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Thursday, May 28, 2015

Actinic Keratoses and Carac (fluorouracil) cream: why is this so expensive?

First, a disclaimer: I don't know why Carac (0.5% flourouracil cream) is so expensive. I will speculate, though, at the very end of this blog.

Sun and the skin: what happens
If a person reaches a certain age, has very little pigment in her skin, and has spent lots of time in the sun, bad stuff happens. The ultraviolet radiation of the sun does all kinds of great things: it makes us happy, causes us to synthesize vitamin D which strengthens our bones and it gives us this healthy glow until we get old and wrinkled and leathery. And even that can be charming. The skin cells put up with this remarkably well for a long time, partly aided by melanin pigment which absorbs the radiation, which is why we tan and freckle, if we are fair skinned. Eventually, though, we absorb enough radiation that it injures the skin and produces cells which multiply oddly. It also damages the skin's elasticity which creates wrinkles.

The cells which reproduce in odd ways peel, creating dry skin or dry spots, or warty growths or even small hard horns. The scaly spots are called "actinic keratoses" which just means sun induced scaly spots. Sometimes the skin cells become cancerous and lump up and create non-healing sores. This is when we regret going out without a hat or sunscreen, but, of course, it is too late.

Topical chemotherapy: good idea or great idea?
In 1957 scientists published a paper showing that flourouracil, a flourine attached to a nucleotide (RNA building block), inhibited liver cancer cells. This became one of our early chemotherapy drugs, and is still an important drug in treating colon cancer. When mixed up in a skin cream, it can kill the abnormal skin cells which grow on our sun exposed skin, allowing the normal ones to take their place.

The way fluorouracil cream was initially used was awesome and terrible. It was applied daily for 4-6 weeks to the affected area and the skin became a war zone. The abnormal cells died, leaving red swollen places where sun damage was most severe. Generally people using it looked pretty bad for weeks or longer. Eventually they healed and got rid of their scaly spots. Many people still use it this way, to good effect. We also found that we could treat just small areas at a time, and even just the scaly spots themselves, and that we could use the cream for shorter courses and avoid the intense inflammation. This was a major advance in therapy since our other main option was to freeze the spots with liquid nitrogen, which was a painful, expensive and seemingly never ending process, and which left little white scars.

A slight catch was that the fluorouracil cream was expensive. It was over $100 for a 30 gram tube. Maybe insurance would pay, but it was top tier, and at least some of the cost made its way to the consumer.

Several years ago my husband was prescribed Carac, one of the first fluorouracil creams. It was expensive, so we have made it last, far longer than the expiration date. It is a prized possession, that tube. We have both spent far too much time in the sun without protection, loving every minute of it, and regretting it now in hindsight. When the scaly spots become too annoying, we use the cream until they go away. But the tube is almost empty. Time to buy some more.

Pretty pricey
I looked online to find out how much it would cost if I bought it internationally. I found a product from India that was not too expensive. It was 5% flourouracil rather than the 0.5%, but that is the percentage in the brand name Efudex which is one of the alternatives in the US, so it seemed reasonable. I got the cream in the mail and tried it and it was slightly granular and didn't work. The effect of the Carac was dramatic. The effect of the Indian cream was essentially nothing. "You get what you pay for," I thought. I asked a compounding pharmacist acquaintance to make me some. I respect this pharmacist. He mixed up flourouracil in a skin cream base at a concentration of 5%. The cream was also grainy and didn't work. It seemed to do a little better than the Indian cream, but nothing like the Carac. Finally I decided to just get the Carac. I asked my friendly neighborhood pharmacist what it would cost. She told me that a tube of Carac, 30 grams, costs around $2000. NO! I will not do that! The amount of active chemical in that little tube, the fluorouracil that is used as intravenous chemotherapy, would cost about $40 retail. It is possible to get generic or brand name 5% fluororuacil creams for prices ranging from $170-$500 for a tube, but that is still horribly expensive, and if they didn't work, that would be an annoying next chapter in this tale of woe. Looking a bit harder I found that there is now a 2% solution which is a little less pricey, though there is nothing that I've read that tells me how or if this works. Maybe I should just make some, but playing around with chemotherapy drugs sounds like a bad idea.

