The Quest for a Generic Premarin – A Bitter Pill to Swallow

Premarin Horse. Google image.

BY JANE ALLIN

The story of the quest for a generic Premarin is an interesting one – one that dates back to the mid 1980’s when the FDA announced that Premarin was effective in combating the bone loss associated with osteoporosis.

To this day an Abbreviated New Drug Application (ANDA) for a generic version has yet to be approved by the FDA – more than 20 years after two companies vying for a piece of the pie lost their bids to market a generic version of Premarin.

The history behind the failure of the FDA to approve any generic version of Premarin is intriguing yet pretentiously motivated based on a so-called “impurity” named delta 8,9-DHES.

Premarin’s patent expired in 1971 and until 1986, when the news of its efficacy in minimizing bone loss associated with osteoporosis was publicized, there was little to no interest from competing drug companies to produce a generic version of the drug.

    “There was not a large market for anyone to do anything about it until Premarin was granted the osteoporosis indication,” says Kenneth Phelps, vice president of clinical operations at Duramed Pharmaceuticals, Inc. (Cincinnati, OH). Duramed had a generic version of Premarin, known simply as conjugated estrogens USP, which it hoped to exploit in this newfound niche. “The market burst open, and Premarin seized the day. [There was talk that] literally every postmenopausal woman should take Premarin for the rest of her life,” Phelps says.” [1]

When Premarin was first introduced in 1942, Wyeth-Ayerst was only required to prove its safety, not its effectiveness and at that point it was unclear exactly what it contained. With time and advancing scientific techniques Premarin was found to be comprised of at least 10 different identifiable and quantifiable estrogens two of which, in 1972, the FDA declared responsible for Premarin’s efficacy – estrone sulfate and equilin sulfate – the rest being ancillary estrogens deemed not to participate in its activity. [2]

This opened the door for competing drug companies to submit Abbreviate New Drug Applications (ANDA) for their generic versions.

In 1991, six years after the announcement about the benefits of Premarin as an osteoporosis preventative, Duramed Pharmaceuticals submitted an ANDA for the approval of Cenestin – a generic version of Premarin.

Around the same time another pharmaceutical company, Barr Laboratories, had also developed a generic version and were eager to compete in the lucrative market offered by this new revelation and the possibility of an untapped target audience.

However the prospect of a generic entering the melee triggered a scientific debate that would persist for many years.

Despite the fact that the generics appeared to be interchangeable with Premarin this was really not the case.

To begin, the FDA discovered that Premarin had a slow-release bioavailability mechanism meaning that generic copies would need to have similar release characteristics to be considered bioequivalent. Testing, however, proved the generics to be immediate release in their action. [3]

This finding further clouded the question of what the actual active ingredients in Premarin were since bioequivalence testing is typically based on the active ingredients, or their metabolites, of the product. This is a function of the complex nature of the CEEs that contain numerous estrogens in smaller quantities in addition to other steroidal compounds that may furnish some level of biological activity in the human body. [4]

Note: CEEs stands for conjugated equine estrogens, made with urine collected from pregnant mares.

Accordingly from a purely scientific perspective they were not the same.

To add fuel to the fire Wyeth-Ayerst also issued dire warnings that this alleged discrepancy of how quickly the estrogen entered the bloodstream could increase the incidence of cancer in users.

Consequently, in 1991, the FDA abruptly withdrew approval of all ANDAs for generic Premarin and swiftly stipulated that in addition to estrone sulfate and equilin sulfate any potential generic must contain three additional estrogens as concomitant components – not considered active ingredients but nonetheless requirements to apply for an ANDA. [5]

Interestingly enough the Canadian version of Premarin was found to be as fast-acting as the generics.

    “Canada’s regulatory agency rejected Wyeth-Ayerst’s objection to a generic Premarin produced by ICN Canada Ltd. and left it on the market. A Canadian drug advisory committee concluded in a 1991 report, “If Wyeth’s position were correct, then Premarin had been producing unsafe plasma levels in Canadian women for years” (J. Carey, 1997, p. 130). This statement apparently went unnoticed by the FDA” [6]

Despite this major setback for Duramed and Barr Laboratories, both companies, eyeing the tidy profits to be made from the potentially burgeoning market for the drug due to its ability to mitigate osteoporosis, forged ahead and developed new generics that would satisfy the estrogen requirements together with demonstration of bioequivalency.

However in the interim Wyeth was already strategizing to protect their control of the HRT and newly-realized osteoporosis market.

