Testosterone Undecanoate Intramuscular Injection (AVEED)

[Michael Scally MD]

April 18, 2013: Joint Meeting of the Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee Meeting Announcement
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm343879.htm

The committee will discuss the efficacy and safety of new drug application (NDA) 22219, AVEED (testosterone undecanoate) intramuscular injection, submitted by Endo Pharmaceutical Solutions, Inc., for the proposed indication of replacement therapy in adult males for conditions associated with a deficiency or absence of testosterone. The safety discussion will focus on postmarketing reports of oil microembolism in the lungs and potential anaphylactic reactions. In addition to AVEED, other approved testosterone injectable products will be referenced, especially in regard to oil embolism and potential anaphylactic reactions reported for those products.

 

[Michael Scally MD]

Briefing Information for the April 18, 2013 Joint Meeting of the Advisory Committee for Reproductive Health Drugs (ACRHD) and the Drug Safety and Risk Management Advisory Committee (DSaRM)
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/ucm348089.htm

 

[Michael Scally MD]

AVEED™ (Testosterone Undecanoate) For Testosterone Replacement For Treatment Of Hypogonadism http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM348092.pdf

 

[Michael Scally MD]

Endo Pharmaceuticals Solutions, Inc. is seeking the approval of testosterone undecanoate injection (proposed tradename, Aveed) for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Aveed will be administered at a dose of 750 mg via intramuscular injection of 3 mLs of solution, followed by a repeat dose of 750 mg after 4 weeks, then 750 mg doses every 10 weeks thereafter. Severe post-injection reactions reported with the use of testosterone undecanoate injection have been identified during the review of this NDA.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM348090.pdf

 

[Michael Scally MD]

FDA Risk/Benefit Assessment

Testosterone replacement therapies have been approved for use in adult males with conditions associated with a deficiency or absence of endogenous testosterone including products that are administered via the intramuscular route. Available data have demonstrated that Aveed replaces serum testosterone to the normal range in adult men. For this injectable testosterone product, the extended dosing interval may increase the likelihood of patient compliance.

Aside from the risk of severe post-injection reactions, Aveed is associated with the typical adverse events reported for an injectable testosterone therapy.

There is a risk of severe post-injection reactions (POME and anaphylaxis) associated with the use of TU. The incidence of these reactions in clinical study database was small but consistent over time and there was a suggestion of a dose-response relationship. The presence of postmarketing reports for both POME and anaphylaxis indicates that these events continue to occur, but the inability to obtain accurate patient exposure information prevents an assessment of the magnitude of this risk.

There are no known approaches to predict or prevent the occurrence of an Aveed-related severe post-injection reaction for any patient. It is unclear whether a “slowly administered” intramuscular injection or a 30 minute post-injection wait time in the healthcare provider’s office will entirely mitigate this risk.

Finally, although several risk mitigation strategies have been discussed during drug development, the burden of these strategies to patients, providers and the overall healthcare system must be considered, and the likelihood that they will adequately mitigate the risk of POME and anaphylaxis in Aveed users is unknown.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM348090.pdf

 

[BBC3]

With consideration for the Decanoate ester as seen in Deca Durabolin, and touted at 10-14 days, I believe the UNdecanoate ranges from 20-30 days in real effective release time. Kinda like comparing the HERBICIDES Atrizine and 2,4-D.. LOL

The Chinese have already done some studies with this one for male contraceptive I believe. You may have posted the link or not already. It was effective..!

 

[boogaloo]

The vote by the committee was split, 9-9. Does it have a chance with the FDA when there's no direct recommendation?

 

[Michael Scally MD]

FDA Accepts Endo's Complete Response Submission to New Drug Application for AVEED™ (Testosterone Undecanoate) Injection
http://phx.corporate-ir.net/phoenix.zhtml?c=123046&p=irol-newsArticle_print&ID=1852255&highlight (Endo Pharmaceuticals - News Release)

MALVERN, Pa., Sept. 5, 2013 /PRNewswire/ -- Endo Pharmaceuticals Inc., a subsidiary of Endo Health Solutions Inc. (Nasdaq: ENDP) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the complete response submission made by Endo to the new drug application (NDA) for its long-acting testosterone undecanoate injection, AVEED™, intended for men diagnosed with hypogonadism. In connection with the acceptance, the FDA assigned Endo's NDA a new Prescription Drug User Fee Act (PDUFA) action date of Feb. 28, 2014.

 

[BBC3]

So I wonder what the real world TRT protocol will be by TRT savvy docs?? I note the data in the attached publication suggest that current products (T CYP I assume) are on an every 2-4 week protocol. So this is important as it sounds like the FDA is only acknowledging Urologist type protocols with regard to the application of replacement hormones for men...?!? Where might that lead I wonder...?

