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FDA approves Viagra

FDA approves Viagra


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On March 27, 1998, the Food and Drug Administration (FDA) approves use of the drug Viagra, an oral medication that treats impotence.

Sildenafil, the chemical name for Viagra, is an artificial compound that was originally synthesized and studied to treat hypertension (high blood pressure) and angina pectoris (a form of cardiovascular disease). Chemists at the Pfizer pharmaceutical company found, however, that while the drug had little effect on angina, it could induce penile erections, typically within 30 to 60 minutes. Seeing the economic opportunity in such a biochemical effect, Pfizer decided to market the drug for impotence. Sildenafil was patented in 1996, and a mere two years later–a stunningly short time compared to other drugs–it was approved by the FDA for use in treating “erectile dysfunction,” the new clinical name for impotence. Though unconfirmed, it is believed the drug was invented by Peter Dunn and Albert Wood.

Viagra’s massive success was practically instantaneous. In the first year alone, the $8-$10 pills yielded about a billion dollars in sales. Viagra’s impact on the pharmaceutical and medical industries, as well as on the public consciousness, was also enormous. Though available by prescription only, Viagra was marketed on television, famously touted by ex-presidential candidate Bob Dole, then in his mid-70s. Such direct-to-consumer marketing was practically unprecedented for prescription drugs (now, sales and marketing account for approximately 30 percent of the pharmaceutical industry’s costs, in some cases more than research and development).

An estimated 30 million men in the United States suffer from erectile dysfunction and a wave of new Viagra competitors, among them Cialis (tadalafil) and Levitra (vardenafil), has blown open the market. Drug companies are now not just targeting older men like Dole, but men in their 30s and 40s, too. As with many drugs, the long-term effects of Viagra on men’s health are still unclear (Viagra does carry warnings for those who suffer from heart trouble), but its popularity shows no signs of slowing.


On This Day: FDA approves Viagra

March 27 (UPI) -- On this date in history:

In 1886, Apache leader Geronimo surrendered to U.S. federal authorities.

In 1933, the U.S. Embassy in Berlin reported that physical mistreatment of Jews in Germany has been "virtually terminated."

In 1958, Nikita Khrushchev replaced Nikolai Bulganin as premier of the Soviet Union.

In 1964, the strongest earthquake to hit North America -- magnitude-9.2 -- struck Alaska, killing 139 people.

In 1976, the first section of Washington, D.C.'s Metro subway system opened with more than 4.6 miles of track on the Red Line running from Farragut North to Rhode Island Avenue in the District of Columbia.

In 1977, two Boeing 747 jumbo jets collided and exploded in flames on a foggy runway at Tenerife, the largest of the Canary Islands, killing 583 people in the worst aviation accident in history.

In 1980, a Norwegian oil platform capsized during a storm in the North Sea, killing 123 people.

In 1996, an Israeli court convicted Yigal Amir and sentenced him to life in prison for assassinating Prime Minister Yitzhak Rabin on Nov. 4, 1995.

In 1998, the U.S. Food and Drug Administration approved Viagra for use as a treatment for male impotence.

In 2004, NASA's unmanned experimental hypersonic plane reached about 5,000 mph in a test flight -- more than seven times the speed of sound.

In 2005, ailing Pope John Paul II appeared at his apartment window before an Easter crowd in St. Peter's Square but was unable to speak. He silently blessed thousands of cheering people, many who wept. The pope died six days later, on April 2. He was 84.

In 2007, leaders of Myanmar staged a military parade to show off the new capital city, Naypyidaw.

In 2013, Julia Pierson became the first woman to head the U.S. Secret Service. Pierson resigned in October 2014.

In 2014, U.S. President Obama Barack Obama visited Pope Francis at the Vatican. It was their first meeting.

In 2016, the Pakistani Taliban killed at least 70 people in a suicide attack at a public park in the eastern city of Lahore.


"FDA's public hearings are being stacked by pharmaceutical companies who are flying in patients"

Adriane Fugh-Berman, a professor at Georgetown University who studies pharmaceutical marketing, agrees that this is a concern: "The open public hearing is now being stacked by pharmaceutical companies who are flying in patients. It's not just Sprout." She adds that these patient testimonies can often be incredibly persuasive and move advisory committees.