Other options
What, then, should someone do with their actinic keratoses? It is just not reasonable to pay $2000 for a tube of cream. Uptodate, which is an online resource used by many physicians to keep abreast of expert management of diseases, says that the treatment of actinic keratoses, besides 0.5% fluorouracil cream, includes use of sunscreen to prevent further appearances of the little spots, dermabrasion to remove the affected skin (ouch)and that the use of topical retinoids (vitamin A derivatives) can help. They also mention that ingenol mebutate and imiquimod creams (both horribly expensive) are better than placebo as is chemical sensitization plus light therapy (I can only imagine what that costs.)

I have decided to use a retinol preparation which is pretty darn cheap and calls itself "wrinkle cream." It is in the cosmetic section of my local drugstore. Retinol is one of several retinoids that are approved for use on the skin, and also treat acne. I will also wear sunscreen and a hat. So far the retinol, when applied to the whole sun-damaged area (for me, the forehead) is helping reduce my sun induced roughness and scaling. Retinoids appear also to reduce the risk of developing squamous cell cancer, a common malignancy in sun exposed skin. For now, at least, my path is clear.

Mysteries persist
But there remain mysteries which I have been unable to solve using books and the interwebs. Why is 0.5% flurouracil 10 times more expensive than 5% fluorouracil, even though the latter is theoretically 10 times stronger? Why do they even make 5% flourouracil cream if the 0.5% stuff works just as well? Is it in some way very difficult to mix flourouracil into a cream? Why does Uptodate recommend 0.5% flourouracil and not 5%? I have no idea. I can speculate a bit about the costs, though.  It's possible that the cost of the 0.5% flourouracil is made to be as high as the newer creams, like imiquimod, which were priced that high because they were relatively new, and are still not generic. All of these creams are still financially viable because they were cheaper and more acceptable than going in to the doctor every few weeks to have him or her freeze a bunch of spots, resulting in what looked like a mild case of chicken pox which healed to make white scars. It's still really hard to believe that anyone would pay $2000 for a little tube of skin cream and that we, as physicians would regularly recommend that they do so.

Addendum 10/26/2015:
There is another treatment for skin aging and actinic keratoses, which also works for acne! Apparently Nicotinamide, vitamin B3, reduces signs of skin aging when used topically and reduces AK's significantly when taken orally at a dose of 500 mg twice daily. This article, out of Australia, also showed some reduction in non-melanoma skin cancers with it. Both topical and oral versions of Nicotinamide are available without a prescription.


Anonymous said...

I am a physician (internist) as well. I have used salicylic acid in the form of good ol' Compound W for years for actinic keratosis on my face and elsewhere. I also had what appeared to be a basal cell or keratoacanthoma on my chest that rapidly grew. I applied the salicylic acid (yes, as an experiment) and just left it on there for several days. The darn thing peeled off and left the skin as smooth as a baby's bottom! You can't even tell anything was ever there!

Janice Boughton said...

That is so great! Also a good example of how old remedies could be tremendously effective but we would never hear about it because they don't make money for anybody who funds research and don't have powerful proponents. Thanks for the tip.

Anonymous said...

25$ in Romania&Hungary. maybe you can find some friends travelling to europe to bring some to you

herbert said...

The salicylic acid response sounds good. An herbalist locally (a fair-skinned Dane), when asked what she would recommend, said that a salve with aloe, black cottonwood bud 'grease', and maybe a St. Johns wort oil infusion would probably work well.
I looked up uracil in the Wiki (and also its 'source' article) and learned that it is found in wheat germ (and some other places), and learned about some of its properties. My organic chem is beyond 'rusty', but some of it made sense to me.|
The cottonwood grease (old "balm of Gilead") is considered a good all-purpose liniment... and is a source (like its cousins, willows) of salicylic compounds. St. Johns wort oil is something that I've seen effectively reduce the 'flare-up' (painful) stage of herpes blisters... so I think the herbal approach might line up well as a "less-than-drastic" approach to using a halogenated chemo drug.

It's funny how bodies respond to various strengths of compounds. My wife takes melatonin to help her sleep... and, after trying 5mg (and larger!) pills, found that the sub-lingual 500mcg pills worked far better. (I am reminded of Theo Colborne's research into tiny amounts of endocrine-mimics in pesticides that adversely affected waterfowl offspring, when exposed at very specific times in their life cycle, in her book "Our Stolen Future".)

