Do you remember the CFC reduction efforts that went into effect in the latter half of the 20th century? CFCs, or chlorofluorocarbons, are a class of compounds that were traditionally used as refrigerants, solvents, or propellants in aerosol spray cans. When scientists determined that CFCs were contributing to the hole in the ozone layer. CFCs participate in a reaction with ozone where they act as a catalyst--i.e., they are not used up--that breaks ozone down into oxygen gas. Because individual CFC molecules are not used up in the reaction, a single CFC molecule may continue to break down thousands of ozone molecules over its lifetime.
What does this have to do with inhalers? By the end of 2008, CFC-containing inhalers will no longer be sold.
Traditional inhalers used to treat respiratory diseases like asthma used CFC-based propellants to deliver an aerosolized spray of medication directly to the lungs. But the time has come to phase out the old inhalers and replace them with new, more environmentally-friendly alternatives. The replacements, HFA inhalers, are just as effective as the old standbys without causing damage to the ozone layer or contributing to greenhouse gas production. The switch is a good thing, on the whole.
For once, Pharma is releasing a bunch of variations on their old products that aren't just a scam to extend their patents. They're actually doing something to help the environment. Y'know, aside from the fact that they're doing so because of Federal mandate.
There are a few minor issues that must be addressed. The new inhalers are just as good as the old ones, but FDA regulations consider them to be different, non-equivalent drug formulations. This means that you can't simply switch back and forth from CFC to HFA--in most states, the physician who writes the prescription must specify that the inhaler to be dispensed is an HFA inhaler. HFA inhalers are also going to cost slightly more--about $50 versus $30 for the old inhalers. But many manufacturers are distributing coupons that might help reduce costs for patients making the switch.
So if you use an inhaler, be prepared--you're going to have to switch, and soon. But the sooner the better, really. With every puff you're taking on an HFA inhaler instead of a CFC inhaler, you're contributing to the efforts to repair the ozone layer. That's like saving the world, one inhalation at at time.
Showing posts with label big pharma. Show all posts
Showing posts with label big pharma. Show all posts
Monday, September 22, 2008
Friday, September 12, 2008
Nationwide Pen Shortage Imminent
As any doctor or pharmacist knows, drug reps are a great source for office supplies. I have to question how much information about their products that they disseminate, and I've mentioned in the past that occasionally reps get way, way too enthusiastic about pushing products that are honestly mediocre attempts to extend the patent life on drugs no one is using anyway. I suppose that's their job, so I can't fault them for it...too much.
But there won't be any more free stuff for listening to their sales pitches.
Here's the interesting bit--this is voluntary. The major drug company association, PhRMA, is adopting these new standards in hopes that they'll avoid legislation actually banning the practice. In essence, they're surendering before the battle even begins because they know that the legislature will not be kind to their pen-pushing ilk. Various bills are already in circulation, so it's probably just a matter of time; voluntary actions on the part of Pharma are unlikely to impress legislators at this rate.
Educational items are still okay, as long as the total value is less than $100. So reps can still hand out literature, books, subscriptions, patient education materials, whatever. Just no more pens and pads. I'm not sure what we're going to write on at my pharmacy now. We have a stockpile of post-its from various pharmaceutical companies, but the supply will eventually run dry. I guess we'll have to settle for store-using real post-it pads.
I think that the best part of this whole story is a statistic cited by Pharmacist's Letter. Only 16% of physicians think that drug rep gifts influence their prescribing. But 61% of physicians think that other doctors are influenced by rep gifts. Hah!
But there won't be any more free stuff for listening to their sales pitches.
Starting in January, drug detailers will have a lighter load to carry when they visit physician offices. That is when new industry guidelines take effect that bar them from leaving behind drugmaker-branded pens, notepads, coffee mugs and other reminder items.
Here's the interesting bit--this is voluntary. The major drug company association, PhRMA, is adopting these new standards in hopes that they'll avoid legislation actually banning the practice. In essence, they're surendering before the battle even begins because they know that the legislature will not be kind to their pen-pushing ilk. Various bills are already in circulation, so it's probably just a matter of time; voluntary actions on the part of Pharma are unlikely to impress legislators at this rate.
Educational items are still okay, as long as the total value is less than $100. So reps can still hand out literature, books, subscriptions, patient education materials, whatever. Just no more pens and pads. I'm not sure what we're going to write on at my pharmacy now. We have a stockpile of post-its from various pharmaceutical companies, but the supply will eventually run dry. I guess we'll have to settle for store-using real post-it pads.
I think that the best part of this whole story is a statistic cited by Pharmacist's Letter. Only 16% of physicians think that drug rep gifts influence their prescribing. But 61% of physicians think that other doctors are influenced by rep gifts. Hah!
Tuesday, May 6, 2008
Advertising in Bizarro World
The other day I picked up a new copy of everyone's favorite pharmacy publication, DrugTopics. I generally like DrugTopics, except when they're running Zicam ads or otherwise uncritically promoting unproven treatments because the manufacturers were willing to pay for a page. The Zicam ads are annoying because they attempt to lend legitimacy to a product that has done everything conceivable to skirt FDA regulation--like calling itself homeopathic when in fact it contains measurable amounts of zinc. At a "1X" and "2X" dilution, a "recommended daily dose" of oral Zicam "cold remedy" tablets contains 80 mg of zinc. That's nearly eight times the typical dietary intake, and your average multivitamin contains about 10 mg as well. In essence, Zicam is about as homeopathic as Prozac, except that Prozac required FDA approval and Zicam didn't. Way to go, guys.
But this post isn't about Zicam. No, another advertisement caught my eye this time around--it was an ad for Luvox CR.
Luvox CR is a new formulation of fluvoxamine, a drug used to treat depression and obsessive-compulsive disorder. It's in the same general family as all the other SSRIs--Prozac, Zoloft, Paxil, Lexapro, et cetera. Granted, there are subtle differences between all of these drugs, but it's fair to say that fluxovamine (more or less) doesn't do anything spectacular by comparison; it is, in fact, one of the oldest SSRIs on the market.
Luvox CR, like many other drugs, is a follow-on drug intended to extend the patent life of a drug entity. Of course, follow-on drugs typically tend to come out a few years before a patent expires as opposed to a decade later, so Luvox CR is kinda missing the boat, but they're trying. All of this is acceptable, if shady, given the tendency of drug reps to push follow-on drugs like they're the greatest thing since sliced bread (and, of course, are totally worth paying $5 a dose for as opposed to the 50 cents the generic version of the old drug might cost).
Here's why I'm making the bizarro world reference. The advertisement's tagline was, and I quote: "NEW LUVOX CR: AN ANTIDEPRESSANT WITH NO GENERIC EQUIVALENT!"
I blinked in curiosity after reading these words. Was this supposed to be a good thing? Are reps supposed to approach psychiatrists, talk them up about the wonders of their new product, and wow them at the end with a concluding "best of all, this drug is going to cost your patients a fortune?" Who is this supposed to impress? I'm pretty sure the only people who think that "no generic equivalent" is a merit are the drug companies.
Or maybe these sorts of advertisements aren't ads at all--they're a warning to uppity pharmacists not to try doing stuff like "saving patients money" by "requesting lower-cost alternatives" and "cutting into pharma's profits."
Did I publish that where it was publicly viewable? Oooops.
Seriously. This is my biggest gripe about the pharmaceutical companies and their method of advertising. I can deal with them buying filet mignon for doctors. I can tolerate the magazine ads and even the occasional television spot, even if I think direct-to-consumer advertising does a lot more harm than good (no statistics, just impressions). What I can't stand is pharma advertising flaws as merits. "Our product costs ten times as much as our competitor's!" is something you would never hear touted as a positive in any other industry.
But hey, I'd much rather pharma play fast and loose with patent laws to try to squeeze a few more good years out of drugs that the FDA has thoroughly reviewed than "big woo" (sometimes the same companies, for that matter) play the get-out-of-jail-free "it's alternative medicine" card. After all, big woo has to slap the quack Miranda warning on all their products.
It's a strange day and age when "costs more!" and "isn't proven to work!" are somehow twisted to be signs of a good product.
But this post isn't about Zicam. No, another advertisement caught my eye this time around--it was an ad for Luvox CR.
Luvox CR is a new formulation of fluvoxamine, a drug used to treat depression and obsessive-compulsive disorder. It's in the same general family as all the other SSRIs--Prozac, Zoloft, Paxil, Lexapro, et cetera. Granted, there are subtle differences between all of these drugs, but it's fair to say that fluxovamine (more or less) doesn't do anything spectacular by comparison; it is, in fact, one of the oldest SSRIs on the market.
Luvox CR, like many other drugs, is a follow-on drug intended to extend the patent life of a drug entity. Of course, follow-on drugs typically tend to come out a few years before a patent expires as opposed to a decade later, so Luvox CR is kinda missing the boat, but they're trying. All of this is acceptable, if shady, given the tendency of drug reps to push follow-on drugs like they're the greatest thing since sliced bread (and, of course, are totally worth paying $5 a dose for as opposed to the 50 cents the generic version of the old drug might cost).
Here's why I'm making the bizarro world reference. The advertisement's tagline was, and I quote: "NEW LUVOX CR: AN ANTIDEPRESSANT WITH NO GENERIC EQUIVALENT!"
I blinked in curiosity after reading these words. Was this supposed to be a good thing? Are reps supposed to approach psychiatrists, talk them up about the wonders of their new product, and wow them at the end with a concluding "best of all, this drug is going to cost your patients a fortune?" Who is this supposed to impress? I'm pretty sure the only people who think that "no generic equivalent" is a merit are the drug companies.
Or maybe these sorts of advertisements aren't ads at all--they're a warning to uppity pharmacists not to try doing stuff like "saving patients money" by "requesting lower-cost alternatives" and "cutting into pharma's profits."
Did I publish that where it was publicly viewable? Oooops.
Seriously. This is my biggest gripe about the pharmaceutical companies and their method of advertising. I can deal with them buying filet mignon for doctors. I can tolerate the magazine ads and even the occasional television spot, even if I think direct-to-consumer advertising does a lot more harm than good (no statistics, just impressions). What I can't stand is pharma advertising flaws as merits. "Our product costs ten times as much as our competitor's!" is something you would never hear touted as a positive in any other industry.
But hey, I'd much rather pharma play fast and loose with patent laws to try to squeeze a few more good years out of drugs that the FDA has thoroughly reviewed than "big woo" (sometimes the same companies, for that matter) play the get-out-of-jail-free "it's alternative medicine" card. After all, big woo has to slap the quack Miranda warning on all their products.
It's a strange day and age when "costs more!" and "isn't proven to work!" are somehow twisted to be signs of a good product.
Wednesday, April 2, 2008
Flagellating a Long-deceased Equine
How much more of this are we going to have to take?
Vaccines do: Prevent potentially fatal or crippling diseases.
Vaccines don't: Cause autism.
Seriously. Only in a wealthy, priviledged country like America do people have the time and resources to blame medical care for ruining the lives of their children. People in third-world countries will quite frequently do anything to get medicine, vitamins, or vaccinations to prevent or treat polio, rickets, malaria, or any number of other diseases that have been effectively eradicated in the first-world--eradicated thanks to medical science, not ambulance-chasing lawyers seeking thimerosal settlements.
Let me restate that. People are spending hundreds of court-hours and millions of dollars in legal fees trying to prove that a medical intervention that people across the globe are dying to get their hands on harmed their children.
Is this really about protecting children? Or is it about reaching into corporate America's deep pockets and snagging a piece of the autism settlement pie with your sticky fingers?
Vaccines do: Prevent potentially fatal or crippling diseases.
Vaccines don't: Cause autism.
