Dr Friedman Shares Clinical Pearls for Using Therapies Off Label

n this podcast, Adam Friedman, MD, professor of dermatology and interim chair of the department of dermatology at George Washington Medical School, discusses off-label uses of various therapies in dermatology, tips for counseling patients, and pearls for getting coverage from insurance companies.

Tables for 4 common therapies used off label located below.

Transcript 

Melissa Weiss: Hello. I am Melissa, associate editor of The Dermatologist. Today, we’re going to be speaking with Dr Adam Friedman, who presented on off-label therapies at the ODAC Dermatology, Aesthetic and Surgical Conference in Orlando, Florida, on January 19th.

Dr Friedman is a professor of dermatology and interim chair of the department of dermatology at George Washington Medical School, as well as the director of the residency program and translational research.

Thank you for speaking with us today, Dr Friedman.

Dr Friedman: My pleasure. Thanks for having me.

Melissa: What are some of the commonly used off-label therapies that you covered in your presentation at ODAC?

Dr Friedman: I think one of the most amazing things about our specialty is that we are the masters of off-label uses. I’d like to give credit to the way we structure our residency training in that there’s a very heavy emphasis on both pathophysiology of disease but also how drugs work, their mechanisms of action.

Then, you marry the two to identify new approaches for areas that have possibly nothing because we have a lot of dermatologic diseases for which there are no indicated drugs. The list is actually quite lengthy, and we’re even becoming known for being off-label bandits.

There is a paper coming out next month in the JAAD looking at common diseases and some less-common diseases, and how often do we as providers or practitioners utilize therapies that are not indicated for those diseases. It’s actually quite often.

In the lecture I gave at ODAC 2020, I focused on a couple in particular that I use quite often. It’s really a short list. Those would be dapsone, hydroxychloroquine, pentoxyfylline, naltrexone, and colchicine. One could even dedicate an entire lecture just to off-label use of biologics, which I do quite a bit. But, those were the big ones because I think that they do cover a broad diverse array of diseases because of the way we think they work. They may be even doing more things than even what we know.

Melissa: When using off-label therapies, what are some of the things dermatologists should think about?

Dr Friedman: Certainly, areas where we’ve got nothing. I think that’s what has the greatest need. I think something to consider, in general, taking a step back, is can you actually get it covered given that it’s not an on-label indication?

There was a recent paper, published actually almost a year ago today, in JAMA Dermatology looking at the Medicare coverage determinations and where these off-label therapies fit in whether or not Medicare, for example, being the gold standard for coverage, were they covering these drugs, especially when they’re not indicated for the specific disease? The answer is no.

There is a push to off off-label, which we really have to fight. From the get-go, having data supporting the use of these off-label drugs or off-label approaches are very important. I mentioned biologics for off-label indication and it could be the infrequency. They may not be using a particular biologic for a complete off-the-reservation diagnosis.

It could be that you need to prescribe a biologic with a greater frequency because the patient’s not getting the expected outcome from the dosing schedule that was approved based on the clinical-trial program that went to the FDA. Having data to support that, and I very often find myself doing that, sending a paper or a case series with the letter of medical necessity has actually yielded great results.

Actually, a wonderful example, just earlier today I got a notification that I received approval for one of my patients for whom I’m using ustekinumab for systemic lupus, which there is an ongoing clinical-trial program. She initially was on the Q12-week dosing. She also happens to have a diagnosis of psoriasis, so it made my life a little easier. We know that biologics are not approved for every 8-week dosing. That’s actually the dosing schedule for inflammatory bowel disease. But, I utilized the data out there and I utilized the fact that this is being explored as an indication and was actually able to get it covered.

It’s on us to know the literature but also contribute to the literature to make it easier to get these drugs.

Now, the ones that I mentioned earlier, dapsone, hydroxychloroquine, pentoxyfylline, naltrexone, that’s both the standard dosing, which is used off-label for chronic pruritus. But, actually, low-dose naltrexone, which is 3 mg, that need to be compounded. In pharmacies, we don’t have that size pill available. Finding the right compounding pharmacy is important because they could be pretty cheap if you find the right place. The place I use for 3 mg, it’s about $90 to $100 for a 3-months supply, which is actually pretty reasonable.