Technically, the FDA asks that members of the public reveal potential conflicts of interest before speaking. But they aren’t required to do so, and the FDA has no ability to enforce transparency. "What goes on between the company and their public that they work with is out of our control," says the FDA's Richard Klein. "Unless Congress were to change laws, I don't see us having any jurisdiction."

On the flip side, Klein added, "You don't want to restrict that speech, either." After all, it doesn't seem right to bar people who suffer from rare diseases or unmet medical conditions from speaking at these events.

So that's one dilemma: How can the FDA incorporate outside views without falling prey to conflicts of interest? Klein, for his part, suggested the FDA's advisory committees are capable of sorting this out by itself. "If the evidence is really against the product in terms of benefit and that risk balance, then the decision probably couldn't be swayed so easily at any meeting by a concerted effort," he said.

That's not entirely comforting, however. What about when the risk-benefit calculus is a little unclear and there are no alternatives on the market, as with flibanserin? Or when, as this case shows, public meetings are overwhelmed by industry allies, drowning out independent voices?

This question also extends beyond public advisory meetings. Experts think drug companies exert influence in all sorts of subtle ways — often in favor of lower standards and faster approvals. Dan Carpenter, a professor of government at Harvard who wrote a history of the FDA, recalls going to a public meeting this summer about reauthorizing the Prescription Drug User Fee Act (PDUFA), the law that allows the agency to collect fees on pharmaceutical companies in order to fund the drug approval process.

This meeting was supposed to include academics, industry representatives, and patient and consumer groups — a mélange of diverse perspectives. But Carpenter noticed that the room was rife with conflicts of interest. One consumer group was funded by pharma. Another academic had worked as an industry consultant.

"The meeting was very tilted toward industry-backed views," Carpenter said. "Overwhelmingly the discussion was focused on how we can make drug approval even easier, how to get drugs even more quickly to patients with less testing, and an atmosphere in the room that suggested the consensus should be that the wheels of drug approvals should be greased as much as possible."

The FDA now approves almost every drug

Nowadays, the FDA is considered the fastest drug approval agency in the world. It takes between six and 10 months to approve drugs — down from about three years, on average, in 1975. So far this year, the agency has approved 96 percent of the new drugs it considered. Nearly everything gets through.

The hard question is whether this is happening because the FDA is especially efficient — or because the agency has been captured by industry and is approving dubious drugs more rapidly.

There's actually a good case that the FDA has become efficient for largely positive reasons. Peter Barton Hutt, a DC-based lawyer who specializes in pharmaceutical regulatory affairs, explained that the agency went from being a "black box" in the 1960s, leaving drug companies guessing about what requirements they needed to meet for approval, to being "one of the most transparent regulatory agencies that has ever existed."

Today it's easy for companies to find out what the FDA requires for approval — what sorts of studies, what sorts of data analyses — which in turn makes the whole process smoother. Pre-approval meetings with the agency are also now common. Drug companies are "no longer groping in the dark," Hutt says.

Other reforms have also sped up the process: Open advisory committee meetings are helpful for drug companies, Hutt said, because industry representatives can easily find out how other similar drugs have fared.

Add it up, and there may be a perfectly benign reason why the approval rate is so high: Companies no longer submit applications for drugs that are likely to get rejected. As Harvard researcher Aaron Kesselheim put it: "It’s actually a minority of drugs that make it all the way to the point of FDA submission and then end up never making it to the market — in part because many drug companies would not spend the resources on doing the pivotal trials and organizing the FDA submission unless they had a strong impression that their drug would be approved."

But that's not the end of the story, either. There are a few other reasons the FDA's drug approval process has sped and opened up — and these are the things critics worry about because they raise the specter of conflicts of interest.

In 1992, Congress originally enacted the Prescription Drug User Fee Act (PDUFA), which allows drug companies to pay user fees to the agency in exchange for speedier reviews of their products. Before the law passed, taxpayer money funded the FDA's programs related to human drug development. Nowadays, about two-thirds of that budget comes from drug companies.

"[This law] dramatically changed the dynamic from regulated industry and FDA," says Michael Carome, the director of Public Citizen's Health Research Group. "The agency became a client of industry. And too often we think the agency is approving products where the standards for demonstrating that a drug is safe and effective — do the benefits outweigh risks — frequently in our view aren’t being met."