Seriously. Only in a wealthy, priviledged country like America do people have the time and resources to blame medical care for ruining the lives of their children. People in third-world countries will quite frequently do anything to get medicine, vitamins, or vaccinations to prevent or treat polio, rickets, malaria, or any number of other diseases that have been effectively eradicated in the first-world--eradicated thanks to medical science, not ambulance-chasing lawyers seeking thimerosal settlements.
Let me restate that. People are spending hundreds of court-hours and millions of dollars in legal fees trying to prove that a medical intervention that people across the globe are dying to get their hands on harmed their children.
Is this really about protecting children? Or is it about reaching into corporate America's deep pockets and snagging a piece of the autism settlement pie with your sticky fingers?
Wednesday, March 19, 2008
The Great Generic "Controversy"
The short version of this post is that there is no controversy. 99% of generic drugs are safe and effective. Given available data and a long history of positive results, there is simply no reason for your pharmacist (or your doctor) to recommend against use of a generic in 99% of all cases.
Let's start off the post with a list of comments I hear from patients on a fairly regular basis on the subject of generic drugs.
•"I want the 'real thing.'"
•"My doctor told me that generics don't work."
•"I'm allergic to generics."
•"How can the generic be as good if it's cheaper?"
•"No one is willing to guarantee that the generic and the brand are exactly the same, so I want the brand."
For starters, generics are "the real thing." They contain the same drug molecule that is responsible for changing your body's function as the brand. They are not cheap imitations. A technician I once worked with explained that people's objection to generic drugs was frequently because of their experience with generic foods; generic Oreos don't taste like "real" Oreos, after all. But unlike drug laws that mandate generics to be the same as brands, there's no law saying that generic Oreos have to taste just like real Oreos.
You aren't "allergic to generics." You just aren't. It isn't possible. An allergy to some component of a specific drug formulation (a dye, a flavoring, whatever) is totally possible. Saying you are allergic to generics is like saying you are allergic to fruit. The category is too big to be plausible.
If you think your doctor told you never to get generics, your doctor either failed to explain the difference between generic and brand adequately, or you are an idiot. A third possibility is that your doctor is a dermatologist. Some huge percentage of dermatologists advocate marking prescriptions for acne creams and similar products as "brand medically necessary" because they claim there is a huge difference. Hm. I'd think that if there were any product where a little bit of variation wouldn't matter much to my health would be my cosmetic face cream. Who knew?
The FDA has already answered the cost question. I won't answer it again.
Pharmacy colleague Abel Pharmboy has already elaborated on the basics of generic drugs. Patients are often confused by the 80-125% rule, so I rarely bring it up in clinical practice, but what it boils down to is this. It has nothing to do with the amount of drug in the tablet. It has nothing to do with the potency of the drug. Generics are equal to the brands in this respect. What differs between brands and generics, in most cases, are the "inert" fillers and binders that hold a tablet together or comprise the granules contained inside a capsule.
You rarely get the full dose of a drug. If you put a 100 mg tablet of drug X in your mouth and swallow it, there is a good chance that only a small percentage of drug X is absorbed (anywhere from 5% to 95%, depending on the drug). The big, technical word for this is bioavailability.
Suppose taking 100 mg of drug X means you have blood levels of 10 nanograms (ng) per deciliter (dL). What the 80-125% rule means is that if you take 100 mg of generic drug X your blood levels could be anywhere from 8 to 12.5 ng/dL and the drug would still be considered acceptable by FDA standards.
And that's the thing. For most drugs, it doesn't matter where you are in that range as long as you're above some minimum and below some toxic maximum, both of which are typically pretty far from the ideal range. Generic ibuprofen versus brands? Not gonna matter. Antibiotics? You're more likely to get sub-therapeutic blood levels because the patient isn't taking the drug properly than you are some bioavailability issue. Blood pressure meds? Your goal BP is based on averages, so it's all going to even out over time. Going generic is not going to cause your blood pressure to fluctuate wildly.
The whole thing only becomes an issue if this is not the first time a patient has taken a drug. If you have never taken a particular drug before, your blood level of that drug is obviously zero. You will start taking the drug, and after a set period of time, your blood level of the drug will reach a "steady" concentration as long as you continue taking your medication appropriately. It is only if you are suddenly switched from brand to generic that you might see a change--and you'd have the same issue if you started on generic and then switched to the brand.
For most drugs, as I mentioned above, there's no difference between our hypothetical 8 and 12 ng/dL. For others--those said to have a narrow therapeutic index--8 ng/dL may mean "no effect" and 12 ng/dL might mean "liver failure."
Of course, with drugs like this, patients must be closely monitored--using blood tests, in many cases--to make sure that they're getting just the right amount of drug. But that doesn't mean that the brand is superior. It means that the patient's therapy should be consistent. If the patient starts on the brand, they should stay on the brand, and if they start on the generic, they should stay on the generic, with no flip-flopping back and forth between the two. Most pharmacists are loathe to switch people back and forth repeatedly on drugs like Synthroid, Dilantin, or Lanoxin. And some states explicitly forbid it in their pharmacy law codes. Seizures in particular are all-or-nothing, so I totally agree with these sentiments.
Some people want to extend this no-substitution issue to all psychoactive drugs. Antidepressants are the big one; some patients really, really want the branded Paxil over the generic (generic brands just don't know how to act), for example (nevermind that brand name Paxil has not been on the market for a few years now).
It's easy to see why this might happen, drug efficacy aside. More expensive medicine makes patients feel better. I'm not saying antidepressants are placebos; the jury is still out on that one, though most evidence favors efficacy, even if it is slight (the drugs would never have been approved otherwise). But paying more for a drug--or a placebo--results in a better outcome for most patients. Perhaps paying more for the drug raises their expectations and subtly influences their mood. With largely subjective disorders like depression, subjective improvements are real improvements.
The case of the Wellbutrin scenario is somewhat unique in that we are talking about an extended-release product.
The process of making a tablet can be extremely simple or extremely complex. It is possible to make aspirin tablets by compressing crystalline aspirin with corn starch and water. At the other end of the spectrum are tablets that are designed with microscopic pores designed to release their contents at a constant (and precise) rate as the tablet passes through the intestinal tract, with the empty tablet shell being excreted with the next bowel movement. Extended-release formulations are generally on the complicated end of the scale, and the design process for these tablets is a great deal more involved. Many drug companies even patent their own extended-release mechanisms, like the OROS mechanism.
Because a generic manufacturer cannot simply use the same extended-release mechanism as the brand-name manufacturer (remember, these mechanisms are often patented), they must design their own tablet designed to release the drug at a similar rate. According to the ConsumerLabs data, the generic buproprion XL tablets released their drug more rapidly than Wellbutrin XL tablets. But the same amount of drug did get released, and the full dose was delivered.
Honestly, this doesn't surprise me in the least. The question is whether or not the increased rate of release is significant. For that, I'm going to have to go to Lexi-Comp's Drug Information Handbook, online edition. This could get a bit technical, but don't worry, I'll sum it up at the end.
The half-life of bupropion is greatly dependent on the person's liver function, ranging from 12 to 30 hours with an average of 21 hours. Bupropion's metabolites, i.e. the by-products of breakdown by the liver, are also active drugs, though they are less potent than bupropion (20-50% potency). These metabolites have half-lives similar to or longer than the primary drug, one of them having a half-life of anywhere from 30 to 40 hours.
What all these numbers ultimately mean is that bupropion hangs around in the body for a long time, and generic tablets releasing the drug over 2 and 1/2 hours instead of 5 hours is not going to significantly effect the "lower bound"--the lowest blood level measured in the peaks and valleys produced by daily administration. Remember that blood levels of a drug look kind of like a normal distribution curve, only flatter or shifted up, depending on the drug. To continue the math analogy, what the more rapid release is going to do is increase the slope of the curve.
This is not going to effect treatment of depression if the benchmark we're looking at is "is the patient maintaining minimum drug levels?" The more likely outcome is that the patient is going to experience a slight increase in side-effects compared to the brand name (if they've been switched from generic to brand recently) due to the fact that their blood levels are climbing more rapidly after administration. Whether or not this is going to be a problem depends on the patient. Last I checked, however, no one was complaining that patients switched to generic Wellbutrin XL were having seizures (which would be extremely unlikely unless the patient had an existing seizure disorder, which is a NO-NO when it comes to prescribing this drug). The specific issue probably never would have come up if it weren't for ConsumerLabs doing a bunch of assays.
Like with most brand-generic issues, the complaint from patients was most likely that the drug "wasn't working" or that they "just didn't feel right." These are the same complaints that come up all the time. That doesn't mean that they shouldn't be investigated; it just means that it's hard for heathcare professionals to filter things out given the poor signal to noise ratio.
I'm still not convinced that the differences between brand and generic Wellbutrin XL are clinically significant, but then, I'm just a pharmacy student. What's troubling is that this information didn't come out sooner, and, as Abel mentioned, the fact that it was kept under wraps until an independent lab started poking around seriously undermines both the generic drug companies and the FDA's trustworthiness in the eyes of the public. That's the true tragedy here; patients are going to think that this failure to disclose information is indicative of serious problems with the generic drug industry when in fact the complete opposite is true. The generic drug industry has a long record of producing safe and effective drugs. Most community pharmacies dispense generic alternatives for over 90% of the prescriptions they fill without any hitches--I know mine does.
Generic drugs are a great thing for patients. Let's not let one little slip--a slip of questionable significance from a clinical perspective--ruin that.
Let's start off the post with a list of comments I hear from patients on a fairly regular basis on the subject of generic drugs.
•"I want the 'real thing.'"
•"My doctor told me that generics don't work."
•"I'm allergic to generics."
•"How can the generic be as good if it's cheaper?"
•"No one is willing to guarantee that the generic and the brand are exactly the same, so I want the brand."
For starters, generics are "the real thing." They contain the same drug molecule that is responsible for changing your body's function as the brand. They are not cheap imitations. A technician I once worked with explained that people's objection to generic drugs was frequently because of their experience with generic foods; generic Oreos don't taste like "real" Oreos, after all. But unlike drug laws that mandate generics to be the same as brands, there's no law saying that generic Oreos have to taste just like real Oreos.
You aren't "allergic to generics." You just aren't. It isn't possible. An allergy to some component of a specific drug formulation (a dye, a flavoring, whatever) is totally possible. Saying you are allergic to generics is like saying you are allergic to fruit. The category is too big to be plausible.
If you think your doctor told you never to get generics, your doctor either failed to explain the difference between generic and brand adequately, or you are an idiot. A third possibility is that your doctor is a dermatologist. Some huge percentage of dermatologists advocate marking prescriptions for acne creams and similar products as "brand medically necessary" because they claim there is a huge difference. Hm. I'd think that if there were any product where a little bit of variation wouldn't matter much to my health would be my cosmetic face cream. Who knew?
The FDA has already answered the cost question. I won't answer it again.
Pharmacy colleague Abel Pharmboy has already elaborated on the basics of generic drugs. Patients are often confused by the 80-125% rule, so I rarely bring it up in clinical practice, but what it boils down to is this. It has nothing to do with the amount of drug in the tablet. It has nothing to do with the potency of the drug. Generics are equal to the brands in this respect. What differs between brands and generics, in most cases, are the "inert" fillers and binders that hold a tablet together or comprise the granules contained inside a capsule.
You rarely get the full dose of a drug. If you put a 100 mg tablet of drug X in your mouth and swallow it, there is a good chance that only a small percentage of drug X is absorbed (anywhere from 5% to 95%, depending on the drug). The big, technical word for this is bioavailability.
Suppose taking 100 mg of drug X means you have blood levels of 10 nanograms (ng) per deciliter (dL). What the 80-125% rule means is that if you take 100 mg of generic drug X your blood levels could be anywhere from 8 to 12.5 ng/dL and the drug would still be considered acceptable by FDA standards.