Having opted out of my pursuit of organic chem in favor of the indulgent life of hippie Luddite in my college days has provided a look at "other paths" to wellness that I'd have shunned in my early days. There's a wonderful book-- well-written, humorous, quirky, homely volume-- by a recently deceased herbalist/biker/outlaw from the West Coast... Michael Moore. The book is "Medicinal Plants of the Pacific West" (Red Crane Books). It's something that I can pick up for a few moments, or an hour, and gather insights, as well as have a good laugh (or wry smile). I know what kind of "spare time" MDs have... but it may please your curiosity... and may provoke a fine reaction that will give you insights into this world around us. (He moved me to dabble again in chem, beyond just making my own wine, beer, yogurt, and tofu.) ^..^

herbert said...

Here is an article on the aromatic compounds in cottonwood:
with some fascinating connections to the responses of our bodies to uv radiation.

Anonymous said...

Hi there,

Was fascinating reading about all the chemistry and implications behind carac and the need for it. I know nothing about all of that but I can help you understand the pricing.

It's simply due to the company manufacturing it, Valeant. They are famous (infamous now) for price gouging.
The FTC had to even step in and curtail their ambitions when they acquired Carac back in 2011 because they were trying to establish a monopoly:

Valeant had another topical equivalent to Carac, Efudex, as well as a generic, and then bought Dermik (a Sanofi division) that owned Carac. This is essentially all they do. They're a company that spends nothing on R&D and only resort to things like these. Buying drugs and raising prices through the roof.

You should check out the kind of distress they put the poor people who suffer from Wilson's disease in.

Valeant owns the two main Wilson disease drugs, Syprine and Cupramine

Here's a nice New York Times article talking about it:

So, not sure it provides any solace at all but at least you're not alone. They're like a vampire that sucks patients dry for all their drugs. Hopefully something will be done about it.

FJOSMITH said...

Co-pay at Walmart pharmacy for Carac $811.17. I have part D drug coverage. This med can be purchased from mail order for $35, but since I have drug coverage; I cannot self pay. There is a law that prevents the pharmacy from selling and shipping this med to me. These laws encourage people to be dishonest. Seeking other alternatives. You pay for your drug coverage monthly and then learn you would be better off with no coverage in some instances. Even with a coupon, pharmacies might not be able to accept. Help me understand!

Lew said...

The 0.5% Fluorouracil coats microspheres that are then mixed into the cream. The 5% is just a cream, as far as I know. I have been using 5% for some years now, maybe 15, and it has always worked for me. At first I used the brand name Efudex, and lately I've used the generic version, which also works great.

My supposition is that the maker of Carac created the microsphere formulation to differentiate themselves. The microsphere thing might allow more drug to be delivered at a lower concentration, and thus lower systemic uptake. However, there is a study online that shows that the plasma level is not much different between the two, and is very low. So I am happy to keep using 5%.

The unfortunate part is that the price has gone up and my medical insurance has gotten worse. So it will now cost me $172 per tube under my Part D plan. However the Brand Efudex can apparently be obtained from a Canadian pharmacy much less expensively. I have read other bad stories about cream made in India, although in reality many of the generic drugs in the US are made in India.

I also found out that Aetna has a plan under which the base cost for the drug (before any insurance reimbursement) is listed on Medicare's web site as $35. Some other plans have it for $47 and up. I found some coupons that are supposed to work at Walmart and Walgreen's for around $100; I'll find out if they do. If not, I'll go the Canadian route.

The explanation for why the prices have skyrocketed is clear - because they can and they have no concern for anyone else. I am reminded of Patent Trolls. These people are not creating anything for our economy. While we can enjoy the idea that their emptiness will someday catch up with them, that doesn't pay for the medicine I need.

It is more difficult to explain why the insurance plans offer the drug at a base price that varies so widely. This would probably be easy to understand if we knew how the middle men have their hands in the market. I suspect that the "coupons" and "non-insurance drug plans" are ways to play one greedy benefit manager off another.

But the hardest thing is to imagine how to fix this screwed up system without making it worse or removing incentives to innovate. (Other countries have been able to do so, but some might say they have been successful only because we haven't). Another hard thing to figure out is how to make it work politically. I expect it would take a determined push over 10-20 years, like some of the other big changes in our society.

Janice Boughton said...

Thanks for the well researched and well written reply. Microspheres. That also explains the texture difference. The ridiculous price hikes on topicals are true of corticosteroids as well.