As a result of their clinical studies Wyeth-Ayerst filed a citizen’s petition in November 1994 requesting that the FDA designate delta (8,9) dehydroestrone (DHES) a concomitant component of conjugated estrogens citing it as having a critical profile and that the FDA not approve any generic versions lacking this component. [7]

In response the FDA ruled unanimously that delta 8,9 DHES was an impurity and was not a required ingredient of any generic. [8]

This move by the FDA led Duramed and Barr to believe that approval of their generics would be forthcoming and both submitted new ANDAs – Duramed in September 1995 and Barr the following July.

But Wyeth-Ayerst was not ready to give up on its fight to maintain control of the market. What followed was a massive advertising campaign of propaganda, both aggressive and defensive, to uphold the credibility of their product.

This strategy consisted of blatant lies and exaggerations of the benefits of Premarin. In addition to relieving the symptoms of menopause it was touted as aiding sexuality, the brain (cognitive function, memory, Alzheimers), cataracts, teeth, heart, bones, colon, you name it – a miracle drug.

Wyeth-Ayerst also “persuaded” physicians to hand out complimentary videos and brochures about the drug.

Premarin foals.
Premarin foals.
    “The brochure, titled Quality,Commitment, and Caring, stated, ‘No synthetic components have ever been introduced to the unique combination of natural estrogens.’ The brochure not only praises Premarin and its ‘unique’ qualities but also featured color photographs of beautiful horses grazing in fields. The captions with these photographs stated, ‘The mares are highly prized and well cared for’ and ‘Providing for the care and well-being of horses is crucial to the production of Premarin.’ The text stated, ‘No other type of livestock ranching has as many checks and balances for animal care and welfare’ ”. [8]

It did not stop here – this devious marketing ploy became politically motivated when Wyeth-Ayerst recruited Senators to pen letters to the FDA to halt generic Premarin progress.

Moreover women’s groups were enlisted to join the cause.

Needless to say large sums of money passed between hands. This in itself is worthy of a story on its own.

While all of this was happening, the US Food and Drug Administration’s advisory panel for Fertility and Maternal Health Drugs met in 1995 to discuss the composition of conjugated equine estrogens but failed to reach a verdict on whether delta 8,9 DHES (and potentially other components) in Premarin were concomitant entities or critical to its clinical benefits.

At the time delta 8,9 DHES was not included in the generic versions of the drug yet Wyeth was resolved to maintain its importance.

Wyeth’s arguments in making the claim for the clinical significance of the delta 8,9 DHES were multi-fold: (1) ~ 18% of circulating estrogens in women taking Premarin, reflecting a far greater bioavailability than indicated by the amount actually present in the product (about 2%-6%); (2) greater activity than predicted by its estrogen receptor binding affinity since the potency of delta-8.9 DHES was found to be similar to estradiol (a potent estrogen); (3) evidence that delta-8,9 DHES might have 10 times the potency of estrone sulfate, a major component in Premarin; (4) different estrogen components have different effects on different tissues, and that there may be synergy between certain components and; (5) two more estrogen components of Premarin (on top of the ten already described) were identified and a characterization of a third was underway. [9]

The counter-argument from Barr Laboratories, one of the generic hopefuls, argued that delta 8,9 DHES and other components of Premarin should be declared impurities claiming that a receptor binding assay showed that both equilin sulfate and estrone sulfate, thought to be the original active hormones, bound to 60% of the available receptors and delta 8,9 DHES only 0.2%. [10]

This fell flat with one panel member who made the comment that this was not new information but rather a theoretical discussion of what Barr believed was correct. [11]

In the end, the only thing the panel agreed upon was that more trials were required, particularly in terms of efficacy related to dosage and comparative safety – a stalemate so to say.

Finally in 1997, with delta 8,9 DHES as the focus of their defense, Wyeth-Ayerst presented newer laboratory and clinical studies to the FDA. Together with the previous findings this data was meant to demonstrated that this particular component of Premarin was not simply a concomitant entity but rather an active constituent of Premarin. After repeated doses of Premarin, the blood concentration of the active metabolites of delta 8,9 DHES were found to be at the same level as the metabolites of both estrone and equilin.

    “An FDA spokesman said that ‘for something to be generic, it has to be exactly identical and deliver the same active ingredients as the original product,’ and the generics have not been able to do that. The generic companies may have products that legitimately treat a lot of the same symptoms of Premarin, but the agency has to know that it is bioequivalent to approve it, he added. One concern is that a generic without exactly the same ingredients may not confer the same long-term clinical benefit of Premarin, such as protection against osteoporosis and cardiovascular disease.

    ‘Although this finding does not prove that the DHES in Premarin has an important therapeutic effect, it underscores the lack of knowledge of the makeup of Premarin and the relative importance of its components, and therefore the lack of a standard on which to evaluate a generic copy,’ said Dr Woodcock. ‘A lot of information is needed before generic versions can make it to the market,’ she noted, adding that there are many other estrogen replacement products available which are approved for long-term use to prevent osteoporosis.” [12]

So where did that leave the generics?