And that's the thing. For most drugs, it doesn't matter where you are in that range as long as you're above some minimum and below some toxic maximum, both of which are typically pretty far from the ideal range. Generic ibuprofen versus brands? Not gonna matter. Antibiotics? You're more likely to get sub-therapeutic blood levels because the patient isn't taking the drug properly than you are some bioavailability issue. Blood pressure meds? Your goal BP is based on averages, so it's all going to even out over time. Going generic is not going to cause your blood pressure to fluctuate wildly.
The whole thing only becomes an issue if this is not the first time a patient has taken a drug. If you have never taken a particular drug before, your blood level of that drug is obviously zero. You will start taking the drug, and after a set period of time, your blood level of the drug will reach a "steady" concentration as long as you continue taking your medication appropriately. It is only if you are suddenly switched from brand to generic that you might see a change--and you'd have the same issue if you started on generic and then switched to the brand.
For most drugs, as I mentioned above, there's no difference between our hypothetical 8 and 12 ng/dL. For others--those said to have a narrow therapeutic index--8 ng/dL may mean "no effect" and 12 ng/dL might mean "liver failure."
Of course, with drugs like this, patients must be closely monitored--using blood tests, in many cases--to make sure that they're getting just the right amount of drug. But that doesn't mean that the brand is superior. It means that the patient's therapy should be consistent. If the patient starts on the brand, they should stay on the brand, and if they start on the generic, they should stay on the generic, with no flip-flopping back and forth between the two. Most pharmacists are loathe to switch people back and forth repeatedly on drugs like Synthroid, Dilantin, or Lanoxin. And some states explicitly forbid it in their pharmacy law codes. Seizures in particular are all-or-nothing, so I totally agree with these sentiments.
Some people want to extend this no-substitution issue to all psychoactive drugs. Antidepressants are the big one; some patients really, really want the branded Paxil over the generic (generic brands just don't know how to act), for example (nevermind that brand name Paxil has not been on the market for a few years now).
It's easy to see why this might happen, drug efficacy aside. More expensive medicine makes patients feel better. I'm not saying antidepressants are placebos; the jury is still out on that one, though most evidence favors efficacy, even if it is slight (the drugs would never have been approved otherwise). But paying more for a drug--or a placebo--results in a better outcome for most patients. Perhaps paying more for the drug raises their expectations and subtly influences their mood. With largely subjective disorders like depression, subjective improvements are real improvements.
The case of the Wellbutrin scenario is somewhat unique in that we are talking about an extended-release product.
The process of making a tablet can be extremely simple or extremely complex. It is possible to make aspirin tablets by compressing crystalline aspirin with corn starch and water. At the other end of the spectrum are tablets that are designed with microscopic pores designed to release their contents at a constant (and precise) rate as the tablet passes through the intestinal tract, with the empty tablet shell being excreted with the next bowel movement. Extended-release formulations are generally on the complicated end of the scale, and the design process for these tablets is a great deal more involved. Many drug companies even patent their own extended-release mechanisms, like the OROS mechanism.
Because a generic manufacturer cannot simply use the same extended-release mechanism as the brand-name manufacturer (remember, these mechanisms are often patented), they must design their own tablet designed to release the drug at a similar rate. According to the ConsumerLabs data, the generic buproprion XL tablets released their drug more rapidly than Wellbutrin XL tablets. But the same amount of drug did get released, and the full dose was delivered.
Honestly, this doesn't surprise me in the least. The question is whether or not the increased rate of release is significant. For that, I'm going to have to go to Lexi-Comp's Drug Information Handbook, online edition. This could get a bit technical, but don't worry, I'll sum it up at the end.
The half-life of bupropion is greatly dependent on the person's liver function, ranging from 12 to 30 hours with an average of 21 hours. Bupropion's metabolites, i.e. the by-products of breakdown by the liver, are also active drugs, though they are less potent than bupropion (20-50% potency). These metabolites have half-lives similar to or longer than the primary drug, one of them having a half-life of anywhere from 30 to 40 hours.
What all these numbers ultimately mean is that bupropion hangs around in the body for a long time, and generic tablets releasing the drug over 2 and 1/2 hours instead of 5 hours is not going to significantly effect the "lower bound"--the lowest blood level measured in the peaks and valleys produced by daily administration. Remember that blood levels of a drug look kind of like a normal distribution curve, only flatter or shifted up, depending on the drug. To continue the math analogy, what the more rapid release is going to do is increase the slope of the curve.
This is not going to effect treatment of depression if the benchmark we're looking at is "is the patient maintaining minimum drug levels?" The more likely outcome is that the patient is going to experience a slight increase in side-effects compared to the brand name (if they've been switched from generic to brand recently) due to the fact that their blood levels are climbing more rapidly after administration. Whether or not this is going to be a problem depends on the patient. Last I checked, however, no one was complaining that patients switched to generic Wellbutrin XL were having seizures (which would be extremely unlikely unless the patient had an existing seizure disorder, which is a NO-NO when it comes to prescribing this drug). The specific issue probably never would have come up if it weren't for ConsumerLabs doing a bunch of assays.
Like with most brand-generic issues, the complaint from patients was most likely that the drug "wasn't working" or that they "just didn't feel right." These are the same complaints that come up all the time. That doesn't mean that they shouldn't be investigated; it just means that it's hard for heathcare professionals to filter things out given the poor signal to noise ratio.
I'm still not convinced that the differences between brand and generic Wellbutrin XL are clinically significant, but then, I'm just a pharmacy student. What's troubling is that this information didn't come out sooner, and, as Abel mentioned, the fact that it was kept under wraps until an independent lab started poking around seriously undermines both the generic drug companies and the FDA's trustworthiness in the eyes of the public. That's the true tragedy here; patients are going to think that this failure to disclose information is indicative of serious problems with the generic drug industry when in fact the complete opposite is true. The generic drug industry has a long record of producing safe and effective drugs. Most community pharmacies dispense generic alternatives for over 90% of the prescriptions they fill without any hitches--I know mine does.
Generic drugs are a great thing for patients. Let's not let one little slip--a slip of questionable significance from a clinical perspective--ruin that.
Wednesday, February 27, 2008
Some Depressing News
A friend of mine sent me a link to an article yesterday, thinking it might be useful blog fodder. However, I didn't have the actual study in front of me--but thanks to The Frontal Cortex, now I do. If you ask me, Jonah has hit the nail on the head when he pointed out the biggest weakness in this study--all of the trials involved were, at most, eight weeks long.
For those unaware, this study was a meta-analysis. A meta-analysis involves doing no new research trials; instead, the results of a large number of old trials are compiled and analyzed using statistical methods. Results from fourty-seven trials were compiled for the meta-analysis; thirty-three of those were only six weeks long. Short trials are known to be less valuable in testing the efficacy of antidepressants; the longer the studies run, the farther apart the placebo and treatment groups usually get. For example, this study demonstrated that if you give patients escitalopram (an SSRI) for sixteen weeks and then switch half of them to placebo without them knowing about it, the placebo group will do significantly worse in terms of probability of relapse into depression.
It's interesting to see placebos compared to antidepressants. According to the PLoS study, placebos had about 80% of the therapeutic activity of SSRIs in the short term--that is, they were about "80% as good" in the six-to-eight week studies they analyzed. This is not actually all that surprising. For many depressed patients--or those with mental illness in general--the placebo effect is huge. Sometimes, the pro-active nature of seeking treatment is enough to bring depressed patients out of a slump, if only temporarily. Patients who feel as though they're finally doing something to fix themselves are likely to experience an emotional boost. And let's face it--not everyone on SSRIs is experiencing symptoms because they have low serotonin, one of the major neurotransmitters behind depression. Other diseases can cause patients to present with depression-like symptoms if they aren't properly ruled out before initiating treatment. That isn't likely the case with this study; before patients can participate in a drug trial for a new antidepressant, other causes of depressed mood must be ruled out.
The problem is that the mainstream media tends to get ahold of things like this and run amok making claims that "a new study proves antidepressants don't work," which is both incorrect and irresponsible. It's incorrect because all this meta-analysis (like many individual trials on the subject) suggests is that SSRIs must be taken long-term to have benefit, and that short-term reactions are largely attributable to placebo effects. There's a big difference between "antidepressants don't work" and "antidepressants have to be taken for months to see major improvement." The rate of relapse for patients switched abruptly to placebo is higher, even if the authors of the meta-analysis aren't convinced that antidepressants create "enough" improvement in the short term to be clinically significant.
To continue, this style of reporting is irresponsible because the everyman is a lot more likely to read a news article with a catchy headline than he is to seek out the original study and pore over the methods of the researchers, either because he has no idea where to look or because he hasn't taken enough statistics to have any idea what the hell these sciencey people are talking about. Which means that the everyman on antidepressants is going to take the words of some reporter at face value--perhaps higher than the words of his doctor, if enough reporters are all saying the same thing--and they're going to throw away their meds, decrying them as a useless waste of money. I've seen this happen before in clinical practice; many mentally ill patients take meds for a while, decide they don't need them any more (either because they "aren't working" or they "feel better"), pitch them, relapse, and start the whole vicious cycle over again.
Is there a tendency to "cover up" the results of clinical trials with negative outcomes? Sure. That's publication bias. But antidepressants aren't the only medications for which reporting bias is an issue--and just because some negative studies don't get published doesn't mean that the positive ones are automatically worthless. The negative studies don't necessarily get swept under the rug as part of some "grand pharma conspiracy." One negative study doesn't prove a drug is ineffective any more than one positive study proves that it is. If the overwhelming trend is positive or negative, then we can make judgments. But even trends can be misleading; you can connect the dots many different ways, depending on where the dots are and what kind of analysis you're doing. And that's one of the risks of meta-analysis studies. There's just as much room for spin there as anywhere else.
So don't throw out the Prozac. There's no such thing as an "official study" that proclaims antidepressants to be therapeutically useless. And any journalist who tells you otherwise is being sucked in by spin just as badly as the drug reps who are trying to push the products--they're just being spun in the opposite direction.
For those unaware, this study was a meta-analysis. A meta-analysis involves doing no new research trials; instead, the results of a large number of old trials are compiled and analyzed using statistical methods. Results from fourty-seven trials were compiled for the meta-analysis; thirty-three of those were only six weeks long. Short trials are known to be less valuable in testing the efficacy of antidepressants; the longer the studies run, the farther apart the placebo and treatment groups usually get. For example, this study demonstrated that if you give patients escitalopram (an SSRI) for sixteen weeks and then switch half of them to placebo without them knowing about it, the placebo group will do significantly worse in terms of probability of relapse into depression.
It's interesting to see placebos compared to antidepressants. According to the PLoS study, placebos had about 80% of the therapeutic activity of SSRIs in the short term--that is, they were about "80% as good" in the six-to-eight week studies they analyzed. This is not actually all that surprising. For many depressed patients--or those with mental illness in general--the placebo effect is huge. Sometimes, the pro-active nature of seeking treatment is enough to bring depressed patients out of a slump, if only temporarily. Patients who feel as though they're finally doing something to fix themselves are likely to experience an emotional boost. And let's face it--not everyone on SSRIs is experiencing symptoms because they have low serotonin, one of the major neurotransmitters behind depression. Other diseases can cause patients to present with depression-like symptoms if they aren't properly ruled out before initiating treatment. That isn't likely the case with this study; before patients can participate in a drug trial for a new antidepressant, other causes of depressed mood must be ruled out.
The problem is that the mainstream media tends to get ahold of things like this and run amok making claims that "a new study proves antidepressants don't work," which is both incorrect and irresponsible. It's incorrect because all this meta-analysis (like many individual trials on the subject) suggests is that SSRIs must be taken long-term to have benefit, and that short-term reactions are largely attributable to placebo effects. There's a big difference between "antidepressants don't work" and "antidepressants have to be taken for months to see major improvement." The rate of relapse for patients switched abruptly to placebo is higher, even if the authors of the meta-analysis aren't convinced that antidepressants create "enough" improvement in the short term to be clinically significant.