Bob McNeal said...

Valeant is reason CARAC is so high.
FTC in 2011 told them to sell the three companies they bought.
Valeant was at Hearing on Feb 4 on why pricing was so high.
there is a 4 hour video of that hearing.
If you want to see it and digest only two drug companies that are abusing pricing it will tell you some of the story.

4 Hour Hearing on Drug Pricing.

Bob McNeal said...

Check this out.

4 Hour Hearing on Drug Pricing.

Anonymous said...

I just picked up a 30 g tube of Carac and it cost me nothing!! My dermatologist gave me some coupon to use at Walgreens and the first/trial tube was free! But, when I run out, I will go for the Compound W. The retail price on Carac was marked as $2,999.00!! Outrageous

Anonymous said...

That is a great deal.
Problem is they will use that loss as a figure for their cost of doing business.
That way that will raise their cost to provide to whomever says that their ROI is justified because advertising and it effects everything.
They know how to manipulate the numbers so they can keep the cost high.
Question how many doctors if you tell them you saw an advertisement on TV or other wise would cure your ills, would prescribe that drug or tell you who is the doctor??
Have a good day.
I am still fighting this drug pricing issue.

Anonymous said...

I paid $35 for Carac for my fist rx and $7 for my second. Let's be careful where and whom we take advice from. No offense but I think I'll pass on taking med advice from a self described "hippie" . There is plenty room for blame here, we can start with Obama,

Janice Boughton said...

Wow! I want your insurance. Re:Obama. He pushed through a healthcare bill that could pass a divided congress. It has improved access. It could have been better. Expensive healthcare is driven by fee for service and health insurance that separates consumers from having influence over cost and quality.

Peg Manning said...

How does one "go the Canadian route"? Just curious. Can we take our US Rx's there and get them filled?

Peg Manning said...

Anonymous: actually, it was not Obama. The Medicare Part D scam was a Republican adventure, and the provision that prevents Medicare from negotiating for drug costs is a Republican measure.

That's why I support single payer. One big block of American consumers to negotiate with the drug companies. Then we'll get prices at least somewhere close to other first world countries.

One Woman's Voice said...

My dermatologist gave me a coupon from Valeant to use when purchasing Carac. With my insurance factored in the tube cost me $35. I am about to go on Medicare, however, and I've been told Carac will not be covered. The coupon specified that it could not be used by anyone on Medicare.

I have yet to begin using the cream. I am terrified. Any tips to minimize the pain?

taoist mlountaingeezer said...

my comment was just erased by denial of email address as being incorrect?~! Try again, without any detail: my Kaiser Medicare 5% flourouracil is $10, retail value to Kaiser Permanente $113, and it works well for me.

Janice Boughton said...

Re: the 5% flourouracil cream--I haven't tried a US formulation of that, so not sure how it works. It is made differently than the 0.5% cream but may work fine. I have reviewed the article, which has been substantially updated, in UpToDate and apparently the 0.5% formulation is better tolerated than the 5%, but the 5% has been used extensively in Europe and is quite effective. There are other treatments available now, not all of them in the US, which may be more tolerable. All of them seem to be associated with an ugly period, during which the affected skin is quite red.

The costs of these different topicals is constantly changing, and I don't doubt that some of the preparations that were very expensive when I wrote this article will become affordable at some future time, or may be affordable now.

Bob McNeal said...

Sorry, I have been investigating this for ten years.
Problem is FDA....
Our all politicians decided to have all drugs go through the FDA and Lobbyist.
You find all drugs that were not approved by FDA had to go through it and then the big guys had the money to develop the drug which had same drugs and could charge what they wanted.
Then you have PLAN D now there is where the water gets muddy.
You need to contact your congress people which I ran into a big lobbyist wall.
It is not just one party it is the SWAMP....
Have a good day.
I feel like a person on the beach with a baby spoon trying to turn back the tide???

Carac $2700! said...

$2700.00!!! My husband went to pick up hid Carac generic prescription & said, "I don't want to buy the pharmacy..."
$2700 is cost prohibitive. He is 75 & does not have insurance.
How can he get it for $35?
Thank you.

Bob McNeal said...

I have used the Spear Fluorouracil Cream and it works. Too bad we can't take the CARAC off market. Big Pharma is too big to fight.
Tried it for 10 years now and five different Senators (they are part of problem)
Try it and should help.