They had several options, none of which was particularly inviting – they could appeal the decision, reformulate their products with delta 8,9 DHES and repeat the bioequivalence testing, conduct trials with Premarin to determine the active ingredients in it and attempt to replicate that, or perform large scale trials to demonstrate whether the long-term long clinical benefits were equivalent.

Unfortunately all of these possibilities were time-consuming, expensive and not without risk of falling short of expectations.

With the road to the generic competition of Premarin effectively blocked, both Duramed and Barr Laboratories chose to go down different pathways. Duramed decided to submit a New Drug Application (NDA) for Cenestin which precluded it as a generic of Premarin – it is not a conjugated estrogen by compendial standard and is specifically called ”synthetic conjugated estrogens-A”. [13]

Cenestin is a mixture of nine synthetically derived estrogen compounds manufactured from soy and yam sources and contains no delta 8,9 DHES.

Barr Laboratories opted to continue its search for a generic form of Premarin. In 2002 Barr announced that it had signed an agreement with Natural Biologics to develop an “AB” conjugated estrogens product using “equine-based” raw materials feeling confident that this would satisfy the requirements for FDA approval of a generic Premarin. Founded in 1993, Natural Biologics was the first company to produce equine-based bulk conjugated estrogens for use in generic product. [14]

Eventually on June 30, 2003, Barr filed an ANDA with the FDA for their version of a generic Premarin.

However this backfired when the U.S. Court of Appeals for the Eight Circuit upheld a lower court decision that Natural Biologics misappropriated trade secrets related to Wyeth’s chemical process for extracting estrogens used in Premarin. [15]

Subsequently Barr withdrew its application pending at the FDA for a generic version of Wyeth’s Premarin.

    “Under the lower court’s ruling, Natural Biologics and ‘anyone acting in concert with it’ are prohibited from using Natural Biologics’ misappropriated process for extracting bulk natural conjugated estrogens for any hormone replacement therapy drug and from further manufacture or sales of Natural Biologics’ bulk product.

    ‘Natural Biologics also must retrieve and destroy any bulk material produced to date, and can no longer engage in research and development of any natural conjugated estrogens product or transfer that knowledge to a third party,’ Wyeth said.” [16]

But the continuing Premarin generic saga fueled by Wyeth’s insatiable greed (now the equally corrupt Pfizer) doesn’t end here. In 2007 they were still fighting to cement their foothold on the HRT market in the US – and of course they won the battle.

    “A group of pharmaceutical wholesalers has lost an appeal brought against Wyeth-Ayerst Laboratories over claims the drug maker hiked up the price of its hormone medication while keeping its competitor out of the lucrative market.” [17]

The claim from competitor, Duramed and their HRT drug Cenestin that received approval from the FDA in 1999, not as a generic version of Premarin, but rather as alternative, was based on Wyeth’s increase in the cost of Premarin following an aggressive campaign by Wyeth to boost the sales of Premarin at the expense of Duramed – their rival in the market share of estrogen supplements for the relief of menopausal symptoms.

The ruse employed by Wyeth, intended to destroy the HRT market share held by Duramed, was sinister and was instigated 3 years prior to Cenestin’s market entry.

Wyeth lured the wholesalers with incentives of rebates for selectively purchasing Premarin over Cenestin – lucrative rebates that matched the rebate rewards to market share. This was termed the “Premarin Preemptive Plan”.

    “In one reimbursement agreement, Wyeth promised rebates only if Premarin’s share in the estrogen market did not fall below 81%.” [18]

Even more despicable were Wyeth’s blatant threats to these wholesalers.

    “Wyeth’s tactics also included warning wholesalers that while they would save money purchasing the lower-priced Cenestin, they would lose much more in rebates. The company demonstrated the effects using its ‘Cenestin Impact Model,’ instructing one wholesaler that it would save $100,000 buying its rival’s drug, but would lose almost $4 million in rebates if Cenestin’s national market share grew to 4%.” [19]

Despite the Machiavellian nature of these contemptible tactics, the only resolve available to Duramed was to demonstrate that while Wyeth was limiting sales of Cenestin via their questionable strategies, at the same time they were increasing the price of Premarin, hence guilty of monopolizing the market and in violation of antitrust laws under the Sherman Act. [20]

In the end it was not just a defeat for Duramed but also for anyone campaigning for the widespread availability of an effective alternative to equine hormones for the relief of menopausal symptoms.

    “Upholding the judgment, the appeals court said it could find no causal connection between Wyeth’s Premarin Preemptive Plan and an increase in the price of its drug.