To continue, this style of reporting is irresponsible because the everyman is a lot more likely to read a news article with a catchy headline than he is to seek out the original study and pore over the methods of the researchers, either because he has no idea where to look or because he hasn't taken enough statistics to have any idea what the hell these sciencey people are talking about. Which means that the everyman on antidepressants is going to take the words of some reporter at face value--perhaps higher than the words of his doctor, if enough reporters are all saying the same thing--and they're going to throw away their meds, decrying them as a useless waste of money. I've seen this happen before in clinical practice; many mentally ill patients take meds for a while, decide they don't need them any more (either because they "aren't working" or they "feel better"), pitch them, relapse, and start the whole vicious cycle over again.
Is there a tendency to "cover up" the results of clinical trials with negative outcomes? Sure. That's publication bias. But antidepressants aren't the only medications for which reporting bias is an issue--and just because some negative studies don't get published doesn't mean that the positive ones are automatically worthless. The negative studies don't necessarily get swept under the rug as part of some "grand pharma conspiracy." One negative study doesn't prove a drug is ineffective any more than one positive study proves that it is. If the overwhelming trend is positive or negative, then we can make judgments. But even trends can be misleading; you can connect the dots many different ways, depending on where the dots are and what kind of analysis you're doing. And that's one of the risks of meta-analysis studies. There's just as much room for spin there as anywhere else.
So don't throw out the Prozac. There's no such thing as an "official study" that proclaims antidepressants to be therapeutically useless. And any journalist who tells you otherwise is being sucked in by spin just as badly as the drug reps who are trying to push the products--they're just being spun in the opposite direction.
Wednesday, February 6, 2008
Oops, I Patented Your Natural Product
What are good ways to lower your cholesterol? You could eat less cholesterol. That helps, but the human liver is great at making cholesterol. In fact, it tends to do so pretty much constantly--but entertainingly enough, the liver works the hardest at producing LDL cholesterol (the "bad" cholesterol) while you're sleeping. No, you shouldn't give up sleep. But what's worth recognizing is that diet isn't the only source of cholesterol, and in fact, the liver probably contributes more bad cholesterol than diet. In fact, removing part of the liver reduced circulating LDL concentrations in animal studies. You could also exercise, drink less alcohol, and give up smoking. All of these things work. But what if they aren't enough?
Statins are a popular target for proponents of "alternative medicine." You don't need statins, they say, you can just take vitamins and eat healthy. Sometimes they promote other unproven supplements or "treatments." Statins are dangerous. Statins are worthless. The lipid hypothesis is false; scientists are lying to you and cholesterol has nothing to do with cardiovascular disease. Here, drink this Kool-aid.
Pigs fed high-cholesterol diets are more likely to develop cardiovascular disease (CVD). And Watanabe rabbits lack a specific gene that prevents them from manufacturing receptors for LDL cholesterol in the liver. Normally, the liver's LDL receptors sense circulating cholesterol levels as a regulatory mechanism; if there's a lot of cholesterol floating around, the liver will react by making less cholesterol. Since the rabbits' livers are unable to compensate for high levels of LDL, they develop arterial plaques with astounding frequency. If fed a high-cholesterol diet, the rate and probability of plaque formation increases. And if animal studies aren't good enough, check out the Framingham heart study, which involves an entire town in Massachusetts that's been followed for three generations to learn more about CVD risk factors. Scientists didn't just pull the lipid hypothesis of atherosclerosis out of thin air. There's a lot of very thorough research and credible data that's been taken into consideration.
All the attempts to "debunk" the lipid hypothesis and the value of statins are crackpottery. Are they miracle drugs or cure-alls? Of course not; no one says they are.
Anyway. "Natural" methods for treating illness are popular with a lot of patients. There's something wholesome-sounding about the word, like your mother would want you to take natural products. Nevermind that natural does not mean safe; botulinum toxin is one of the most dangerous substances in the world, and it's made by bacteria. All-natural! Maybe that's why people are willing to inject it into their faces to get rid of wrinkles.
Here's a secret. Statins are natural.
Have you heard of red yeast rice? It's an interesting product. Monascus purpureus, a fungus that grows on rice, produces a wide variety of chemical compounds, including a group called mevinic acids. Naturally fermented red rice yeast is about 0.4% mevinic acids by weight. Red yeast rice supplements are not always what they claim to be on the label, but there's presumably some statin-equivalent content in there.
How about mevastatin? Mevastatin was isolated from Penicillium citrinum mold. Man, mold is great stuff. We play with mold long enough and we have this interesting tendency to serendipitiously find antibiotics and anti-cancer compounds.
Like penicillin, statins were originally isolated as naturally-occuring substances. The major mevinic acid compound in red yeast rice was named lovastatin. And guess what? It got patented. It's called Mevacor. Huh. I thought the natural medicine folks were always saying that the reason Big Pharma isn't willing to seriously investigate "natural remedies" is because they can't be patented?
That claim, of course, is a load of Penicillium fungus. Sure, you can't patent vitamin C, but you can patent unique compounds that you discover, no matter where they come from. Statins are some of the top money-makers for Pharma today (for better or for worse), and they got their start in yeast and mold colonies. Pharma would have to be incredibly to stupid to ignore nature as a potential source for useful drug compounds. It's true that most of the statins prescribed are synthetic compounds like simvastatin (Zocor). But simvastatin was made by modifying lovastatin to increase its effectiveness. Inspired by nature, proven by science. Saying Zocor is unnatural is like saying cutting trees into two-by-fours to build houses instead of just using felled logs is unnatural. By altering a naturally-occuring substance, we can make it a better drug than it would be otherwise.
If something proves to be useful, medicine will use it, whether it's "natural" or not--a false dichotomy to begin with. And if it isn't, medicine will discard it. Scientific analysis is the only way to tell the difference. And anyone who tries to tell you differently needs to go read about penicillin.
Statins are a popular target for proponents of "alternative medicine." You don't need statins, they say, you can just take vitamins and eat healthy. Sometimes they promote other unproven supplements or "treatments." Statins are dangerous. Statins are worthless. The lipid hypothesis is false; scientists are lying to you and cholesterol has nothing to do with cardiovascular disease. Here, drink this Kool-aid.
Pigs fed high-cholesterol diets are more likely to develop cardiovascular disease (CVD). And Watanabe rabbits lack a specific gene that prevents them from manufacturing receptors for LDL cholesterol in the liver. Normally, the liver's LDL receptors sense circulating cholesterol levels as a regulatory mechanism; if there's a lot of cholesterol floating around, the liver will react by making less cholesterol. Since the rabbits' livers are unable to compensate for high levels of LDL, they develop arterial plaques with astounding frequency. If fed a high-cholesterol diet, the rate and probability of plaque formation increases. And if animal studies aren't good enough, check out the Framingham heart study, which involves an entire town in Massachusetts that's been followed for three generations to learn more about CVD risk factors. Scientists didn't just pull the lipid hypothesis of atherosclerosis out of thin air. There's a lot of very thorough research and credible data that's been taken into consideration.
All the attempts to "debunk" the lipid hypothesis and the value of statins are crackpottery. Are they miracle drugs or cure-alls? Of course not; no one says they are.
Anyway. "Natural" methods for treating illness are popular with a lot of patients. There's something wholesome-sounding about the word, like your mother would want you to take natural products. Nevermind that natural does not mean safe; botulinum toxin is one of the most dangerous substances in the world, and it's made by bacteria. All-natural! Maybe that's why people are willing to inject it into their faces to get rid of wrinkles.
Here's a secret. Statins are natural.
Have you heard of red yeast rice? It's an interesting product. Monascus purpureus, a fungus that grows on rice, produces a wide variety of chemical compounds, including a group called mevinic acids. Naturally fermented red rice yeast is about 0.4% mevinic acids by weight. Red yeast rice supplements are not always what they claim to be on the label, but there's presumably some statin-equivalent content in there.
How about mevastatin? Mevastatin was isolated from Penicillium citrinum mold. Man, mold is great stuff. We play with mold long enough and we have this interesting tendency to serendipitiously find antibiotics and anti-cancer compounds.
Like penicillin, statins were originally isolated as naturally-occuring substances. The major mevinic acid compound in red yeast rice was named lovastatin. And guess what? It got patented. It's called Mevacor. Huh. I thought the natural medicine folks were always saying that the reason Big Pharma isn't willing to seriously investigate "natural remedies" is because they can't be patented?
That claim, of course, is a load of Penicillium fungus. Sure, you can't patent vitamin C, but you can patent unique compounds that you discover, no matter where they come from. Statins are some of the top money-makers for Pharma today (for better or for worse), and they got their start in yeast and mold colonies. Pharma would have to be incredibly to stupid to ignore nature as a potential source for useful drug compounds. It's true that most of the statins prescribed are synthetic compounds like simvastatin (Zocor). But simvastatin was made by modifying lovastatin to increase its effectiveness. Inspired by nature, proven by science. Saying Zocor is unnatural is like saying cutting trees into two-by-fours to build houses instead of just using felled logs is unnatural. By altering a naturally-occuring substance, we can make it a better drug than it would be otherwise.
If something proves to be useful, medicine will use it, whether it's "natural" or not--a false dichotomy to begin with. And if it isn't, medicine will discard it. Scientific analysis is the only way to tell the difference. And anyone who tries to tell you differently needs to go read about penicillin.
Tuesday, January 29, 2008
Seeing the Forest for the Trees
I have mentioned my aggravation with Forest Pharmaceuticals before in the context of their excessive promotion of Namenda, a drug to "delay the progression" of Alzheimer's disease. While Namenda is effective, the drug reps I've talked to have a tendency to really push it as being significantly better than it actually is, especially since we're looking at doubling the cost per patient and increasing "pill burden" for patients or their caretakers. There's nothing more depressing to me than seeing families spending a fortune on medications for Alzheimer's while watching their loved ones deteriorate despite treatment.
On the other hand, Forest's Lexapro is a follow-on drug that's actually been demonstrated to be better than its parent. So maybe they aren't all bad.
Then they released Bystolic.
Bystolic is a beta-blocker. The market is positively overflowing with beta-blockers. Metaprolol, atenolol, propranolol...a dozen or more drugs. Granted, they have subtle differences, but Bystolic doesn't bring anything new to the table.
Beta-blockers reduce adrenergic (adrenaline-mediated) stimulation of the heart and blood vessels, slowing heart rate and dilating arterioles to decrease blood pressure. B-blockers aren't as good at lowering BP directly as some other drugs, but they are quite useful in preventing further damage to the heart after a myocardial infarction (heart attack) and in treating irregular heartbeats. Intriguingly, propranolol can even be used to prevent migraines, though the precise mechanism of action is not well-understood.
Bystolic is only approved to lower high blood pressure, but Forest is hoping to get it approved for patients with heart failure as well. Unfortunately for Forest, we already have a great cousin drug that has both indications--carvedilol--and it's available generically as of last year.
I realize that sometimes drugs get stuck in the research pipeline and the company gets so far into development that not releasing the drug is a bad financial move even if the drug is not likely to "sell." But Forest has likely spent enough money producing Bystolic that they must find a way to get physicians to prescribe it despite the fact that Bystolic is a "useless" drug. Sure, it works, but no sane clinician is going to prescribe it given a myriad of equally effective alternatives that cost one-fourth as much.
Unless, of course, Forest sends out their reps to promote it. Which means that it's a safe bet that Forest is going to spend a lot of money to advertise a drug that you'd have to be incredibly foolish to prescribe. Drug research and development costs are very high, but pharmaceutical advertising inflates prices beyond what is reasonable. And if given a sufficiently convincing sales pitch, many physicians might prescribe the drug anyway. Many doctors just don't know how much drugs cost. I have personal experience in the matter; I make a lot of phone calls when I'm working to ask physicians to switch to cheaper alternatives or to permit generic substitution when they've signed something "dispense as written" for no good reason (dermatologists, I'm looking at you).