There may be something to those concerns: The average review time for a drug dropped from three years down to one year after the law came into effect, according to a study in Health Affairs. But that research also found that the FDA seemed to be approving riskier drugs following PDUFA. With the passage of the act, there was a 25 percent increase in medicines that needed to be pulled from the market out of safety concerns or that received a new black box warning (which signal that the drug carries very serious side effects).

Other drugs with marginal benefits and potentially dangerous side effects have recently made it through the FDA: Belsomra for insomnia, Contrave for weight loss. A 2010 study in the European Journal of Clinical Pharmacology looked at 122 new drugs approved between 1999 and 2005. Only 10 percent performed better than drugs that were already available. Similarly, a number of studies that have found that since the mid-1990s, about 85 to 90 percent of new drugs don't offer any clinical advantages for patients.

Harvard's Kesselheim is quick to caution that it's hard to tease out causation here, and there's a real debate among academics as to the pros and cons of PDUFA. "I think most rational people recognize that having industry fund the FDA is suboptimal for many reasons," he says. "But having an FDA that isn’t starved for funds as it was in the 1980s is also vitally important."

When I asked an FDA spokesperson about the potential for conflict of interest, she said reviewing thousands of applications for new drugs is extremely labor-intensive work. "It takes steady and reliable funding to maintain and support a staff of trained reviewers capable of accomplishing this vital task," she wrote in an email. "We’re gratified that Congress agrees and has continued to reauthorize the program over the years."

But there have been another unexpected side effect of PDUFA. It gets Congress more involved in shaping the FDA's approval process, which opens another door for pharma lobbying. After all, the law's user fees have to be renewed every five years. And, Carome said, lawmakers frequently tack on provisions to reauthorization bills that are only loosely related to the fees — but are often favorable to the drug industry, like pathways for speedier approval of "breakthrough" or innovative drugs for serious conditions.

Another example: In 2007, as part of PDUFA reauthorization, Congress enacted the Risk Evaluation and Mitigation Strategies (REMS) program. This program allows the FDA to approve drugs that might prove risky for some populations, albeit with controls on how the drug is used. So, for instance, flibanserin will be available through specially certified health-care professionals and pharmacies that have gone through some training. Doctors will need to assess the ability of patients to stay away from drinking while on flibanserin, and women who take it will have to acknowledge they understand the risks.

"I think that has made the FDA a lot more comfortable approving drugs," says Matthew Herper, a Forbes researcher who compiled data on the FDA's faster approval process.

These changes aren't necessarily a win for patients. In 2012, researchers in JAMA looked at the various new pathways for expedited approvals of innovative drugs and worried that some of the medicines offered a small benefit "with substantial risks not yet fully understood." They warned doctors that the "FDA's emphasis on rapid drug approval" underscored the need to be ultra-conservative in their prescribing practices.

"In an ideal world," said physician and author Ben Goldacre, "it wouldn't matter that the FDA had a low bar, because doctors and organizations like NICE [which review evidence and advise governments on which drugs to purchase] would demand high-quality evidence of effectiveness on real-world outcomes before prescribing drugs to patients. Unfortunately, the reality is that this vital filter is patchy."

The FDA may soon be approving more drugs — and faster

Congress is now considering yet more legislation to speed up the FDA approval process even further — and lower the standards for data that the regulator uses to make clinical decisions.

In July, the House passed the 21st Century Cures Act by an overwhelming 344-77 vote. The pharma-backed bipartisan effort actually has a chance of passing through the Senate and getting signed into law.

Critics have pointed out that hidden in the bill's 352 pages is language that could erode the quality of evidence the FDA uses to evaluate new drugs and devices, making it easier for companies to bring substandard or dangerous medicines and medical devices to patients. Rather than fixing certain regulatory problems researchers have flagged, this bill could open the floodgates.

The underlying premise of the 21st Century Cures Act is that the FDA is slowing down the passage of lifesaving cures to people who need them. Again, patients are advocating for the bill's passage. Yet, as a number of observers have pointed out, the problem isn't the FDA. It's that drug companies themselves aren't developing innovative drugs. The problem, in other words, is the pipeline.

"There's no evidence the FDA blocks innovation or makes innovation harder or makes it more costly," said Kesselheim. "The goal in drug development isn't merely innovation, it is innovation that works to help patients. When drugs are shown to be effective and safe, the FDA is the fastest regulatory agency in terms of approvals of new drugs in the world."

