 1800 and 2500 ng/dL, and greater than 2500 ng/dL.

One hundred and forty-five (87%) of the 166 hypogonadal men who received JATENZO had a mean total testosterone concentration (Cavg) within the normal eugonadal range at the end of treatment.

The percentage of patients who received JATENZO and had Cmax less than or equal to 1500 ng/dL, between 1800 and 2500 ng/dL, and greater than 2500 ng/dL at the final PK visit were 83%, 3%, and 3%, respectively. Note that the testosterone concentrations were not measured in serum but the effects of different sample preparation conditions were accounted for in the data analysis of the results shown here. The titration scheme for use in clinical practice is based on serum total testosterone [see Dosage and Administration (2.2)].