Come on, Forest. You can do better than this. I know I saw your vague, almost viral ads in pharmacy magazines and got a little excited about your "new development in the treatment of hypertension." At least throw us another direct renin inhibitor instead of trying to pass off a totally underwhelming drug as the next big thing.
On the other hand, Forest's Lexapro is a follow-on drug that's actually been demonstrated to be better than its parent. So maybe they aren't all bad.
Then they released Bystolic.
Bystolic is a beta-blocker. The market is positively overflowing with beta-blockers. Metaprolol, atenolol, propranolol...a dozen or more drugs. Granted, they have subtle differences, but Bystolic doesn't bring anything new to the table.
Beta-blockers reduce adrenergic (adrenaline-mediated) stimulation of the heart and blood vessels, slowing heart rate and dilating arterioles to decrease blood pressure. B-blockers aren't as good at lowering BP directly as some other drugs, but they are quite useful in preventing further damage to the heart after a myocardial infarction (heart attack) and in treating irregular heartbeats. Intriguingly, propranolol can even be used to prevent migraines, though the precise mechanism of action is not well-understood.
Bystolic is only approved to lower high blood pressure, but Forest is hoping to get it approved for patients with heart failure as well. Unfortunately for Forest, we already have a great cousin drug that has both indications--carvedilol--and it's available generically as of last year.
I realize that sometimes drugs get stuck in the research pipeline and the company gets so far into development that not releasing the drug is a bad financial move even if the drug is not likely to "sell." But Forest has likely spent enough money producing Bystolic that they must find a way to get physicians to prescribe it despite the fact that Bystolic is a "useless" drug. Sure, it works, but no sane clinician is going to prescribe it given a myriad of equally effective alternatives that cost one-fourth as much.
Unless, of course, Forest sends out their reps to promote it. Which means that it's a safe bet that Forest is going to spend a lot of money to advertise a drug that you'd have to be incredibly foolish to prescribe. Drug research and development costs are very high, but pharmaceutical advertising inflates prices beyond what is reasonable. And if given a sufficiently convincing sales pitch, many physicians might prescribe the drug anyway. Many doctors just don't know how much drugs cost. I have personal experience in the matter; I make a lot of phone calls when I'm working to ask physicians to switch to cheaper alternatives or to permit generic substitution when they've signed something "dispense as written" for no good reason (dermatologists, I'm looking at you).
Come on, Forest. You can do better than this. I know I saw your vague, almost viral ads in pharmacy magazines and got a little excited about your "new development in the treatment of hypertension." At least throw us another direct renin inhibitor instead of trying to pass off a totally underwhelming drug as the next big thing.
Sunday, December 23, 2007
Patchwork
This is the dumbest thing ever.
Fentanyl is an opioid analgesic, like morphine or codeine. Unlike everyone's favorite analgesics, Tylenol #3 and Vicodin, fentanyl is most commonly administered via a transdermal patch that is worn on the skin. Oral forms are available, but considerably less common (notably orally-disintegrating tablets and even a narcotic sucker). Fentanyl is very potent, and must be used in small doses--25 micrograms (or 0.025 mg) of fentanyl per hour over a 24-hour period is recommended for patients taking between 60 and 134 milligrams of oral morphine per day. Fentanyl should not even be initiated in patients taking less than this--for comparison's sake, 60 mg of morphine is equivalent to 30 mg of oxycodone. Your standard Percocet tablet has 5 mg of oxycodone per tablet.
I may be belaboring the point. In any case, fentanyl is potent stuff. It takes very little fentanyl to match an equivalent dose of some other opioid painkiller.
Prescribing fentanyl for patients with anything less than chronic pain due to cancer or long-term injuries is irresponsible. The package insert itself says that using fentanyl patches for short-term pain is a mistake. Physicians prescribing the patches for patients with headaches are only part of the problem; there are no statistics available, as far as I can tell, but I'm willing to bet that much of the problem not misprescribing of fentanyl. The problem is misuse. Not in the sense of drug abuse, but rather in the sense of improper administration of the patches. Heating pads are a popular means of relieving chronic pain. But putting a heating pad over a fentanyl patch will dramatically increase the rate of transfer from the patch into the patient's bloodstream, potentially resulting in death when the patient's central nervous system stops triggering the breathing reflex. Patients who slap on a patch and then get into a hot tub may not get out.
An interesting issue is that transdermal patches must contain much more active ingredient than is to be delivered to the patient because the rate of transfer from the patch to the bloodstream is dependent on the difference between drug in the skin and drug in the patch. In short, a patch that only delivers 0.025 mg per hour may have to contain 3 mg of total drug to keep the flow moving. This means that a "used" patch still contains a lot of drug, and improper disposal of the patch can result in children or animals getting ahold of a lot of "leftover" fentanyl--easily fatal, should the patch be chewed or torn.
These deaths are so preventable it's ridiculous. A little patient education about the proper use and disposal of fentanyl would have saved nearly everyone involved. This is the task set before pharmacists. This is the value of proper patient counseling. Like all drugs, fentanyl has risks. But the risks can be minimized if patients are properly informed. Counseling for such drugs should be legally mandated--and furthermore, drugstores should be required to give pharmacists the time and staffing to perform the task adequately. These deaths aren't the fault of pharma. They're due to ignorance and irresponsibility. Pharmacists need to educate their patients--and patients need to pay attention instead of quacking away on cellphones while they sign the pick-up log for their fentanyl patches.
If in two weeks I have to read another article about fentanyl patches for the fourth month in a row I'm going to go crazy.
Fentanyl is an opioid analgesic, like morphine or codeine. Unlike everyone's favorite analgesics, Tylenol #3 and Vicodin, fentanyl is most commonly administered via a transdermal patch that is worn on the skin. Oral forms are available, but considerably less common (notably orally-disintegrating tablets and even a narcotic sucker). Fentanyl is very potent, and must be used in small doses--25 micrograms (or 0.025 mg) of fentanyl per hour over a 24-hour period is recommended for patients taking between 60 and 134 milligrams of oral morphine per day. Fentanyl should not even be initiated in patients taking less than this--for comparison's sake, 60 mg of morphine is equivalent to 30 mg of oxycodone. Your standard Percocet tablet has 5 mg of oxycodone per tablet.
I may be belaboring the point. In any case, fentanyl is potent stuff. It takes very little fentanyl to match an equivalent dose of some other opioid painkiller.
Prescribing fentanyl for patients with anything less than chronic pain due to cancer or long-term injuries is irresponsible. The package insert itself says that using fentanyl patches for short-term pain is a mistake. Physicians prescribing the patches for patients with headaches are only part of the problem; there are no statistics available, as far as I can tell, but I'm willing to bet that much of the problem not misprescribing of fentanyl. The problem is misuse. Not in the sense of drug abuse, but rather in the sense of improper administration of the patches. Heating pads are a popular means of relieving chronic pain. But putting a heating pad over a fentanyl patch will dramatically increase the rate of transfer from the patch into the patient's bloodstream, potentially resulting in death when the patient's central nervous system stops triggering the breathing reflex. Patients who slap on a patch and then get into a hot tub may not get out.
An interesting issue is that transdermal patches must contain much more active ingredient than is to be delivered to the patient because the rate of transfer from the patch to the bloodstream is dependent on the difference between drug in the skin and drug in the patch. In short, a patch that only delivers 0.025 mg per hour may have to contain 3 mg of total drug to keep the flow moving. This means that a "used" patch still contains a lot of drug, and improper disposal of the patch can result in children or animals getting ahold of a lot of "leftover" fentanyl--easily fatal, should the patch be chewed or torn.
These deaths are so preventable it's ridiculous. A little patient education about the proper use and disposal of fentanyl would have saved nearly everyone involved. This is the task set before pharmacists. This is the value of proper patient counseling. Like all drugs, fentanyl has risks. But the risks can be minimized if patients are properly informed. Counseling for such drugs should be legally mandated--and furthermore, drugstores should be required to give pharmacists the time and staffing to perform the task adequately. These deaths aren't the fault of pharma. They're due to ignorance and irresponsibility. Pharmacists need to educate their patients--and patients need to pay attention instead of quacking away on cellphones while they sign the pick-up log for their fentanyl patches.
If in two weeks I have to read another article about fentanyl patches for the fourth month in a row I'm going to go crazy.
Saturday, December 1, 2007
Take a Deep Breath
The FDA is currently re-evaluating warnings on long-acting beta-agonist drugs used for asthma. This isn't the first time that the subject has come up. It made the news way back in 2003 and was discussed again in 2005. What's the deal?
Beta-agonist drugs stimulate part of the body's autonomic nervous system, or ANS. The ANS is responsible for managing many body functions, some of which are unconscious and others which are conscious. The ANS is further subdivided into the sympathetic and the parasympathetic systems. Put simply, the sympathetic nervous system is associated with the "fight or flight" response; for example, stimulation results in an increase in heart rate. The parasympathetic nervous system is associated with the "rest and digest" response. Among other things, stimulation results in increased movement of the musculature of the stomach and bowels and salivation.
One of the reactions associated with "fight or flight" is the widening of the bronchial tubes, the cartilaginous passageways through the lungs that carry air. Because the sympathetic nervous system receptors on the bronchi are different from those on the heart or the skeletal muscle, it is possibly to stimulate them selectively. These receptors are called "beta-2" receptors, and an agonist is a drug that stimulates a response; therefore, selective beta-2 agonists stimulate only the bronchi, dilating them and making it easier for patients to breathe without simultaneously increasing the heart rate. In asthma, the bronchi become inflamed and constrict, making breathing considerably more difficult, especially during periods of exercise or physical activity.
The most well-known beta-2 agonist is probably albuterol, staple of asthmatics of all ages. If you were ever on a sports team as a kid or even just played outdoors you probably knew at least one person who used an albuterol inhaler. Albuterol is an excellent drug, and it works quickly but its duration of action is relatively short--about six hours. Six hours may sound like a lot, but most people need to breathe all the time. Patients with asthma who find themselves gasping every time their albuterol starts to wear off may find themselves in serious trouble, and shortness of breath can be very scary.
So pharmaceutical chemists developed drugs that work the same way as albuterol, but that would have a longer duration of action. Serevent is one of them. Advair is much more commonly prescribed; it combines salmeterol, the long-acting beta-2 agonist in Serevent, with an inhaled corticosteroid for further bronchodilation and relief of asthma-related inflammation. Before long-acting beta-2 agonists became available, inhaled corticosteroids were the first option for long-term control of asthma symptoms. Salmeterol even has a neat pharmaceutical mechanism; it is structurally similar to albuterol, but has a long chemical "tail" that embeds itself in cell surfaces, resulting in very slow release of the drug to its site of action.
Logically, it seems like salmeterol should be just like albuterol, only better.
A 28-week placebo-controlled study conducted in 1996 in the U.S. (the SMART study) suggested that patients on long-acting beta-2 agonists actually had more asthma related deaths than those on placebos. However, the increase in deaths was not statistically significant in the Caucasian participants in the study--and they made up 71% of the study's population of 25,858 patients. African Americans made up the second-largest group at 17%, and while the number of deaths in African Americans was statistically significant, only 1% of African Americans enrolled in the study suffered an asthma-related death. This could be attributed to the smaller sample size; the study was not designed to provide strong data about possible differences in drug effect between ethnic groups.
So what's going on? Is salmeterol killing people? Is it an ineffective drug? This "salmeterol paradox" is certainly strange. The whole purpose of long-acting beta-2 agonists was to add another option to improve long-term control of asthma. Researchers at Cornell suggest that using long-acting beta-2 agonists may ultimately worsen underlying inflammation and increase "bronchial hyper-responsiveness." Some other data suggests that use of salmeterol causes roughly five deaths per year.