Drug companies are also pressuring the FDA to become more lenient on another aspect of regulation: marketing. In the US, companies can only advertise their drugs for FDA-approved indications, not so-called "off label" uses (as when doctors prescribe, say, birth control for acne). But recently, two pharmaceutical companies have turned this into a First Amendment issue, suing the FDA for violating their right to free speech. If others follow, this will hamper the FDA's power to crack down on misleading marketing practices and encourage companies to make all kinds of claims about their products, not necessarily evidence based.

Yale's Gonsalves argued that we already have a far weaker FDA today. "We've tipped the balance far away from rigor now, and patients will pay the price, because they will now become more and more unsure of what the drugs they put in their bodies are actually doing in the most essential sense: Do they extend health and life?"

Gonsalves learned about the dangers of lobbying the FDA early on, during his years as an HIV activist.

"At the start, we were under some illusions about the FDA and drug development, and thought that the agency had lots of drugs in the queue for approval for study or marketing and they were depriving us of life-saving medicines," he said. "We wanted access as soon as we saw some promising data."

A year or two later, activists realized they were wrong. "We had pushed the FDA to approve based on the slimmest of data and at great speed, and really didn’t know much about how or if these drugs were doing any good at all."

Correction: A previous version of this article said the flibanserin alcohol interaction study was submitted to the FDA after the agency's last rejection in 2013. (It was submitted before.)


FDA approves Vyleesi, a new ‘Female Viagra.' What issues can it actually solve?

Pop culturally, female sexual desire is treated as the holy grail: oft-sought, oft-imitated, oft-worshipped and oft-misunderstood. But outside of Hollywood writers’ rooms, the holy grail does not always worship back.

On Friday, the Food and Drug Administration approved a new drug to treat a lack of female sexual desire. Bremelanotide, brand name Vyleesi and colloquially known as “Female Viagra,” comes fittingly boxed in pink. Previously, the only FDA-approved drug in the lady-libido market was flibanserin (brand name Addyi), designed to treat hypoactive sexual desire disorder (HSDD) in premenopausal women. Addyi’s downsides were numerous the drug was designed to be taken daily and interacted negatively with alcohol.

Vyleesi has emerged as a white horse in comparison: the drug has not been found to interact with alcohol and is injected 45 minutes prior to sexual activity by using an auto-injector pen in the abdomen or thigh.

Though the drug is linked to Viagra in its end goal, and though both drugs are taken on an as-needed basis (Vyleesi should not be used more than once every 24 hours and more than eight times per month), the similarities stop there. Viagra treats erectile dysfunction, a specific physical mechanism, while Vyleesi treats sexual desire, a complex coalescence of social, emotional and physical factors. According to Dr. Lauren Streicher, director of Northwestern Medicine’s Center for Sexual Medicine and Menopause, the drug “turns (the) off switch to on.” Bremelanotide is a melanocortin, a peptide in the brain that increases dopamine and inhibits the release of serotonin.

“The brain is such an important part of female sexuality,” said Amanda Atkins, a licensed Chicago therapist who works with women on sexual issues. “Female Viagra stimulates arousal in neurotransmitters in the brain, and it doesn’t control blood flow to the vagina in the way that Viagra does.”

Streicher emphasized that in her view, the drug is a net good there are no severe side effects other than potential nausea, and individuals with high blood pressure are warned away. This is not to say, however, that the drug would be step one on a patient’s treatment plan. Libido, according to Streicher, is “multifactorial.” Beyond the physiological, underlying causes of a lack of libido might include a history of trauma, medication, depression or stress and treatments for HSDD only apply to women who actively want to address their lack of sexual desire. Vyleesi is not a perfect solution — according to Streicher, it won’t work for all women. But luckily, neither is it a coercive one.

“It’s not going to make someone hypersexual,” Streicher said. “It’s not going to make them say, ‘Wow, the mailman, he never looked good to me before and now I want to jump him.’ It’s not going to make you want to have sex with someone that you otherwise wouldn’t be receptive to.”

