The Travels of a Prescription Drug

Prescription drugs can take a winding path to market. It takes much investigation and pre-clinical work before the first molecule enters a human subject’s body. After that there are still years of clinical trials ahead before a new drug makes it to market. Many candidates fail at some stage along the way.

Drugmakers invest huge amounts of money to get that new wonder drug into patients’ hands. Our patent system gives the maker 17 years to sell as much of the drug as they can for as much money as they can before other makers are allowed to produce their own generic version. The generics have to undergo their own testing and approval before coming on the market, but initial costs are much lower and the price of a brand-name drug tends to come down significantly once generics are available.

Unfortunately for the makers of the original drug, the patent clock starts as soon as they’ve identified their molecule, and keeps running while the trials are underway. This means that the competition-free time for a new drug is significantly less than 17 years. But sometimes the maker has a backup strategy.

Extending the Life of a Drug

If you’ll recall your dusty high-school chemistry, molecules are three-dimensional objects. And many molecules come in 2 mirror-image versions of each other—left- and right-handed versions if you will. As it turns out, for many of these molecules only one of the -handed versions has an effect in the body.

So when a manufacturer finds a molecule that will work as a new drug, the first introduction might be a mixture of both the left and right versions. This is a natural result of the manufacturing process, so it’s not like the maker is adulterating their product in any way. But it does mean that only half of the molecules of product X are doing you any good.

Here’s where the backup comes in. The patent was originally granted on the left-and-right mixture. The 17-year limit is coming up, and voila! here’s a “new” version that’s really only the active half of the original. There’s still patient trials to conduct, but no investigative work to be done, and the trials can typically be shorter and smaller (and so cheaper) because the original drug has already been shown to be safe and effective.

When Drugs Do the Splits

Here’s an example of how that works. In 1989 the FDA approved the drug Prilosec for the treatment of frequent heartburn and GERD (gastroesophageal reflux disease). Prilosec is the molecule omeprazole. In 2002 the FDA approved generic omeprazole. It’s no coincidence that in February of 2001 the FDA had approved Nexium to treat the same conditions—Nexium’s molecule is esomeprazole, the left-handed version of omeprazole.

While Prilosec had market exclusivity for 13 years, for Nexium it was 14 years (generic esomeprazole was approved earlier this year). One more year of protection might not seem like much, but in 2013 Nexium was the #2-selling prescription drug in the US, with sales of more than $6 billion.

I want to emphasize that there’s nothing underhanded about this process. The manufacturer simply adds a step to separate the two -handed versions, and packages the one that’s effective. And I’m not picking on Nexium, it just happens to be one I have data for at hand. But keep in mind that, in this example if Nexium works for you at whatever it’s costing you for your prescription, then the drugstore’s generic OTC version of Prilosec will probably work just as well.

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Sexual Desire in Women

I admit it, I’m a guy. Not quite a bro, but I have been blessed/afflicted with the Y chromosome. So read what’s here with that in mind.

Yesterday’s post was about the approval of the drug flibanserin, aka “Viagra for women.” From my perspective it doesn’t seem like a good idea, and I laid out my reasoning in that post. Today I want to get into what was behind the FDA’s OK of flibanserin, after two failed attempts at approval.

The Politics of Drug Approval

Flibanserin didn’t all of a sudden get any safer. Three events have changed on the political landscape since the drug was first turned down in 2010.

  • Low libido in women has been medicalized—along with so much else—so now they have a condition that needs to be treated: Hypoactive Sexual Desire Disorder.* (This is close to what used to be called “frigidity” in women, with all its pejorative baggage.)
  • The FDA has placed female sexual dysfunction its list of top 20 unmet needs.
  • An advocacy group has formed around the issue. Even the Score is an association of 26 organizations, ranging from the Red Hot Mamas to the National Association of Clinical Nurse Specialists.

Throwing everything in the basket, the environment was ripe for approval.

Research Into Women’s Sexual Health

The viewpoint of Even the Score is that, since there are now more than 20 prescription treatments for low sexual functioning in men, there should be some for women too. The video on the Even the Score website makes the point. The group blames the difference on indifference to women’s interests. Or maybe on actual antipathy to women’s sexual health—both physical and mental.

Here’s where my being a guy comes in. I want my partner (that’s my wife) to be more interested in sexual relations. Just about anything that will do that gets my support. Put 5 guys together in a room, and they’ll tell you the same thing. Unfortunately, put 35 guys in a room, call them an FDA advisory panel (which used to be all male), and the topic of women’s health in general got pushed to the end of the agenda. As a result, research into almost all areas of women’s health lags behind. Fortunately that’s changing, but there’s still a long way to go to catch up.

So I partly agree and partly disagree that the discrepancy is a result of ignoring a women’s issue. It’s true that we’re still wandering in the weeds of pharmacology when it comes to women’s sexual drive, but it’s pretty much the same for men.

Desire Is a Mystery

The simple fact is that we know very about what triggers sexual desire. The search for Love Potion No. 9 has been going on for millennia. But Spanish fly doesn’t work. Powdered rhino horn doesn’t work. Sorry, not even chocolate works. In some older men, higher levels of testosterone can help. But for most of us, the hunt goes on.

We do have a good idea of what kills libido. Depression, stress, and anxiety will all depress your sex drive. Keep in mind that flibanserin was first developed as an antidepressant. My view is that if you can take care of other aspects of your mental and emotional health, your sex drive will take care of itself.