Colchicine also is usually well-covered. I’ve had issues getting it covered for off-label uses. For obviously the more approachable, older, cheaper medications, it’s not such a big deal. When you get to more expensive therapies, then you need to have the evidence to support your approach.

Melissa: What other barriers are there for using therapies off-label?

Dr Friedman: I think there’s 2 general issues that can come up. One is the patient! You’re suggesting the patient use a systemic medication for something it wasn’t meant for. I’ve had plenty of patients say, “I don’t want to be experimented on,” or “how do you know it’s safe for someone like me?” Certainly, pharmacists can contribute to the problem.

A great example, I mentioned pruritus before, for chronic pruritus, utilizing antidepressants, antipsychotics, anti-seizure medications. For chronic pruritus, I use a lot of gabapentinoids in my practice, SSRIs. The patient goes, if I don’t prepare them, the patient will go to the pharmacy. The pharmacist will start counseling them on their antidepressant or antipsychotic.

You get a very angry call. “You think I’m crazy? Why are you putting me on this?” Of course, we’re not putting them on the medication because we think they’re crazy or have a psychiatric illness, they may have that, too, but that’s irrelevant, we’re using this because of how it works on the central nervous system to impact itch.

Preparing the patient, explaining why you’re using the medication for the intended reasons, how it works, at least as much as we know, so that when they go and pick it up, they’re not surprised. Those surprises really are what cause a lot of headaches.

The second part, of course, in terms of dermatologists being uncomfortable, is that these off-labels uses, for many there’s limited data. If you’re not a gunslinger or a risk-taker, certainly you may be a little more hesitant. That’s why I think the ones I selected for my lecture were my go-tos because these are drugs that have been around for quite some time.

Dapsone has been around since the first half of the 20th century. I believe it was first synthesized in 1908. We know a lot about the safety. We can get a lot of good guidance, whether you’re using it for dermatitis herpetiformis, bullous lupus, or even non-neutrophilic diseases, granuloma annulare, for example, urticaria, we have really good guidance of what labs you take before starting. How do you have to counsel a patient? What do you need to follow? At what doses do we see efficacy? Often, 100 and 200 mgs a day is what you need for a lot of the neutrophilic dermatosis, but not always for urticarial syndromes or urticaria. I just used it as one example. Some of the older ones and also cheaper ones may make those more comfortable. Talking about them and sharing that data could get those who aren’t so familiar on board.

Certainly, the same is true for all the other ones. I said these are pretty longstanding, old medications. Hydroxychloroquine, even older. It was first described in the late 1800s for the utilization in systemic lupus. We know what to expect. It has been around for so long that there are papers with the title stating why all lupus patients should be on hydroxychloroquine or anti-malarial. I think it’s a little easier.

Sometimes, it’s more for when you have the newer medications, we get our hands on them for one particular indication, and then the gears start turning up there. I go, “What else can I use this for?”

I very much think like that, but that’s more of an exception than the rule. That’s where, of course, getting case series/case reports out there in literature is so unbelievably important and discussing at meetings like ODAC 2020. It’s so important to get people comfortable with using even newer therapies.

Melissa: In line with that, what other research or clinical practice is needed to either get these drugs approved for dermatology diseases or to start to address gaps for diseases that don’t have a lot of options?

Dr Friedman: It’s tough because, once again, we’re wearing different hats when we discuss these issues. At the end of the day, it’s money. To take a drug through the phase program from bench to bedside, you’re talking, and obviously it’s going to vary depending on whether it’s an established drug with other approved indications. Also, even if it has that, if you’re talking about a different age population, if you’re talking pediatric or as adult, it could be 18 to 20 years and 20 to 30 million dollars later. It could be a lot less. Very often money is what makes these decisions go forward or a fail to start.

If you can access these, like the drugs I mentioned, hydroxychloroquine, dapsone, even low-dose naltrexone, which you can get compounded, why would a pharmaceutical company spend the time and money to get that indication when they know we’re going to use these off-label? There are some examples where experience with a drug in one particular arena can lead to label extension.

A great example is with adalimumab, which is a biologic, that is actually approved in multiple facets of medicine in dermatology for psoriatic arthritis, for psoriasis, for hidradenitis suppurativa but has many indications in rheumatology and GI space. The indication was extended to adolescents for hidradenitis suppurativa. This was actually not based on any clinical data per se. There was no clinical-trial program. It was actually mathematical modeling based on their original data. They were able to extend it down to a very relevant age for this disease without actually doing a single clinical study. It was based on the mass amount of data they had in the past.