Still, Dr. Sheena Hoffmann, a Chicago clinical psychologist, worried that the drug might interfere with the processes she ordinarily uses to examine and treat a lack of female sexual desire. During her training, Hoffman said, she learned a model of integrating emotional, nonsexual and sexual touch into struggling relationships.

The three prongs serve as steps that build upon each other, meaning that a woman should be heard emotionally before moving to physical touch, then should feel safe before moving to sexual touch. Too often, Hoffmann said, women are trained to see any physical contact from their partners as an initiation for sexual contact, which, she said, “cuts intimacy off at its knees.”

“My concern is if there’s something out there that exists that can help women override how they’re feeling in terms of their emotional connection to their partner, that doesn’t seem like a good idea to me,” Hoffmann said. Her caveats would be postmenopausal women or women struggling with libido after a significant medical change — for example, cancer. But treating the drug as a “Female Viagra,” she said, “makes (me) sick to (my) stomach” in its ignorance of female sexuality and its “responsive” nature, an idea introduced by Emily Nagoski’s 2015 book, “Come As You Are."

Taking a middle ground, Atkins likened the drug to treatments for depression. While some patients can function with a combination of therapy and lifestyle changes, others need medication. This discovery would, however, typically come after working with a therapist to address the root causes of the problem.

Streicher agreed with this approach. When patients come to the Center for Sexual Medicine, they fill out a questionnaire that helps physicians decide how to address the problem at hand, and the center retains sex therapists as part of its typical treatment. A woman who enjoys sex when she has it but never desires it, and is in an otherwise loving relationship, might be a good candidate for Vyleesi.

But this drug, Streicher said, is not a means to an end — forget the holy grail. If female sexual desire is highly intricate, its treatment must be, too. According to Atkins, desire doesn’t exist in a vacuum, and the answer doesn’t lie in any one pink box.

“We have to think about what are women bringing into relationships in terms of sexual expectations, body image,” Atkins said. “A pill just cannot fix all of it. But in the right situation, it definitely can help.”


FDA History

The Food and Drug Administration is the oldest comprehensive consumer protection agency in the U. S. federal government. Since 1848 the federal government has used chemical analysis to monitor the safety of agricultural products -- a responsibility inherited by the Department of Agriculture in 1862 and later by the FDA.

Although it was not known by its present name until 1930, FDA’s modern regulatory functions began with the passage of the 1906 Pure Food and Drugs Act, a law a quarter-century in the making that prohibited interstate commerce in adulterated and misbranded food and drugs. Harvey Washington Wiley, Chief Chemist of the USDA Bureau of Chemistry, had been the driving force behind this law and headed its enforcement in the early years, providing basic elements of protection that consumers had never known before that time.

Since then, the FDA has changed along with social, economic, political and legal changes in the United States. Examining the history of these changes illuminates the evolving role that FDA has played in promoting public health and offers lessons to consider as we evaluate current regulatory challenges.


Which Medications Cause ED?

Many medications have impotence or sexual dysfunction listed as a side effect. Have your healthcare provider review your medications for this side effect to determine if any prescription or OTC drug treatment may be contributing to symptoms.

Medications that may lead to erectile dysfunction include:

If you regularly experience sexual function or ED problems, contact your doctor for evaluation and treatment.


A new ‘female Viagra’ approved by FDA despite skepticism

The Food and Drug Administration on Friday approved sales of a new drug intended to enhance sexual desire in women.

Marketed as Vyleesi, also known as bremelanotide, the medication is a shot that comes in a push pen device that can be self-administered as needed for premenopausal women who experience distress as a result of low sexual desire.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton Joffe, director of the FDA Center for Drug Evaluation and Research’s Division of Bone, Reproductive and Urologic Products, said in a statement. “Today’s approval provides women with another treatment option for this condition. As part of the FDA’s commitment to protect and advance the health of women, we’ll continue to support the development of safe and effective treatments for female sexual dysfunction.”

Julie Krop, chief medical officer for AMAG Pharmaceuticals Inc., which makes the drug, recommends using it about 45 minutes before the “anticipation” of intimacy. She said the drug activates key brain receptors involved in sexual responses by reducing inhibition and increasing what’s known as neural excitation.

“It’s not just about low sexual desire, but about how it impacts patients’ relationships and quality of life,” Krop said in an interview. “These women are really suffering.”

