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.