I, of course, really don't know for sure. What I do know is that the statistics here look kind of funny. The FDA has to be conservative in its rulings; some evidence of risk is good enough for them to put a warning on a drug to cover their backs. But in nearly three-quarters of the sample group the number of deaths due to asthma-related causes was not statistically significant. What other factors might cause an increase in asthma-related deaths?
Well, the patients on salmeterol obviously have worse asthma than those who can manage with nothing more than an albuterol inhaler. The SMART study also mentions that deaths were higher in patients taking salmeterol but not taking an inhaled steroid. Er. This doesn't necessarily strike me as a "blame salmeterol" situation. Again, wouldn't patients requiring a steroid in addition to both long and short-acting beta agonists to get control of their asthma obviously be the worst off? The need for salmeterol and other drugs in its class is an indication in itself that the patient's condition is deteriorating.
I'm not convinced by the SMART study or any of the follow-up research that I've seen that long-acting beta-agonists are the cause of asthma-related deaths. More robust studies are going to be required to weed out other possible underlying causes. The real question, then, is whether anyone is going to bother to do them.
Beta-agonist drugs stimulate part of the body's autonomic nervous system, or ANS. The ANS is responsible for managing many body functions, some of which are unconscious and others which are conscious. The ANS is further subdivided into the sympathetic and the parasympathetic systems. Put simply, the sympathetic nervous system is associated with the "fight or flight" response; for example, stimulation results in an increase in heart rate. The parasympathetic nervous system is associated with the "rest and digest" response. Among other things, stimulation results in increased movement of the musculature of the stomach and bowels and salivation.
One of the reactions associated with "fight or flight" is the widening of the bronchial tubes, the cartilaginous passageways through the lungs that carry air. Because the sympathetic nervous system receptors on the bronchi are different from those on the heart or the skeletal muscle, it is possibly to stimulate them selectively. These receptors are called "beta-2" receptors, and an agonist is a drug that stimulates a response; therefore, selective beta-2 agonists stimulate only the bronchi, dilating them and making it easier for patients to breathe without simultaneously increasing the heart rate. In asthma, the bronchi become inflamed and constrict, making breathing considerably more difficult, especially during periods of exercise or physical activity.
The most well-known beta-2 agonist is probably albuterol, staple of asthmatics of all ages. If you were ever on a sports team as a kid or even just played outdoors you probably knew at least one person who used an albuterol inhaler. Albuterol is an excellent drug, and it works quickly but its duration of action is relatively short--about six hours. Six hours may sound like a lot, but most people need to breathe all the time. Patients with asthma who find themselves gasping every time their albuterol starts to wear off may find themselves in serious trouble, and shortness of breath can be very scary.
So pharmaceutical chemists developed drugs that work the same way as albuterol, but that would have a longer duration of action. Serevent is one of them. Advair is much more commonly prescribed; it combines salmeterol, the long-acting beta-2 agonist in Serevent, with an inhaled corticosteroid for further bronchodilation and relief of asthma-related inflammation. Before long-acting beta-2 agonists became available, inhaled corticosteroids were the first option for long-term control of asthma symptoms. Salmeterol even has a neat pharmaceutical mechanism; it is structurally similar to albuterol, but has a long chemical "tail" that embeds itself in cell surfaces, resulting in very slow release of the drug to its site of action.
Logically, it seems like salmeterol should be just like albuterol, only better.
A 28-week placebo-controlled study conducted in 1996 in the U.S. (the SMART study) suggested that patients on long-acting beta-2 agonists actually had more asthma related deaths than those on placebos. However, the increase in deaths was not statistically significant in the Caucasian participants in the study--and they made up 71% of the study's population of 25,858 patients. African Americans made up the second-largest group at 17%, and while the number of deaths in African Americans was statistically significant, only 1% of African Americans enrolled in the study suffered an asthma-related death. This could be attributed to the smaller sample size; the study was not designed to provide strong data about possible differences in drug effect between ethnic groups.
So what's going on? Is salmeterol killing people? Is it an ineffective drug? This "salmeterol paradox" is certainly strange. The whole purpose of long-acting beta-2 agonists was to add another option to improve long-term control of asthma. Researchers at Cornell suggest that using long-acting beta-2 agonists may ultimately worsen underlying inflammation and increase "bronchial hyper-responsiveness." Some other data suggests that use of salmeterol causes roughly five deaths per year.
I, of course, really don't know for sure. What I do know is that the statistics here look kind of funny. The FDA has to be conservative in its rulings; some evidence of risk is good enough for them to put a warning on a drug to cover their backs. But in nearly three-quarters of the sample group the number of deaths due to asthma-related causes was not statistically significant. What other factors might cause an increase in asthma-related deaths?
Well, the patients on salmeterol obviously have worse asthma than those who can manage with nothing more than an albuterol inhaler. The SMART study also mentions that deaths were higher in patients taking salmeterol but not taking an inhaled steroid. Er. This doesn't necessarily strike me as a "blame salmeterol" situation. Again, wouldn't patients requiring a steroid in addition to both long and short-acting beta agonists to get control of their asthma obviously be the worst off? The need for salmeterol and other drugs in its class is an indication in itself that the patient's condition is deteriorating.
I'm not convinced by the SMART study or any of the follow-up research that I've seen that long-acting beta-agonists are the cause of asthma-related deaths. More robust studies are going to be required to weed out other possible underlying causes. The real question, then, is whether anyone is going to bother to do them.
Saturday, November 17, 2007
My Drug Can Beat Up Your Drug
Abel Pharmboy's post about GSK intimidating doctors makes a recent development all the more darkly humorous.
Apparently, Takeda Pharmaceuticals, the company that makes Actos, is going to go on an advertising spree informing patients how safe it is. More precisely, they're making a point to tell you that, according to at least one study, it doesn't increase the risk of heart attacks or strokes. You know, in all fairness, the black box warning doesn't say anything about heart attacks or strokes--strictly speaking, it's about congestive heart failure, in which the heart is unable to pump sufficient blood to keep up with the needs of the body. And while it's true that Avandia and Actos have different effects on patient lipids, with Actos having a more favorable effect on HDL and triglycerides, the mechanism by which thiazolidinediones (the class of drugs to which Avandia and Actos both belong) increase the risk of heart failure is more likely related to the fact that they cause fluid retention and edema--which has nothing to do with lipid levels.
And even if Takeda did dig up a study saying that the overall risk of mortality for patients on Actos was better, turning it into a direct-to-consumer full-page newspaper ad is just crass. I expect this kind of mudslinging in politics, but in medicine?
Apparently, Takeda Pharmaceuticals, the company that makes Actos, is going to go on an advertising spree informing patients how safe it is. More precisely, they're making a point to tell you that, according to at least one study, it doesn't increase the risk of heart attacks or strokes. You know, in all fairness, the black box warning doesn't say anything about heart attacks or strokes--strictly speaking, it's about congestive heart failure, in which the heart is unable to pump sufficient blood to keep up with the needs of the body. And while it's true that Avandia and Actos have different effects on patient lipids, with Actos having a more favorable effect on HDL and triglycerides, the mechanism by which thiazolidinediones (the class of drugs to which Avandia and Actos both belong) increase the risk of heart failure is more likely related to the fact that they cause fluid retention and edema--which has nothing to do with lipid levels.
And even if Takeda did dig up a study saying that the overall risk of mortality for patients on Actos was better, turning it into a direct-to-consumer full-page newspaper ad is just crass. I expect this kind of mudslinging in politics, but in medicine?
Friday, November 9, 2007
Marketing and Medicine: Part Two
Last entry, I mentioned that there are at least 14 different formulations produced with the Tylenol brand name to help treat cough, cold, and flu symptoms. Here's a piece of valuable information. There aren't anywhere near 14 different drug ingredients on the market for cough, cold, and flu.
Any pharmacist can tell you that all these products are just rehashings and reformulations of the same five or six different drugs in different combinations with fancy new labels. And Tylenol isn't the only corporation using this strategy; they all are. Pfizer has half a dozen different Sudafed products to capitalize on the popularity of the brand. Wyeth's Robitussin is the same deal.
There are five big drug classes used to treat cold and flu symptoms: Pain relievers/fever reducers, antihistamines, decongestants, cough suppressants, and expectorants. Most of the multi-symptom cold products contain Tylenol, otherwise known as acetaminophen, as a pain-reliever and fever reducer. You'll see a lot more combination products with acetaminophen than you will other pain relievers like ibuprofen because acetaminophen has fewer gastrointestinal side-effects and isn't as likely to interact with other medications. And no matter how many different "cough" products you see marketed, there are only two FDA-approved "cough" ingredients commonly available OTC, those being dextromethorphan and guaifenesin. Dextromethorphan is a cough suppressant available in a wide variety of products, commonly those tagged with "DM," like Mucinex-DM, but you'll rarely find it by itself. Guaifenesin is an expectorant, which thins secretions in the lungs and chest to make them easier to cough up.
The attentive reader (or those living outside the U.S.) will note that I didn't mention codeine, because getting codeine cough syrup without a prescription in the States is practically impossible because of how much paperwork and hassle is involved in selling it. It's more abusable, honestly doesn't work any better than dextromethorphan, and a huge pain in the ass for both pharmacists and the chains they work for.
So no matter how many cough medicines are on the shelves, they all contain more or less the same thing in different boxes. And it doesn't matter what the box looks like; all that matters are the active ingredients listed on the back.
My personal favorite "misleading" branding/packaging in the Tylenol line is either Tylenol Sore Throat liquid or Tylenol Severe Allergy. The sore throat liquid is a great source of amusement for me because Tylenol itself is an excellent treatment for a sore throat; there's no need to add anything else to it. But many people think that medication for a sore throat or to stop a cough needs to be a liquid so that it can coat the throat. This is totally false. Liquids might have a soothing effect on the throat, such as hot tea, but as long as the acetaminophen dosage is the same, it doesn't matter whether you drink it or swallow a tablet. It's all going into your bloodstream before it does any real work, although the liquid might theoretically work slightly faster because liquids are absorbed more quickly. That has more to do with what goes on in your intestinal tract than anything involving your throat.
The "severe allergy" product amuses me because the only ingredient in the product that will do anything to reverse an allergic reaction is diphenhydramine, otherwise known as Benadryl. If you're having a truly "severe" allergic reaction, you need an EpiPen or steroids like prednisone. Benadryl is just not going to cut it.
Combination products with three or four different ingredients are a "shotgun" approach to symptoms. True, you're probably covering all the potential problems, but you're also probably taking at least one medication that you don't need. Tylenol PM is my least favorite product on the pharmacy shelf; it's a combination of acetaminophen and diphenhydramine. Acetaminophen, flat-out, does not cause drowsiness. It plays absolutely no role in helping you sleep. It's the diphenhydramine that knocks many people out. Again with the Benadryl. I always tell people looking for the Tylenol PM to get a box of generic diphenhydramine instead. It's going to have the exact same effect, it's cheaper, and you're not taking unnecessary acetaminophen, which can be toxic to the liver. True, most people aren't going to even approach a toxic dose of acetaminophen by taking Tylenol PM, but if you start combining cold products without reading the labels it's pretty easy to approach the 4 grams/day limit. The manufacturers know this, too, which is why a lot of packaging carries text that says "acetaminophen warning" now.
So be pharmsavvy and ignore the front of the box. Flip it around, check the ingredients, and ask your pharmacist for help selecting individual products for specific symptoms instead of assuming that just because something says "cold and flu" that it's the magic remedy you're looking for.
Any pharmacist can tell you that all these products are just rehashings and reformulations of the same five or six different drugs in different combinations with fancy new labels. And Tylenol isn't the only corporation using this strategy; they all are. Pfizer has half a dozen different Sudafed products to capitalize on the popularity of the brand. Wyeth's Robitussin is the same deal.