The drug is intended to be a treatment for hypoactive sexual desire disorder, or HSDD, which the medical community recognizes can be a serious issue. The FDA acknowledged that it’s not clear how Vyleesi acts in the brain to affect sexual desire or distress. It advises women to use no more than one dose in 24 hours or eight a month.

And there’s disagreement about whether drugs are the right approach — low sexual desire can be a result of numerous psychological, physiological or external factors, including stress — and how widespread the condition really is.

One study estimated that as many as 1 out of 10 women may have low sexual desire, and the FDA several years ago convened a meeting to better understand the impact of female sexual dysfunction.

Critics have pointed out that nearly all of the doctors on the recent panel that defined HSDD were consultants or advisory board members for Sprout Pharmaceuticals, the drugmaker that introduced the world to the first women’s libido drug, Addyi, also known as flibanserin, in 2015.

On Vyleesi, several women’s health advocates said more information was needed before approval. They noted that the FDA had not convened an advisory panel to scrutinize the drug.

“It is unfortunate that the FDA decided to approve this drug despite the skimpy peer-reviewed data and complete lack of long-use safety information,” said Diana Zuckerman, president of the National Center for Health Research. “The good news is that it doesn’t need to be taken every day, the way Addyi does. The bad news is that the public can’t have confidence in the safety of the drug because we don’t have access to long-term safety information about it.”

Cynthia Pearson, executive director of the National Women’s Health Network, said the group was “disappointed” by the approval and said that women “simply do not have enough information to make an informed decision about whether the drug is safe and effective.”

Earlier this year, Sprout caused a stir with a campaign that told women they have a “right to desire.” “Why aren’t we talking about it?” the ads asked. Women’s groups that focus on access to birth control and abortion took issue with the idea of invoking civil rights language for what they essentially called a sales pitch.

AMAG, which is based in Waltham, Mass., has done its own disease awareness outreach about HSDD this year through its Instagram and Facebook “unblush” campaign, which told women that “HSDD is nothing to blush about.”

Addyi never really took off, partly because it is a daily pill that takes a while to work, and the product carries a “black box” label that warned of serious side effects such as dizziness and low blood pressure when the drug was taken with alcohol. The FDA softened the warning in April to advise women that while complications may still exist with alcohol, they needn’t avoid it entirely. In May, Sprout released the results of three safety studies that appeared to bolster the idea that the link to side effects was not as clear as previously thought.


A new ‘female Viagra’ approved by FDA despite skepticism

The Food and Drug Administration on Friday approved sales of a new drug intended to enhance sexual desire in women.

Marketed as Vyleesi, also known as bremelanotide, the medication is a shot that comes in a push pen device that can be self-administered as needed for premenopausal women who experience distress as a result of low sexual desire.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton Joffe, director of the FDA Center for Drug Evaluation and Research’s Division of Bone, Reproductive and Urologic Products, said in a statement. “Today’s approval provides women with another treatment option for this condition. As part of the FDA’s commitment to protect and advance the health of women, we’ll continue to support the development of safe and effective treatments for female sexual dysfunction.”

Julie Krop, chief medical officer for AMAG Pharmaceuticals Inc., which makes the drug, recommends using it about 45 minutes before the “anticipation” of intimacy. She said the drug activates key brain receptors involved in sexual responses by reducing inhibition and increasing what’s known as neural excitation.

“It’s not just about low sexual desire, but about how it impacts patients’ relationships and quality of life,” Krop said in an interview. “These women are really suffering.”

The drug is intended to be a treatment for hypoactive sexual desire disorder, or HSDD, which the medical community recognizes can be a serious issue. The FDA acknowledged that it’s not clear how Vyleesi acts in the brain to affect sexual desire or distress. It advises women to use no more than one dose in 24 hours or eight a month.

And there’s disagreement about whether drugs are the right approach — low sexual desire can be a result of numerous psychological, physiological or external factors, including stress — and how widespread the condition really is.

One study estimated that as many as 1 out of 10 women may have low sexual desire, and the FDA several years ago convened a meeting to better understand the impact of female sexual dysfunction.

Critics have pointed out that nearly all of the doctors on the recent panel that defined HSDD were consultants or advisory board members for Sprout Pharmaceuticals, the drugmaker that introduced the world to the first women’s libido drug, Addyi, also known as flibanserin, in 2015.