It should further go without saying, that the APPLICATION process and how well and accurately the IM solution is Pinned becomes much more critical with the Undecanoate product. Don't want to miss there...

It also leads me to wonder as it this becomes mainstream protocol, what will this tell us about the real effects of fat soluble esters that get deposited about the body due to "Injection Point Shrinkage" - as I call it. Could this potentially present problems due to freshly applied esterfied testosterone going round the body in general circulation and "biting" in areas like heart muscle, liver, etc...?!?

FDA Risk/Benefit Assessment



http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM348090.pdf

 

[lxm]

FYI

Nebido (1000mg, 3ml) UK protocol is below

3ml injected, followed by a pre-load 3ml at 6 weeks, followed by maintenance 3ml every 12 weeks.

 

[BBC3]

Kinda Odd - IMHO.. Its pretty common knowledge that it becomes somewhat ineffective to try to get any more than 2mls max into a single glute pin site, 1ml shoulder, etc... Again the risk is the leakage away from the pin incision PRIOR to the solution saturating into the local muscle. Theres no doubt I would demand 1.5 MLs in each butt cheek. Again, it will also be critical that a 25ga pin be used to HELP avoid the immediate leakage back out the hole, and still with plenty of pressure for a couple mins to give time to saturate. I wonder how much BB is in the solution? and it they increased beyond the standard 20% seen in Cyp and Enan..??? But really, the RN's administering the shot will most likely not have a clue the importance and just "gig and go", which will leave opportunity for failure. Finally if any of my hypothesis is correct about the notion of a DEPOT injectable, and the actual physical action of the involvement of the metabolism ACCESSING it, splitting into two sites will also change the way it is released and distributes. As, in a vacuum and in real concept, the LIFESPAN of a depot injection has nothing to do with biological serum elimination half lives of drugs as commonly perceived. Because what we are really talkng about is how well the injected ESTERFIED Testosterone "bites to fat"... That is, binds with muscle tissue, and how difficult a time esterase enzymes have ACCESSING and BREAKING DOWN the esters to cause the T to become available. Which further begs the question - how will a subject with a pre-existing esterfied steroid already in the muscle, and with regard to any potential SATURATION of local physical tissue?? In short, how much ester can a given muscle group hold?? Thjis should also affect Injection Point Shrinkage rates as potential failures on the solution to bite and form the depot. Realistically, then notion of implanting a DEPOT of Undecanoate is the closest thing to implanting a "liquefied pellet".

One of the points I am making is that theoretically an esterfied hormone SHOULD ALL RELEASE AT THE EXACT SAME MOMENT. The reason it does not can only be attributed to the way the body PHYSICALLY GAINS access to it to metabolize it. To effectively lodge and entire 3 ccs in a single point in a muscle would MORE LIKELY present a very different outcome when breaking it into (2) depots in TWO different muscle areas. On the one hand, the cutting in half to two areas will probably make for a more stable, BUT FASTER release of the depots, HOWEVER, a large 3ml pin which may present considerable shrinkage may redistribute immediately biting in many other areas around the body (as well as much more into adipose tissue local to the injection site). But I would forecast that the initial result over the first month would be an available DEPOT source similar to two depots due to the widespread ester around the body being more readily accessible - and only then slowing after the stuff that got spread around was exhausted. Then the subject with TWO depots might have a more potent remaining effective source in month two. Again, and back to the concern from my previous post, what is going to be the biological consequence of the undecanoate that spreads systemwide biting to heart, liver, etc...?

What are the consequences of Esterfied SynT running through the liver and kidneys? I wonder how many passes undecanoate can make around the body prior to the liver simply destroying the foreign matter? Thats in a bubble of course, as realistically, the ester will find SOMEWHERE to bite prior to a single complete pass. Then you really wonder what the action of having an ester attached to the colon, eyes, PROSTATE, etc.. IS, and how it would affect the performance of said organs/tissues.. 3mls is a SHITPILE of injectible to attempt in one location....!

Finally, forget about cycling with this. I would forecast that 4-6 of these injections would be enough to render one shut down/partially shut down for AT LEAST a year post usage. This is the version the Chinese have proven very successful as male contraceptive in fact. Seems like I might have even tried some of that back when Airsealed was in business and which gave me gyno issues for more than a year. It was so bad that even just attempting to pin an entire 200mg dose of Test Cyp as TRT would flare it back up. Speaking of, I now note that my BB is completely gone at this moment and has been for a year I suspect - and I've been on full 200mgs for a while now. So thats more proof of the insidious hang time with the longer esters... Its funny though, because while shut down and gyno activity was severe, my labz never really indicated that strong a TT level during that time period...!?!