    ‘That Wyeth recognized that its superior market position decreased the necessity of adjusting its own price does not demonstrate that its particular efforts against Cenestin prompted a price increase,’ the circuit judges ruled.” [21]

Yet another incident of the FDA, the government as a whole, and the law in bed with Big Pharma – nothing new here.

Brand name drug companies have all sorts of tricks up their sleeve, so to say, when it comes to intervening in national procedures for generic drug approvals as well as preventing entrance of generics to the marketplace when a drug falls off the patent cliff, often for years beyond patent expiration.

For every day the legal system delays approval of a lower-cost generic, a brand name pharmaceutical company collects millions more dollars in unlawful proceeds.

This is far more cost-effective than allowing the entrance of the generic to the market place – the legal fees pale in comparison to the revenue collected from the sales of patent-expired drugs that maintain market exclusivity.

This is nothing new – it has gone on for years.

Why? It’s simple – the U.S. government has failed to enact reforms.

However, in reality, it is not so simple. The FDA is failing at its stated mission – all at the expense of the consumer – from pocketbook to grave.

    “. . . . systematic, quantitative evidence that since the industry started making large contributions to the FDA for reviewing its drugs, as it makes large contributions to Congressmen who have promoted this substitution for publicly funded regulations, the FDA has sped up the review process with the result that drugs approved are significantly more likely to cause serious harm, hospitalizations, and deaths.” [22]

FDA Conflict of Interest Cartoon

The diabolical intentions of the pharmaceutical industry to increase market share and boost profits falls nothing short of criminal.

The failure of the U.S. government, particularly the FDA, to push for reforms continues.

To date, Big Pharma and its lobbyists have been largely successful in being able to maintain business as usual.

After all – it’s all about the bottom line.
____

[1] http://goo.gl/obDhLE
[2] http://goo.gl/4CKIHu
[3] See also at 1.
[4] See also at 2.
[5] See also at 2.
[6] http://www.sagepub.com/jowett5estudy/cases/77821_c2.pdf
[7] http://goo.gl/Shmgr3
[8] See also at 7.
[9] http://goo.gl/1HkRvt
[10] See also at 9.
[11] See also at 9.
[12] http://goo.gl/Q8CPVg
[13] http://goo.gl/oaLnjZ
[14] http://goo.gl/TXX5mx
[15] http://goo.gl/nwqe7G
[16] See also at 15.
[17] http://goo.gl/VFSgYO
[18] See also at 17.
[19] See also at 17.
[20] See also at 17.
[21] See also at 17.
[22] http://goo.gl/8RYyUC

LEARN MORE
THE DRUGS, THE WOMEN AND THE HORSES

© THE HORSE FUND

Premarin Horses: How many does it take to make a billion dollars? Part 3

Newest Member of the Premarin Family ― Duavee

Premarin foals.
Premarin foals.

How will this new drug impact profits and inevitably the PMU mares and their foals?

DUAVEE®, the Premarin® ― bazedoxifene combination therapy for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis in women who have not undergone hysterectomy was FDA-approved in October 2013 amid speculation regarding its safety profile and Pfizer/Wyeth’s lengthy struggle to gain approval.

Pfizer anticipates that DUAVEE® will be available in the U.S. in the first quarter of 2014.

This is the first approval of DUAVEE® in any country worldwide ― an approval of a combination drug with the component bazedoxifene yet to receive FDA approval on its own ― its approval is valid only in combination with Premarin®, at least in the US ― a conundrum in itself and worthy of further debate.

Some market analysts estimate DUAVEE®’s peak sales to reach $200 million (USD)/annum. [1]

DUAVEE® will be sold as a combination of 0.45 mg CEEs / 20 mg bazedoxifene however no pricing information is available yet as Pfizer has yet to launch it. If it sells for the same average cost per dose as Premarin® ― roughly $3.50 ― the number of mares, in addition to those currently on the pee lines, can be approximated.

Number of doses = Total Sales ($) / Cost per dose ($)
= $200,000,000 / $3.50/dose
= 57,142,857 doses
Total mg required = 57,142,857 doses x 0.45 mg/dose
= 25,714,286 mg
Number of mares = Total mg required / # of mg per mare
= 25,714,286 mg / 9466 mg/mare
= 2,716 mares

However all may not be lost on this new drug.

Despite the fact that Pfizer re-labeled this combination formula as innovative with an improved safety profile over conventional HRT it has a risk history of its own. Originally known as Aprela® Wyeth started work on it in 1999 as part of a program with Ligand anticipating a FDA approval in 2007 however it took 6 more years for the FDA to finally put its rubber stamp on it all the while citing concerns over health risks.