There are five big drug classes used to treat cold and flu symptoms: Pain relievers/fever reducers, antihistamines, decongestants, cough suppressants, and expectorants. Most of the multi-symptom cold products contain Tylenol, otherwise known as acetaminophen, as a pain-reliever and fever reducer. You'll see a lot more combination products with acetaminophen than you will other pain relievers like ibuprofen because acetaminophen has fewer gastrointestinal side-effects and isn't as likely to interact with other medications. And no matter how many different "cough" products you see marketed, there are only two FDA-approved "cough" ingredients commonly available OTC, those being dextromethorphan and guaifenesin. Dextromethorphan is a cough suppressant available in a wide variety of products, commonly those tagged with "DM," like Mucinex-DM, but you'll rarely find it by itself. Guaifenesin is an expectorant, which thins secretions in the lungs and chest to make them easier to cough up.
The attentive reader (or those living outside the U.S.) will note that I didn't mention codeine, because getting codeine cough syrup without a prescription in the States is practically impossible because of how much paperwork and hassle is involved in selling it. It's more abusable, honestly doesn't work any better than dextromethorphan, and a huge pain in the ass for both pharmacists and the chains they work for.
So no matter how many cough medicines are on the shelves, they all contain more or less the same thing in different boxes. And it doesn't matter what the box looks like; all that matters are the active ingredients listed on the back.
My personal favorite "misleading" branding/packaging in the Tylenol line is either Tylenol Sore Throat liquid or Tylenol Severe Allergy. The sore throat liquid is a great source of amusement for me because Tylenol itself is an excellent treatment for a sore throat; there's no need to add anything else to it. But many people think that medication for a sore throat or to stop a cough needs to be a liquid so that it can coat the throat. This is totally false. Liquids might have a soothing effect on the throat, such as hot tea, but as long as the acetaminophen dosage is the same, it doesn't matter whether you drink it or swallow a tablet. It's all going into your bloodstream before it does any real work, although the liquid might theoretically work slightly faster because liquids are absorbed more quickly. That has more to do with what goes on in your intestinal tract than anything involving your throat.
The "severe allergy" product amuses me because the only ingredient in the product that will do anything to reverse an allergic reaction is diphenhydramine, otherwise known as Benadryl. If you're having a truly "severe" allergic reaction, you need an EpiPen or steroids like prednisone. Benadryl is just not going to cut it.
Combination products with three or four different ingredients are a "shotgun" approach to symptoms. True, you're probably covering all the potential problems, but you're also probably taking at least one medication that you don't need. Tylenol PM is my least favorite product on the pharmacy shelf; it's a combination of acetaminophen and diphenhydramine. Acetaminophen, flat-out, does not cause drowsiness. It plays absolutely no role in helping you sleep. It's the diphenhydramine that knocks many people out. Again with the Benadryl. I always tell people looking for the Tylenol PM to get a box of generic diphenhydramine instead. It's going to have the exact same effect, it's cheaper, and you're not taking unnecessary acetaminophen, which can be toxic to the liver. True, most people aren't going to even approach a toxic dose of acetaminophen by taking Tylenol PM, but if you start combining cold products without reading the labels it's pretty easy to approach the 4 grams/day limit. The manufacturers know this, too, which is why a lot of packaging carries text that says "acetaminophen warning" now.
So be pharmsavvy and ignore the front of the box. Flip it around, check the ingredients, and ask your pharmacist for help selecting individual products for specific symptoms instead of assuming that just because something says "cold and flu" that it's the magic remedy you're looking for.
Thursday, November 8, 2007
Marketing and Medicine: Part One
Brand recognition is a huge part of the American shopping experience. We frequently buy things based solely on whose name is on the package. A study I read a while back suggested that children ages 3 to 5 reported food in McDonald's wrappers tasted better, even if the food was identical to food in plain wrappers or the food--carrot sticks, for example--wasn't served at McDonald's.
This creates a huge problem when it comes to self-medication.
The aisles of your typical community corpo-pharmcy are well-stocked with a plethora of available options. Colorful boxes with household names like Tylenol, Advil, Sudafed, Mucinex and Robitussin stand out amongst less well-marketed remedies like Chlor-Trimeton. The average American consumer cannot be expected to remember each and every ingredient that goes into typical OTC products, so they rely on friendly packaging to tell them what to buy. The Tylenol brand alone has a dizzying number of spin-offs: Tylenol Allergy, Tylenol Sinus Congestion and Pain, Tylenol Chest Congestion, Tylenol Cold Multi-symptom, Tylenol PM, Tylenol Sore Throat Daytime, Tylenol Sore Throat Nighttime, Tylenol Cough and Sore Throat Daytime...according to the Tylenol website, the Tylenol corporation manufacturs 14 products to treat cough, cold and flu symptoms in adults. And that's just a sample.
The problem is that what's on the front of the label has nothing to do with what's in the medication.
I think the best example is Pepto-Bismol. Pepto-Bismol is one of those ubiquitous drugs that some people just love to death. It is often touted as the cure for every possible source of nausea known to man, hangovers, heartburn, diarrhea, intestinal abuse by five-alarm chili, and jock itch. I even managed to find a blogger talking about making Pepto-Bismol ice cream as his ultimate remedy for "the morning after."
In case it weren't obvious, I was joking about the jock itch.
Pepto-Bismol, if you've been living in a cave with no television for the past several decades, is a thick, pink liquid that contains an ingredient called bismuth subsalicylate, or BSS for short. BSS is a pretty interesting drug in that scientists aren't entirely sure how it works for some of its purposes; the stomach-soothing effects are mediated by affecting gastrointestinal mucosal linings, for example, but the heartburn effects are less well-understood. It also comes in a chewable tablet form for those who dislike having to chug the more traditional form of the pink stuff; it's also a whole lot more convenient for travelling, unless you really like carrying an 8-ounce bottle of pink goo.
Then there's Children's Pepto. The packaging for Children's Pepto is very similar to the regular Pepto, though it only comes in chewable tablet form. Children's Pepto doesn't contain BSS at all. In fact, Children's Pepto contains calcium carbonate, which, aside from being a mainstay of blackboards across the globe, is the acid-neutralizing compound found in Tums and Rolaids. It isn't chemically related to BSS at all, and it doesn't have nearly the same versatility; unlike BSS, Children's Pepto isn't going to do anything for diarrhea, for example.
The issue is not that Children's Pepto contains an "inferior" ingredient. The issue is that regular Pepto's BSS is a salicylate, like aspirin. And use of salicylates in children is linked to the development of Reye's syndrome, a life-threatening neurological disorder.
Pepto-Bismol has plenty of warnings on the back telling you not to give it to children--if you read the fine print. But it's an easy mistake for a parent to make, given the fact that brand recognition, not the drug facts on the back label, is what motivates most people to make their OTC purchases in the first place. Children's Tylenol is still Tylenol, but at a lower dose; it's easy to see why someone might assume the same is true for Pepto-Bismol, a drug commonly thought to be totally harmless, and administer it to their child.
So pay absolutely zero attention to what's on the front of a medication label. Turn it around and read the back. Read it closely. Check the active ingredients. And if you're uncertain in the least whether or not a product is right for you, ask your pharmacist. That's what they're for.
This creates a huge problem when it comes to self-medication.
The aisles of your typical community corpo-pharmcy are well-stocked with a plethora of available options. Colorful boxes with household names like Tylenol, Advil, Sudafed, Mucinex and Robitussin stand out amongst less well-marketed remedies like Chlor-Trimeton. The average American consumer cannot be expected to remember each and every ingredient that goes into typical OTC products, so they rely on friendly packaging to tell them what to buy. The Tylenol brand alone has a dizzying number of spin-offs: Tylenol Allergy, Tylenol Sinus Congestion and Pain, Tylenol Chest Congestion, Tylenol Cold Multi-symptom, Tylenol PM, Tylenol Sore Throat Daytime, Tylenol Sore Throat Nighttime, Tylenol Cough and Sore Throat Daytime...according to the Tylenol website, the Tylenol corporation manufacturs 14 products to treat cough, cold and flu symptoms in adults. And that's just a sample.
The problem is that what's on the front of the label has nothing to do with what's in the medication.
I think the best example is Pepto-Bismol. Pepto-Bismol is one of those ubiquitous drugs that some people just love to death. It is often touted as the cure for every possible source of nausea known to man, hangovers, heartburn, diarrhea, intestinal abuse by five-alarm chili, and jock itch. I even managed to find a blogger talking about making Pepto-Bismol ice cream as his ultimate remedy for "the morning after."
In case it weren't obvious, I was joking about the jock itch.
Pepto-Bismol, if you've been living in a cave with no television for the past several decades, is a thick, pink liquid that contains an ingredient called bismuth subsalicylate, or BSS for short. BSS is a pretty interesting drug in that scientists aren't entirely sure how it works for some of its purposes; the stomach-soothing effects are mediated by affecting gastrointestinal mucosal linings, for example, but the heartburn effects are less well-understood. It also comes in a chewable tablet form for those who dislike having to chug the more traditional form of the pink stuff; it's also a whole lot more convenient for travelling, unless you really like carrying an 8-ounce bottle of pink goo.
Then there's Children's Pepto. The packaging for Children's Pepto is very similar to the regular Pepto, though it only comes in chewable tablet form. Children's Pepto doesn't contain BSS at all. In fact, Children's Pepto contains calcium carbonate, which, aside from being a mainstay of blackboards across the globe, is the acid-neutralizing compound found in Tums and Rolaids. It isn't chemically related to BSS at all, and it doesn't have nearly the same versatility; unlike BSS, Children's Pepto isn't going to do anything for diarrhea, for example.
The issue is not that Children's Pepto contains an "inferior" ingredient. The issue is that regular Pepto's BSS is a salicylate, like aspirin. And use of salicylates in children is linked to the development of Reye's syndrome, a life-threatening neurological disorder.
Pepto-Bismol has plenty of warnings on the back telling you not to give it to children--if you read the fine print. But it's an easy mistake for a parent to make, given the fact that brand recognition, not the drug facts on the back label, is what motivates most people to make their OTC purchases in the first place. Children's Tylenol is still Tylenol, but at a lower dose; it's easy to see why someone might assume the same is true for Pepto-Bismol, a drug commonly thought to be totally harmless, and administer it to their child.
So pay absolutely zero attention to what's on the front of a medication label. Turn it around and read the back. Read it closely. Check the active ingredients. And if you're uncertain in the least whether or not a product is right for you, ask your pharmacist. That's what they're for.
Wednesday, November 7, 2007
Irrational Exuberance
Alan Greenspan, former Federal Reserve Chairman, used the phrase "irrational exuberance" to refer to a kind of overenthusiasm for the market during an economic boom; notably, he only used it once, and there was a worldwide plummet in stock prices following that speech, but I think it's an appropriate term to refer to something that I've thought about quite a bit.
I love the drug companies. I really do. We've come a long way in the past 50 years in terms of effective pharmacological treatments for illnesses across a broad spectrum because of dedicated scientists and researchers working to develop the next blockbuster drug. These companies really are doing the public a great service. Just to throw out an example, cholesterol-lowering statin drugs are estimated to have saved 83,000 lives in the last 20 years. Most people nowadays die of heart disease or cancer instead of typhoid and diphtheria, and the death rate due to coronary artery disease in the U.S. has dropped 25% since 1994.
The drug companies are providing a valuable service. And like any other service, we have to pay for it. I don't think that's wrong, really, because pharmaceutical research companies have to make money too. It's not a crime to want to make money, especially if you've invented or discovered something useful, whether it's a rubber O-ring that holds together mechanical parts better than existing joint fasteners or a tiny carbon-based compound that relieves migraines. Of course pharma is "in it for the money." They have to eat, too. If I didn't get paid to do my job, I'd quit. I sincerely doubt you can find anyone who's willing to work for free full-time, no matter what field we're talking about.
What I don't like is when they're being dishonest about it.