FYI

Nebido (1000mg, 3ml) UK protocol is below

3ml injected, followed by a pre-load 3ml at 6 weeks, followed by maintenance 3ml every 12 weeks.

 

[TheWall]

I was just reading up on Aveed. It looks like it is finally moving forward:

FDA Accepts Endo's Complete Response Submission to New Drug Application for Aveed (Testosterone Undecanoate) Injection

MALVERN, Pa., Sept. 5, 2013 /PRNewswire/ -- Endo Pharmaceuticals Inc., a subsidiary of Endo Health Solutions Inc. (Nasdaq: ENDP) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the complete response submission made by Endo to the new drug application (NDA) for its long-acting testosterone undecanoate injection, Aveed, intended for men diagnosed with hypogonadism. In connection with the acceptance, the FDA assigned Endo's NDA a new Prescription Drug User Fee Act (PDUFA) action date of Feb. 28, 2014.

 

[TheWall]

This looks promising:

The good news is that Endo wasn't required to run any additional clinical studies for Aveed, but merely to adjust its dosing and medication guide to ensure safe usage of the injectable drug. Given that the previous FDA panel vote from its third attempt at approval ended in a 9-9 stalemate, there are no assurances that the FDA is going to grant approval to Endo's Aveed here.

Not so much here:

...the main basis for the rejection being concerns from the FDA regarding severe adverse events such as anaphylaxis and pulmonary oil microembolism

Does anyone have more information on these adverse reactions? Is it really just dosing or are there other factors that contribute to mortality on this therapy?

 

[kjcmjc]

U.S. FDA Approves AVEED

Endo | A Global Specialty Healthcare Company

Scroll down under latest news. Aveed approved on 3/6/14.

 

[BBC3]

The PROBLEM with IM based testosterone preparations (which is unwritten, but speculated by M.E.), is that the release rate is not only NON-Linear, I suspect ITS AS CURVY AS THAT HOTTEST WHORE IN THE HOUSE...[)]

And due to multiple variables ranging from...:
1. Application (how well its injected)
2. Release Rate vs. actual biological DEMAND.
3. What actually happens in the Human biological control system regulating De-esterfication and ELIMINATION
4. The entire concept of biological ACCESS/DISPOSITION pertaining to METABOLISM of a DEPOT Administration
5. Injection Protocol with regard to LOCAL SITE APPLICATION/Location should become CRITICAL in this scenario.

Just thinking aloud...

 

[TheWall]

As I understand it, this has been in use in Europe for a while. Any information from across the pond on long term use?

 

[TheWall]

From what I have read on forums out of the UK, the ramp up from gels/shots to depo can be horrible. The total t/free t rises and falls slowly. So, on my last day before my shot I'm at TT=400, it will take several weeks to reach my normal high (around TT=800). From what I read, during that time, the poster was under "normal" (different measuring in the UK). One of the posters was continuing gel until the next shot in order to maintain while the depo ramped up. I hope US doctors will have some method of T control/saturation when switching therapies.

 

[Michael Scally MD]

FDA Approves Aveed Testosterone Jab, with Restrictions
http://www.medscape.com/viewarticle/821632

The US Food and Drug Administration (FDA) has approved testosterone undecanoate injectable (Aveed, Endo Pharmaceuticals), for the treatment of men with hypogonadism, but with a boxed warning and very strong prescribing restrictions.

...

The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary-oil microembolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits outweigh the risks.

...

The REMS requires that patients must be observed for 30 minutes following injection to rule out serious POME or anaphylaxis, that healthcare settings and providers be specially certified in order to prescribe and dispense Aveed, and that they must have on-site equipment and trained personnel to manage such emergencies.

 

[Millard]

The FDA is requiring that Aveed's label contain a boxed warning regarding the risks of serious pulmonary-oil microembolism (POME) and anaphylaxis and is making the product available only through a restricted distribution scheme known as a risk evaluation and mitigation strategy (REMS) to ensure that it is used only in men for whom the benefits outweigh the risks.
...
The REMS requires that patients must be observed for 30 minutes following injection to rule out serious POME or anaphylaxis, that healthcare settings and providers be specially certified in order to prescribe and dispense Aveed, and that they must have on-site equipment and trained personnel to manage such emergencies.

This kinda kills its marketability.

 

[toolman]

This kinda kills its marketability.

Exactly what I was thinking. I would enjoy fewer pinning's but not at the cost of having to go somewhere and get my injections and then sit there for 30 some odd minutes...which is always longer in a waiting room before being cleared to leave.