With the still lingering fear of developing cancers from CEE-derived HRT and the fact that there are other best-seller osteoporosis drugs currently on the market ― for example Evista® from Eli Lily which generated $1 billion last year as well and its generic to be introduced within the month ― DUAVEE® may not become the block-buster Wyeth/Pfizer once thought.

Particularly encouraging is that inside information reveals that even Pfizer is vacillating on the roll-out of this drug.

The veil of controversy over safety efficacy and its long and tortuous road to FDA approval seems to have cooled the hype associated with its introduction to the market. In fact speculation has it that Pfizer may never put this drug on the market – a Godsend to the horses and women alike.

Comments made by Pfizer employees on a public forum reveal a decidedly different picture from the one painted by Pfizer-proper. Here are a few interesting and illuminating remarks.

    Look into why this drug has taken so long throughout R&D phases. Wyeth Women’s Health talked about this drug coming to market by 2005.”

    Just wait until the recall. This drug will make your uterus collapse.”

    It’s the biggest joke at Pfizer. Enormous amounts of money being spent for what will be the biggest failed launch since Exubera.”

    Bingo! The cost to promote this DuaDog far exceeds the profitability for the first five years. Any CSO could sell this thing for a better ROI. It’s not rocket science but simple math. Launch is seriously being questioned and could become a no go at any moment.”

    This product is a DOG! I hear that there is debate internally as to whether or not to even launch.”

    DUAVEE: Dropped Uterus And Vaginal Equine Estrogen”.

Shareholders also understand and do not want to bear the brunt of more lawsuits, nor do the innocent women and their families. It is obvious that few have faith in the safety profile of this drug or its marketability ― two risky drugs and limited clinical data makes for a bad recipe.

It is time to stop this madness.

Big Pharma ― rotten to the core ― deception, fraud, kickbacks, price-setting, bribery and illegal sales activities ― anything to keep their profits rolling in. They will stop at nothing to expand their profit base, even if it means harming or killing countless innocents, humans and animals alike.

God bless the mares and their foals and whatever fate awaits them for they are undeniably the persecuted innocents ― without voice or choice they suffer at the hands of greed and merciless degenerates with stilted vision who fail to comprehend the difference between right and wrong ― a capitalist system where underlying principles are lost to a delinquent world that worships money.

    Where in this wide world can men find nobility without pride,
    Friendship without envy, or beauty without vanity?
    Here, where grace is laced with power and strength tempered by gentleness.
    He serves without servility, he has force without enmity.
    There is nothing so powerful, nothing less violent.
    There is nothing so quick, nothing more patient.
    Our pioneers were borne on his back,
    Our history is his industry.
    We are his heirs and he is our inheritance…
    The horse
    .’

    ― ROBERT DUNCAN

END
__________
[1] http://www.fiercebiotech.com/special-reports/duavee-pfizer-stuck-hot-flash-med-took-years-get-market

Links to All Parts of this Report

PART 1: Introduction (A billion dollars ― lots of zeros)
PART 2: Every Figure Tells a Story (Calculations and Result)
PART 3: Newest Member of the Premarin Family ― Duavee (Approved by FDA October 2013, originally submitted under the name Aprela)

Say no to Pfizer’s DUAVEE® and yes to safer alternatives

Rescued Premarin Foals. Image Vivian Grant Farrell.
Rescued Premarin Foals. Image Vivian Grant Farrell.

by JANE ALLIN

News of the FDA’s approval of Pfizer’s new combination drug – DUAVEE® – for the treatment of menopausal symptoms and prevention of osteoarthritis has traveled fast around the globe as have the myths surrounding it.

An online article originating in the UK is riddled with untruths and outright lies claiming that DUAVEE® is the panacea that all women have been waiting for – a drug that will “PREVENT” breast cancer. Nothing could be further from the truth.

What is appalling is that this clever marketing ploy may put thousands of credulous women at risk, even young women who need not expose themselves to the unknown risks of this novel and potentially lethal drug derived from Pregnant Mare’s Urine.

“A menopause treatment which could prevent breast cancer, rather than causing it, may soon be available for British women. Evidence shows the new hormone replacement therapy pill is even more effective at combating menopause symptoms, such as hot flushes, than the standard treatment. But crucially, early trials show it may prevent growth of breast cancer tumors. Existing forms of HRT, by contrast, are thought to cause the disease. Researchers say it could be given to millions of women worldwide who are too afraid to take menopause treatment due to the risk of breast cancer. And they also believe it could be given to younger women with a strong family history of the disease to prevent it occurring.”