On Vyleesi, several women’s health advocates said more information was needed before approval. They noted that the FDA had not convened an advisory panel to scrutinize the drug.

“It is unfortunate that the FDA decided to approve this drug despite the skimpy peer-reviewed data and complete lack of long-use safety information,” said Diana Zuckerman, president of the National Center for Health Research. “The good news is that it doesn’t need to be taken every day, the way Addyi does. The bad news is that the public can’t have confidence in the safety of the drug because we don’t have access to long-term safety information about it.”

Cynthia Pearson, executive director of the National Women’s Health Network, said the group was “disappointed” by the approval and said that women “simply do not have enough information to make an informed decision about whether the drug is safe and effective.”

Earlier this year, Sprout caused a stir with a campaign that told women they have a “right to desire.” “Why aren’t we talking about it?” the ads asked. Women’s groups that focus on access to birth control and abortion took issue with the idea of invoking civil rights language for what they essentially called a sales pitch.

AMAG, which is based in Waltham, Mass., has done its own disease awareness outreach about HSDD this year through its Instagram and Facebook “unblush” campaign, which told women that “HSDD is nothing to blush about.”

Addyi never really took off, partly because it is a daily pill that takes a while to work, and the product carries a “black box” label that warned of serious side effects such as dizziness and low blood pressure when the drug was taken with alcohol. The FDA softened the warning in April to advise women that while complications may still exist with alcohol, they needn’t avoid it entirely. In May, Sprout released the results of three safety studies that appeared to bolster the idea that the link to side effects was not as clear as previously thought.


Contents

Erectile dysfunction Edit

Tadalafil once-daily is FDA-approved for ED, for sale in 2.5, 5, 10, and 20 mg strengths. The price of the 5 mg and 2.5 mg are often similar, so some people score and split the pill. [9]

Benign prostatic hypertrophy Edit

A meta‐analysis found that tadalafil 5 mg once‐daily is an effective treatment for lower urinary tract symptoms due to prostatic hyperplasia and that such treatment had a low rate of adverse effects. [10] Tadalafil 10 mg is FDA-approved for men as a once-daily therapy to treat and prevent symptoms of benign prostatic hypertrophy (BPH), such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence. [ medical citation needed ]

Pulmonary arterial hypertension Edit

Tadalafil 40 mg is approved in the United States, Canada, and Japan as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension (PAH).

The pulmonary vascular lumen is decreased in PAH as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil causes pulmonary artery vasodilation, and inhibits vascular remodeling, thus lowering pulmonary arterial pressure and resistance. Right heart failure is the principal consequence of severe pulmonary arterial hypertension.

The most common potential side effects when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, acid reflux, back pain, muscle aches, flushing, and stuffy and runny nose. These side effects reflect the ability of PDE5 inhibition to cause vasodilation (cause blood vessels to widen), and usually resolve after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and these symptoms usually resolve within 48 hours of onset.

Vision Edit

In May 2005, the US Food and Drug Administration (FDA) found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy). Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, unrelated to PDE5 use. The FDA concluded that they were not able to draw a cause and effect relationship, only an association the label of all three PDE5 inhibitors was changed to alert clinicians to that fact. A 2019 meta-analysis found that tadalafil exposure was not associated with NAION. [11]

Hearing Edit

In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including tadalafil, requires a more prominent warning of the potential risk of sudden hearing loss as the result of postmarketing reports of temporary deafness associated with use of PDE5 inhibitors. [12]

Tadalafil is metabolized predominantly by the hepatic CYP3A4 enzyme system. The presence of other drugs which induce this system can shorten tadalafil half-life and reduce serum levels, and hence efficacy, of the drug.

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the corpus cavernosum. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic guanosine monophosphate (more commonly known as cyclic GMP or cGMP) in smooth muscle cells. cGMP relaxes smooth muscle and increases blood flow to the corpus cavernosum.

The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5. However, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil's inhibition of PDE5 will have no effect without sexual stimulation. [13]

Duration of action Edit

Although sildenafil, vardenafil, and tadalafil all work by inhibiting PDE5, tadalafil's pharmacologic distinction is its longer half-life (17.5 hours), [14] compared to sildenafil and vardenafil, which are both 4–5 hours. [15] This translates to a longer duration of action, which is partly responsible for "The Weekend Pill" nickname. Furthermore, the longer half-life is the basis for tadalafil's daily therapeutic use in treating pulmonary arterial hypertension.