*At least that’s what it was called at the time the New Drug Application was put together for the FDA. Now, with the release of the updated DSM-5 (Diagnostic and Statistical Manual, the medical Bible for mental and emotional health practitioners), HSDD has been split into male and female versions: Male HSDD and Female Sexual Arousal/Interest Disorder.

Drug Disapproval—Flibanserin

The FDA’s approval of “Viagra for women” was all over the news this morning. Sigh. This is just wrong in so many ways. Let’s dive right in.

First, the characterization is completely off. Viagra treats a physical response, while flibanserin (brand name Addyi; and how do you say that?) treats libido, the mental aspect. The makers of Viagra and other meds for erectile dysfunction (ED) have said that if the desire’s not there, their med won’t help. And flibanserin won’t help with a woman’s physical response to sex.

Second, flibanserin is flat-out dangerous. The FDA had already denied approval twice over safety concerns, primarily nausea, dizziness, and headaches. This might not seem like much, but given the level of benefits the adverse effects were enough to kill the application twice. The makers did more studies, as asked. This time around the dangers were even more severe than first thought—but the benefits were no greater. Still, our FDA said “Yes.”

Just Say “No” to Flibanserin

Flibanserin is intended to treat a newly defined condition called Hypoactive Sexual Desire Disorder—in essence, low libido in premenopausal women. How low is “low”? Your guess is as good as mine. The makers of flibanserin define “low” as in the bottom 10% of desire. With more than 75 million women in the US between the ages of 20 and 54, 10% of that number is a nice population of new “patients.”

But what may seem low to one woman may be just fine for another. Measuring any aspect of mental or emotional functioning is a tricky business to begin with. Even in conditions such as depression and anxiety, which have been studied extensively for decades, assessment tools are notoriously imprecise. In physical conditions, part of a doctor’s job is to determine the cause behind your symptoms. Why is your blood pressure so high? What’s causing those headaches? Leaving treatment of a mental or emotional condition to your MD, though, is just asking for the symptom-treatment approach

The makers have said that they’ll require physicians to undergo training before being able to prescribe the drug, and it will be available only through “certified” pharmacists. I’ve taken some of these online training courses: two pages of text then 10 questions at the end, and voila! you’re certified. The seller has also agreed not to conduct any direct-to-consumer promotions for 18 months. Beginning in month 19, though, watch out for ads that could make your mom blush—and maybe your daughter too.

What’s Wrong About Flibanserin

As I said above, the perils of taking this drug are many and great.

  • Flibanserin tends to make you sleepy, so directions will say to take it before bedtime. There were reports in the trials of auto accidents and falls because women were getting sleepy.
  • Flibanserin makes you sleepy because it messes with your brain chemistry. Flibanserin affects receptors for serotonin and dopamine, and was first developed as an antidepressant. When researchers heard about an increase in libido from some participants, the light bulb went on.
  • Flibanserin doesn’t play nice with alcohol. So not nice, in fact, that there’s a “black-box” warning (the most serious kind) in the prescribing instructions, cautioning users not to consume alcohol while taking the drug. Umm… you want to feel like having sex more often, and no alcohol? How realistic is that for most people?
  • Flibanserin doesn’t play nice with contraceptives either. Typical hormonal contraceptives increase the frequency and severity of adverse effects, without improving the benefits. So have more sex but don’t use the Pill (or any other form of hormonal contraceptive).
  • It’s pink. Really? That’s the best marketing device you could come up with?

By the way, I don’t want to come across here as being against women’s sexuality—or even alarmed by it like some Victorian-era patriarch. I’ll go into that aspect of this drug tomorrow.

PS I came across this little tidbit about flibanserin on Friday. Take it in the spirit it’s offered.

Why Did My Doc Recommend This New Drug?

According to the CDC (that’s the US Centers for Disease Control and Prevention), a full three quarters of doctor’s office visits end up with the patient leaving with a prescription. The most common drugs here are painkillers, but also high on the list are drugs for depression and for high cholesterol. Altogether, that’s 2.6 billion prescriptions a year. Given the thousands of drugs available, and the dozens of new drugs coming out every year, how does your doctor decide what to recommend?

More than likely, your doctor has a cabinet full of samples, left behind by a friendly drug rep along with a stack of glossy brochures. There’s really only one good reason for you to be a lab rat. If you’ve given everything else an honest chance, and nothing has worked for you, then maybe the new drug therapy is right. But the sad truth is that for many drugs, the negative effects show up long after the positive ones. The quick “I feel better” or “My lab results look great” soon outweighs any concerns about potential side effects.

A classic example is the drug combination fen-phen, prescribed in the early ‘90s to promote weight loss. The combo helped people lose weight, sure enough. It wasn’t until much later that those same patients started showing up with a condition called primary pulmonary hypertension, in which the heart is damaged so badly that it can’t pump blood properly.

The litany of drugs that damage the heart is sobering: antihistamines, antibiotics, diabetes drugs, and more have been withdrawn from the market because of their potential to cripple or kill you. Now there are two new drugs in a novel class of cholesterol-lowering medications. An FDA panel has recommended approving these new drugs for use, even though we’re more than two years away from completing the main trials. There’s been little evaluation of cardiac risk.

Even if the full FDA goes ahead with approval, it will be a while before these new drugs—currently named Praluent and Repatha—are available to the public. Still, as soon as the OK is given, you can bet there will be hordes of drug reps touting the benefits of their products, even though the final trial results won’t be in. When your doc recommends one of these wonder drugs, your response should be, “Tell me more.”