Source: http://www.dailymail.co.uk/health/article-2466651/New-HRT-drug-help-PREVENT-breast-cancer.html

MYTHS AND FACTS

Myth: DUAVEE® prevents breast cancer.
Fact: DUAVEE® comes with the same boxed warning as well as other warnings and precautions that appear on the labels of previously approved estrogen products (i.e. Premarin®, Prempro®) including increased risk of breast, endometrial and ovarian cancer. The effect of DUAVEE® on the risk of breast, endometrial and ovarian cancers is “UNKNOWN”.
Source: http://www.pfizerpro.com/hcp/duavee/safety-info
Myth: DUAVEE® is more effective at combating menopausal symptoms than standard HRT
Fact: DUAVEE® is more effective than a placebo, yet conventional HRT (i.e. Premarin®, Prempro®) reduces the incidence of these symptoms to a much greater extent.
Source: http://seekingalpha.com/article/1670062-safety-concerns-may-prevent-fda-approval-of-ligands-drug-aprela
Myth: DUAVEE® can be given to millions of women world-wide as well as younger women with a strong history of breast cancer.
Fact: DUAVEE® is only intended for postmenopausal women with an intact uterus, should not be used in women with undiagnosed abnormal uterine bleeding; known, suspected, or past history of breast cancer or estrogen-dependent neoplasia; active or past history of venous or arterial thromboembolism; hypersensitivity to estrogens, bazedoxifene, or any ingredients; known hepatic impairment or disease; known thrombophilic disorders. Women who are or may become pregnant and nursing mothers should not use DUAVEE®.

Repeat — The effect of DUAVEE® on the risk of breast, endometrial and ovarian cancers is “UNKNOWN”.

Source: http://www.pfizerpro.com/hcp/duavee/safety-info
Myth: DUAVEE® is safe.
Fact: DUAVEE®’s safety profile is tenuous at best. Bazedoxifene, the osteo- component, (currently not approved by the FDA) is proven to increase the incidence of stroke, deep vein thrombosis, retinal thrombosis and hot flushes while conjugated equine estrogens (CEEs) extracted from pregnant mare’s urine increase the risk of many cancers and other life-threatening diseases. Boxed warnings clearly outline the seriousness and potentially life-changing side effects of DUAVEE®.
Source: http://www.drugs.com/duavee.html

BEWARE BIG PHARMA

There is a deep conflict of interest when pharmaceutical companies sponsor trials on their own drugs; recall that the clinical studies for DUAVEE® (formerly Aprela®) were funded by Pfizer.

What is most unsettling about the approval of DUAVEE® is that Pfizer is notoriously known for their participation in so-called “ghost management” of research and publication – corporate science so to say. See http://goo.gl/Waon4x.

Sadly “ghost writing” and failing to publish negative and unfavorable results from clinical trials is commonplace for unscrupulous Big Pharma and medical researchers. This precise conspiracy was used by Wyeth, now a division of Pfizer, where ghostwriters were hired to prepare over 40 medical journal articles promoting the benefits of its hormone-replacement drug Premarin® while downplaying the risks. See http://goo.gl/3K1bBn.

Did DUAVEE® gain FDA-approval using the same tactics? We will never know.

SAFER NON-HORMONAL PRESCRIPTION ALTERNATIVE NOW AVAILABLE

Brisdelle(TM) (Paroxetine) capsules Now Available by Prescription Nationwide. (PRNewsFoto/Noven Pharmaceuticals, Inc.)

Brisdelle™

While the FDA’s approval of DUAVEE® is indeed disappointing, one can only hope that due to the established serious risks of each individual component of this drug, physicians will be cautious in prescribing it.

Of particular interest is the recent FDA approval of the first non-hormonal therapy proven to treat severe vasomotor symptoms (VMS). Despite the fact that any drug carries with it some level of risk, Brisdelle™, manufactured by Noven Pharmaceuticals is, undoubtedly, a safer alternative to the unknown effects of DUAVEE® over the longer term.

Keep in mind that the boxed warnings for DUAVEE® are identical to those for Premarin® and Prempro® – all three of these drugs contain CEEs and when assimilated in the body form equine metabolites that have toxic properties with carcinogenic risk factors. See http://goo.gl/7lO5i9

Brisdelle™ is a low-dose (7.5 mg/day) version of paroxetine (paroxetine mesylate). This is in the same group of drugs such as Paxil (paroxetine hydrochloride) and Pexeva (paroxetine mesylate) – serotonin reuptake inhibitors (SSRIs) used to treat a number of psychiatric disorders but in higher doses than Brisdell™ (www.brisdelle.com). Noven also manufactures Pexeva™.

Two randomized, double-blind, placebo-controlled studies with a total population of 1,175 menopausal women experiencing moderate to severe hot flashes were used to evaluate the efficacy and safety of Brisdell™. See http://goo.gl/04xsPn.