Comparison with actions of other PDE5 inhibitors Edit

Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil. [16] Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition. [17]

Sildenafil and vardenafil also inhibit PDE1 more than tadalafil. [16] PDE1 is found in the brain, heart, and vascular smooth muscle. [16] It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation, flushing, and tachycardia. [16]

Tadalafil inhibits PDE11 more than sildenafil or vardenafil. [16] PDE11 is expressed in skeletal muscle, the prostate, the liver, the kidney, the pituitary gland, and the testes. [16] The effects on the body of inhibiting PDE11 are not known. [16]

Tadalafil can be synthesized starting from (D)-tryptophan methyl ester and piperonal via a Pictet–Spengler reaction. This is followed by condensations with chloroacetyl chloride and methylamine to complete the diketopiperazine ring: [19]

The FDA's approval of sildenafil in 1998 [20] was a ground-breaking commercial event for the treatment of ED, with sales exceeding US$1 billion. Subsequently, the FDA approved vardenafil in 2003, [21] and tadalafil in 2003.

It initially was developed by the biotechnology company ICOS, and then again developed and marketed worldwide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Tadalafil was approved in 2009 in the United States for the treatment of pulmonary arterial hypertension [22] and is under regulatory review in other regions for this condition. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for pulmonary arterial hypertension in the United States to United Therapeutics for an upfront payment of $150 million.

Tadalafil was discovered by Glaxo Wellcome (now GlaxoSmithKline) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. [23] [24] In 1993, the Bothell, Washington biotechnology company ICOS Corporation began studying compound IC351, a phosphodiesterase type 5 (PDE5) enzyme inhibitor. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company's core markets. [17] In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a new drug application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the American Urological Association that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour half-life (thus Cialis is advertised to work for up to 36 hours, [25] after which time there remains approximately 25% of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra).

In 2007, Eli Lilly and Company bought the ICOS Corporation for $2.3 billion. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S (CMC).

Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname. [26]

On October 6, 2011, the US FDA approved tadalafil [27] to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in males in which the prostate gland becomes enlarged, obstructing the free flow of urine. Symptoms may include sudden urges to urinate (urgency), difficulty in starting urination (hesitancy), a weak urine stream, and more frequent urination — especially at night. The FDA has also approved tadalafil for treatment of both BPH and erectile dysfunction (ED) where the two conditions co-exist.

Marketing Edit

In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers. [28] Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the Grey Global Group, to run the Cialis advertising campaign. [29] Marketers for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug Stuart Elliot of The New York Times opined: "The continuous presence of women in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with their men, in contrast to the primarily male-driven imagery for Levitra and Viagra." [29] Iconic themes in Cialis ads include couples side by side in matching bathtubs and the slogan "When the moment is right, will you be ready?" [29] Cialis ads were unique among the ED drugs in mentioning specifics of the drug. [30] As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 Super Bowl. [30] Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including priapism. [30] Although many parents objected to the Cialis ad being aired during the Super Bowl, Janet Jackson's halftime "wardrobe malfunction" overshadowed Cialis. [30] In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads. [28] In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively. [30] Cialis has sponsored many sporting events, including the America's Cup and the PGA Tour, once being title sponsor of the PGA Tour Western Open tournament. [31]

Economics Edit

In Australia, tadalafil is subsidised through the Repatriation Pharmaceutical Benefits Scheme (RPBS) for patients with a specific accepted war-caused or service-related disability. [32]

In the US, while some health insurance providers cover at least part of the cost (typically limiting the number of doses covered per month), many providers, including those operating under Medicare Part D, do not cover the cost of medications prescribed for erectile dysfunction. [33] [34]

In the UK, a generic version of tadalafil became available in November 2017, reducing its price per pill, and is available on the NHS. [ citation needed ] Additionally, Tadacip, manufactured in India by Cipla, is considerably less expensive. [ citation needed ]


See Also

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Drug Status

Availability Prescription only Rx

Pregnancy & Lactation Risk data available

CSA Schedule* Not a controlled drug N/A

Approval History Drug history at FDA

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Prevnar 20 (pneumococcal 20-valent conjugate vaccine) is a vaccine indicated.

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