I don't mean dishonesty that they're trying to hide. I can't do anything if Lilly or Glaxo or Roche or whoever is committing tax fraud or exploiting weird financial loopholes to widen their profit margins, and while I do care about it, it's outside my area of expertise. I'll leaave that to the lawyers and the accountants to scrutinize. No, what drives me nuts is when pharma is talking about their latest product like it's the greatest invention since the wheel when in fact it's about as useful as most of the gadgets you see on late-night infomercials.
Usually this sort of thing comes up when a company is about to lose their patent on a drug, at which point they attempt to extend the life of their branded drug entity by rolling out products with new release mechanisms (Coreg vs. Coreg CR, for example) or "follow-on" drugs that are actually derivatives of the original drug molecule. The drug Celexa is a great example--Celexa's generic name is "citalopram." It's an antidepressant. Like many drugs, its structure is complex enough that the "mirror image" of that structure is not the same compound. Essentially, at least one set of chemical functional groups is "reversed" in its rotational arrangement in three-dimensional space. This is really kind of complicated, so here's a way better link to explain what I'm takling about:
Someone else can teach you organic chemistry.
Usually, the left-rotating and right-rotating compounds get designated as L (levo, or left) or D (dextro, or right) enantiomers of a substance. Sometimes the letter S is used, for the Latin word for left ("sinister").
Anyway, Celexa as a drug is a 50/50 mixture of both S-citalopram and R-citalopram. Some pharmaceutical chemists playing around in the lab figured out that the S-citalopram is the part that's doing the real work, so some time later they decided to develop a way to just synthesize the pure S-form (which is harder, incidentally) and marketed the new drug as "escitalopram." Say it aloud. Cute name, no?
Escitalopram is available in dosages that are half of what Celexa comes in--Celexa tablets come 10, 20, and 40 mg. Escitalopram tablets are 5, 10, and 20 mg. The theory is that by getting rid of that R-form and dosing the patient with only the pure S-form you end up with fewer side-effects or better efficacy. Sometimes that's true. Sometimes it isn't.
Escitalopram, for the curious, is the popular antidepressant Lexapro. By purifying the S-form from what chemists call the "racemic mixture" (the 50/50 mix of both forms), Forest Pharmaceuticals gets to call what they've cooked up a "new drug" and has an exclusive patent on their creation for about the next 20 years. Joy! Studies do suggest that Lexapro works a little better than Celexa, and that it's slightly better tolerated, but it's also pricier because it's currently brand-name-only: $80.31 for 30 tablets of the 10 mg strength vs $39.99 for the roughly equivalent generic citalopram 20 mg tablets. It might be worth the difference. It might not. The drug companies really want you to think it is, and they tell doctors that Lexapro is way, way better than Celexa, because it's about twice as expensive. They tell pharmacists that it's better, too, and occasionally bother to produce the graphs that prove it. And pharma is really big on phrases like "not equivalent" when they're comparing their new drugs or dosage forms to old drugs or dosage forms. They insist very strongly that the drugs are not the same, and woe to any pharmacist who dares suggest the older drug is just as good as the new one. Some patients will ultimately try both and like one or the other better. That's cool for them.
I don't appreciate pharma sending a rep into our store to talk about how Lexapro is so much better than generic citalopram that any effort to inform patients that yes, there are generic antidepressants that are cheaper (if you would like to save money) is tantamount to blasphemy. How dare you compare their superior product to the clearly inferior generic products on the market, even those that their company also makes! Their newest branded product is a bargain at ten times the price, even if it's only 5% better than the generic!
The Forest Pharmaceuticals rep who came into our store gave us the schpiel about Lexapro being awesome, but that bothered me a lot less than his pitch for Namenda. He vehemently expressed his opinion that Namenda was the coolest thing in the entire world because "the evidence is so strong for it. I always ask all the doctors who I talk to if they would want the opportunity to add Namenda to their drug regimen if they had Alzheimer's, and they always say, 'well, yes, I would.'"
Background. Namenda is a drug to treat Alzheimer's disease. Wait, I take that back. It's a drug to prevent Alzheimer's disease from getting worse. Wait, no, that's not really true either. It's a drug to make Alzheimer's disease get worse more slowly. That's about right.
The other big drug on the market for Alzheimer's management is called Aricept. You start a patient on Aricept as soon as you suspect they have Alzheimer's, because it works best in mild to moderate cases, but if you don't catch it for some reason, it can work in more severe cases. One study showed an improvement or stabilization of cognitive function in 63% of patients taking it (versus 39% on placebo, not terrible). It's worth a shot to put a patient on Aricept because it's about the best we can do right now.
However, the rep was trying to convince us that Aricept plus Namenda was vastly superior to Aricept alone, saying that there was a whole wealth of evidence available.
The information I've found suggests that the gains on cognitive function scales for treatment with Namenda are roughly a 5% absolute increase. OH MAN. We're still looking at only marginal improvement no matter how we approach drug therapy for Alzheimer's disease. This is totally worth spending an extra $1600 in prescription drug costs a year, considering that Aricept costs about $1700 a year by itself, excluding medical insurance. Behold the power of sarcasm.
Don't come to me and tell me how awesome your drug is unless you're prepared to prove it. And if your drug really isn't all that awesome, quit telling me how awesome it is. The FDA may have approved it because you demonstrated it was better than placebo with studies that showed statististical significance, but don't hype it up when we're talking about 5% absolute gains. I realize that it's the job of people who do marketing to get way more excited about their products than is rational, but this is medicine. That just won't do here.
I love the drug companies. I really do. We've come a long way in the past 50 years in terms of effective pharmacological treatments for illnesses across a broad spectrum because of dedicated scientists and researchers working to develop the next blockbuster drug. These companies really are doing the public a great service. Just to throw out an example, cholesterol-lowering statin drugs are estimated to have saved 83,000 lives in the last 20 years. Most people nowadays die of heart disease or cancer instead of typhoid and diphtheria, and the death rate due to coronary artery disease in the U.S. has dropped 25% since 1994.
The drug companies are providing a valuable service. And like any other service, we have to pay for it. I don't think that's wrong, really, because pharmaceutical research companies have to make money too. It's not a crime to want to make money, especially if you've invented or discovered something useful, whether it's a rubber O-ring that holds together mechanical parts better than existing joint fasteners or a tiny carbon-based compound that relieves migraines. Of course pharma is "in it for the money." They have to eat, too. If I didn't get paid to do my job, I'd quit. I sincerely doubt you can find anyone who's willing to work for free full-time, no matter what field we're talking about.
What I don't like is when they're being dishonest about it.
I don't mean dishonesty that they're trying to hide. I can't do anything if Lilly or Glaxo or Roche or whoever is committing tax fraud or exploiting weird financial loopholes to widen their profit margins, and while I do care about it, it's outside my area of expertise. I'll leaave that to the lawyers and the accountants to scrutinize. No, what drives me nuts is when pharma is talking about their latest product like it's the greatest invention since the wheel when in fact it's about as useful as most of the gadgets you see on late-night infomercials.
Usually this sort of thing comes up when a company is about to lose their patent on a drug, at which point they attempt to extend the life of their branded drug entity by rolling out products with new release mechanisms (Coreg vs. Coreg CR, for example) or "follow-on" drugs that are actually derivatives of the original drug molecule. The drug Celexa is a great example--Celexa's generic name is "citalopram." It's an antidepressant. Like many drugs, its structure is complex enough that the "mirror image" of that structure is not the same compound. Essentially, at least one set of chemical functional groups is "reversed" in its rotational arrangement in three-dimensional space. This is really kind of complicated, so here's a way better link to explain what I'm takling about:
Someone else can teach you organic chemistry.
Usually, the left-rotating and right-rotating compounds get designated as L (levo, or left) or D (dextro, or right) enantiomers of a substance. Sometimes the letter S is used, for the Latin word for left ("sinister").
Anyway, Celexa as a drug is a 50/50 mixture of both S-citalopram and R-citalopram. Some pharmaceutical chemists playing around in the lab figured out that the S-citalopram is the part that's doing the real work, so some time later they decided to develop a way to just synthesize the pure S-form (which is harder, incidentally) and marketed the new drug as "escitalopram." Say it aloud. Cute name, no?
Escitalopram is available in dosages that are half of what Celexa comes in--Celexa tablets come 10, 20, and 40 mg. Escitalopram tablets are 5, 10, and 20 mg. The theory is that by getting rid of that R-form and dosing the patient with only the pure S-form you end up with fewer side-effects or better efficacy. Sometimes that's true. Sometimes it isn't.
Escitalopram, for the curious, is the popular antidepressant Lexapro. By purifying the S-form from what chemists call the "racemic mixture" (the 50/50 mix of both forms), Forest Pharmaceuticals gets to call what they've cooked up a "new drug" and has an exclusive patent on their creation for about the next 20 years. Joy! Studies do suggest that Lexapro works a little better than Celexa, and that it's slightly better tolerated, but it's also pricier because it's currently brand-name-only: $80.31 for 30 tablets of the 10 mg strength vs $39.99 for the roughly equivalent generic citalopram 20 mg tablets. It might be worth the difference. It might not. The drug companies really want you to think it is, and they tell doctors that Lexapro is way, way better than Celexa, because it's about twice as expensive. They tell pharmacists that it's better, too, and occasionally bother to produce the graphs that prove it. And pharma is really big on phrases like "not equivalent" when they're comparing their new drugs or dosage forms to old drugs or dosage forms. They insist very strongly that the drugs are not the same, and woe to any pharmacist who dares suggest the older drug is just as good as the new one. Some patients will ultimately try both and like one or the other better. That's cool for them.
I don't appreciate pharma sending a rep into our store to talk about how Lexapro is so much better than generic citalopram that any effort to inform patients that yes, there are generic antidepressants that are cheaper (if you would like to save money) is tantamount to blasphemy. How dare you compare their superior product to the clearly inferior generic products on the market, even those that their company also makes! Their newest branded product is a bargain at ten times the price, even if it's only 5% better than the generic!
The Forest Pharmaceuticals rep who came into our store gave us the schpiel about Lexapro being awesome, but that bothered me a lot less than his pitch for Namenda. He vehemently expressed his opinion that Namenda was the coolest thing in the entire world because "the evidence is so strong for it. I always ask all the doctors who I talk to if they would want the opportunity to add Namenda to their drug regimen if they had Alzheimer's, and they always say, 'well, yes, I would.'"
Background. Namenda is a drug to treat Alzheimer's disease. Wait, I take that back. It's a drug to prevent Alzheimer's disease from getting worse. Wait, no, that's not really true either. It's a drug to make Alzheimer's disease get worse more slowly. That's about right.
The other big drug on the market for Alzheimer's management is called Aricept. You start a patient on Aricept as soon as you suspect they have Alzheimer's, because it works best in mild to moderate cases, but if you don't catch it for some reason, it can work in more severe cases. One study showed an improvement or stabilization of cognitive function in 63% of patients taking it (versus 39% on placebo, not terrible). It's worth a shot to put a patient on Aricept because it's about the best we can do right now.
However, the rep was trying to convince us that Aricept plus Namenda was vastly superior to Aricept alone, saying that there was a whole wealth of evidence available.
The information I've found suggests that the gains on cognitive function scales for treatment with Namenda are roughly a 5% absolute increase. OH MAN. We're still looking at only marginal improvement no matter how we approach drug therapy for Alzheimer's disease. This is totally worth spending an extra $1600 in prescription drug costs a year, considering that Aricept costs about $1700 a year by itself, excluding medical insurance. Behold the power of sarcasm.
Don't come to me and tell me how awesome your drug is unless you're prepared to prove it. And if your drug really isn't all that awesome, quit telling me how awesome it is. The FDA may have approved it because you demonstrated it was better than placebo with studies that showed statististical significance, but don't hype it up when we're talking about 5% absolute gains. I realize that it's the job of people who do marketing to get way more excited about their products than is rational, but this is medicine. That just won't do here.
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