Results from two Phase 3 clinical studies, published in Menopause, the peer-reviewed, scientific journal of The North American Menopause Society, show that Brisdell™ reduced both the frequency and severity of hot flashes compared to a placebo. See http://goo.gl/771fTH.

The mechanism by which hot flashes are reduced is complex and thought to differ from those involved in the treatment of psychiatric disorders.

Brisdell™ carries with it the same risks and side effects as higher-dosage SSRI anti-depressants but is well tolerated for the vast majority of people. See http://goo.gl/04xsPn.

Furthermore the adverse effects and withdrawal symptoms associated with higher paroxetine doses appear to be avoided with the lower 7.5 mg dose. See http://goo.gl/771fTH.

“The approval of Brisdelle™ is significant because it meaningfully expands the therapeutic options for the 24 million women in the U.S. affected by moderate to severe VMS, two-thirds of whom are not currently treating these often debilitating symptoms,” said Joel Lippman, M.D., FACOG, Noven’s Executive Vice President – Product Development and Chief Medical Officer. “Noven has long focused on developing and offering therapies to address women’s menopausal health concerns, and we are pleased to address the diverse needs of this population.”

See http://goo.gl/Q31hZI.

Some may ask – why recommend yet another prescription drug manufactured by a pharmaceutical company? First and foremost is that Brisdelle™ (paroxetine 7.5 mg) is free from pregnant mare’s urine together with the fact that cancer and other dire health risks are not side effects – killing two birds with one stone so to speak.

It has long been known that certain antidepressants are effective in reducing hot flashes in menopausal women. Selective serotonin reuptake inhibitors (SSRIs) affect the brain’s use of the neurotransmitter chemical serotonin which is thought to have a role in regulating body heat. Moreover, increased serotonin can also improve menopausal perimenopausal irritability, depression and moodiness. Paroxetine is one such drug belonging to the family of SSRIs.

When evaluating potential medications for treatment of a particular condition, prescription or otherwise, there is a need to consider the benefit-risk balance of any or all recommended drugs/therapies. In some cases the decision is a difficult one to make. One factor of relevance is how long a drug has been on the market and its long-term safety profile.

Paroxetine was first marketed in 1992 by the pharmaceutical company Smithkline Beecham, now GlaxoSmithKline and is sold under the trademark Paxil. Generic versions have been available since 2003 when the patent ran out. See http://goo.gl/4Oia1A. As with any drug there are side effects associated with Brisdelle™ (low dose paroxetine 7.5 mg) but none of them include the insidious cancers and other life-threatening risks associated with CEEs and SERMs.

Encouragingly several studies of higher dose (20 mg) paroxetine for the treatment of depression and depression-associated anxiety have shown that it is effective, well-tolerated and safe with nausea being the commonest adverse event reported. See http://goo.gl/j6AfcI.

What’s more, side effects tend to occur early during therapy and are usually temporary with no new adverse events emerging over the long term. See http://goo.gl/j6AfcI.

Despite the fact that Brisdelle™ is a new drug in the paroxetine family of SSRIs the history of paroxetine derivatives is well established. A full description of possible side effects of Brisdelle™ can be found here.

Keep in mind that the boxed warnings for DUAVEE® are identical to those for Premarin® and Prempro® – all three of these drugs contain CEEs and when assimilated in the body form equine metabolites that have toxic properties with carcinogenic risk factors.

As with any prescription drug there are warnings and precautions to be aware of, some of them serious; those listed for Brisdelle™ are taken from the safety profiles of other SSRIs at higher doses. For the most part, common side effects are mild and decrease in frequency with continued therapy (headaches, fatigue, malaise, lethargy, nausea, vomiting).

Although no drug is 100% safe, the bottom line is that apart from patients 24 and younger (possibility of a small increased of suicide risk during the first few months of medication (http://goo.gl/E92LP1) paroxetine has a favorable risk-benefit profile for the greater majority of people.

Given that Brisdelle™ will be prescribed to women suffering from the symptoms of perimenopause or menopause the risk of suicide in this cohort is significantly diminished. In fact some studies show that there is no increase in suicidality in older people while others conclude that a greater suicide risk is not associated with any type/class of antidepressants including SSRIs. See http://goo.gl/1MbGYZ; http://goo.gl/gpxklG.

In contrast DUAVEE® contains Premarin® – a known carcinogen, and bazedoxifene – a selective estrogen receptor modulator (SERM) not yet approved by the FDA due to increased risks of stroke and deep vein thrombosis. See http://goo.gl/84qdBw.

Nothing more to say there – two drugs, both with serious life-threatening risks associated with them. One drug a demonstrated killer the other not even approved by the FDA.

In no way is this intended to promote the use of prescription drugs for the treatment of menopausal symptoms. Not all drugs are suitable for everyone nor are they without some risk – this is simply a comparison of the perceived risk/benefit profiles of Brisdelle™ and DUAVEE®. While there are risks associated with both drugs, the boxed warnings are especially disconcerting for DUAVEE® given the track record of HRT medications containing conjugated equine estrogens (CCEs).

There is a long ugly history for these drugs – adulterated with deception, conspiratorial marketing campaigns, fraud and most importantly death – while the emotional and physical scars of the survivors and their families live on. Together with an unapproved drug known to increase the risk of stroke and deep vein blood clots – clots that may break loose into the bloodstream and migrate to the lungs causing pulmonary embolism and potentially death – the safety profile of DUAVEE® seems ill-omened.

In fact Premarin® itself is a precursor of deep vein thrombosis and pulmonary emboli. According to a recent joint University of Washington (UW) – Group Health study in JAMA Internal Medicine, women who were prescribed estradiol – a bio-equivalent estrogen – experienced fewer vascular events than did those prescribed Premarin®. See http://goo.gl/KXTaiD.

Furthermore, compared to estradiol users, Premarin® users had levels of blood clotting (coagulation) factors that made them more apt to form blood clots, demonstrating that conjugated equine estrogens contribute directly to these thrombotic events. See http://goo.gl/KXTaiD.

Seriously, is DUAVEE® worth the risk?

Menopause is a natural transition in every woman’s life, not an illness. Often the symptoms can be alleviated through safe, humane alternatives rather than relying on drugs derived from conjugated equine estrogens extracted from pregnant mare’s urine.

Brisdelle™ is the first approved prescription non-hormonal drug shown to be effective in the treatment of menopausal symptoms but there are other options that may be equally effective. Please refer to our compilation of alternative treatments on the International Horse Fund website at http://www.horsefund.org/pmu-alternatives-to-cee-drugs.php.

LEST WE FORGET THE HORSES

When God created the horse, he said to the magnificent creature:
I have made thee as no other.
All the treasures of the earth shall lie between thy eyes.
Thou shalt cast thy enemies between thy hooves,
but thou shalt carry my friends upon they back.
Thy saddle shall be the seat of prayers to me.
And thou fly without any wings, and conquer without any sword.
~ The Koran

END.

© Int’l Fund for Horses

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FDA rejects possible Premarin replacement drugs

By Jane Allin, Typewriter Keys

Belgian Quarter Horse crosses are the most used for the collection of pregnant mare's urine for the production of drugs like Premarin and Prempro.
Belgian / Quarter Horse crosses are the most used horses for the collection of estrogen rich pregnant mare’s urine used in the production of HRT drugs Premarin and Prempro. Untold hundreds of thousands of mares have suffered and their foals killed.

With concerns about risks associated with conventional hormone replacement therapy (HRT) manufactured from the urine of pregnant mares (i.e. Premarin®, Prempro®) Depomed Inc., a specialty pharmaceutical company headquartered in Newark, California, submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) on July 31, 2012 for Serada™ – an extended time release formulation designed to provide women with prolonged relief of menopausal “hot flashes” with potential for reduced side effects.

Approximately one month later on August 29, 2012, Noven Pharmaceuticals announced that it had submitted a NDA for low-dose mesylate salt of paroxetine (LDMP) to the FDA also seeking approval for the treatment of vasomotor symptoms associated with menopause.[1] LDMP is an investigational oral non-hormonal therapy specifically developed for the treatment of vasomotor symptoms due to menopause.

Hormone replacement therapy manufactured from pregnant mare’s urine is currently the only FDA-approved single-agent therapy for the treatment of menopausal hot flashes

The FDA formally accepted the application for Serada™ on October 15, 2012 and established a Prescription Drug User Fee Act (PDUFA) action date of May 31, 2013.[2] Similarly, the application for LDMP was also accepted with an assigned PDUFA action date of June 28, 2013.[3] These dates represent the goal date for the completion of the FDA NDA review.

Hormone replacement therapy manufactured from pregnant mare’s urine is currently the only FDA-approved single-agent therapy for the treatment of menopausal hot flashes.[4] In the United States alone there is an estimated 32 million women who experience menopausal hot flashes, of whom 13 million seek medical treatment.[5]

Moreover, vasomotor symptoms – hot flashes and night sweats – are the most common medical complaint of perimenopausal and postmenopausal women affecting upwards of 80% of women experiencing menopause.[6] In fact, there is evidence that sleep disturbances due to moderate to severe hot flashes is the leading driver of women seeking prescription HRT products.[7]

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