Sometimes, it actually can be easier. I’m sure that still took a lot of money, effort to get there, but it’s certainly easier than putting together a program. That’s why it’s on us. We can’t wait for others to get that indication. We need to take the extra steps, generate the data that will arm you when you go back to the insurance companies after you receive the denial letter to then push them. You know, ask for that peer-to-peer even though it’s typically not a peer you’re talking to, it’s a podiatrist talking to you about getting approval for a biologic for an autoimmune blistering disease, which is absurd. Hey, that’s what it is. If you have the data, you’re more likely to really change the tides versus just shooting from the hip and just sharing your own anecdotal information.

Melissa: Do you mind sharing some of your experiences with talking to patients about off-label uses and working with insurance companies, as well as the best way to find data?

Dr Friedman: In terms of addressing the off-label component with a patient, it’s going to be highly variable. There are a couple of different scenarios. One would be a patient who has failed conventional therapies that are indicated. A great example of that would be urticaria.

Urticaria has antihistamines, which makes sense because it’s a mass-cell disease. It has one biologic, omalizumab, which has very quickly moved from being third-line to the next choice for chronic idiopathic urticaria. There are patients who may not want that and there are practices that may not be able to deliver it because it’s a little onerous in what you have to do. It’s a very viscous solution. You have to stir the medication anywhere from 30 to 45 minutes before administering. And, you can’t get rid of the patient. He has to stick around your office for 2 hours after due to the risk of anaphylaxis, even though the risk is quite low. No one’s going to just say, “oh, I’m going to roll the dice on this one.” Of course, that’s the patient it happens to. Beyond that, everything else is off-label.

Before omalizumab was available, we would use second-line therapies like calcium channel blockers. We have doxepin, which is an antidepressant with strong antihistamine activity, third-line immunosuppressants range from cyclosporine and methotrexate, mycophenolate mofetil. Hydroxychloroquine has been looked at, dapsone has been looked at in that space. Even narrowband ultraviolet radiation, which doesn’t have the indication.

I figure in that scenario where if you’ve explored the on-label things and it didn’t work, say: “Listen. We don’t have a lot of things that are truly meant for this condition. In my experience, this makes sense. This is the next step. We have a lot of experience using this medication. This is what you need to know about it. These are the risks associated with using these medications. Depending on which one, you may need to do some blood work.”

In this case, these patients are very uncomfortable. They don’t want to be told, “that’s it. We have nothing else.” Also, the disease will dictate how willing the patient is to try something that may not be tried or true and have the FDA stamp of approval for that indication.

Granted, realize every medication we’re using off-label is approved for something, has gone through safety. It’s not like we’re taking something we compounded in our bathroom sink. These are things that are regulated. It’s just that they weren’t meant for the indication for which we’re using them. I think it is more presenting it that way. Confidence is important, and I think the willingness to try I find is so important. I’ve had so many patients say, “oh, the last 3 doctors gave up on me. They didn’t know what else to do.”

My response to that is to say: “Well, listen. That’s not going to happen. We’re going to try things that may not necessarily be meant for this, but because of the way they work, they certainly may offer you some relief. This is going to be a partnership. We’re going to work together. We’re going to find a cocktail, a regimen, that is going to hopefully provide you with some relief.”

It’s rare now I’ll get pushback. But, there are patients who don’t want anything. There are patients who want to be cured of a chronic disease for which there is no cure and they want it to happen with natural products that are over the counter. Those people always doctor-shop.

In most cases, for a lot of these conditions for which we’re using off-label medications, even common ones, it’s often because we’ve tried the conventional things if there are any. If not, we’re climbing the therapeutic ladder weighing in both known and possibly published efficacy data and matching it with the safety that we know.

Melissa: Do you have any other recommendations for using off-label therapies?

Dr Friedman: I spoke a little bit about getting insurances on board. A great example of this, which I was surprised by, is colchicine. Colchicine has been around for quite some time, approved for gout.

It is a naturally occurring alkaloid derived from a plant of the lily family. For those patients who say, “I want something natural,” that is a nice go-to. You got it, here take this, and go hug a tree if you want. I think that the natural elements are going to get some patients on board. We know how it works. There’s significant data from the last 30 years from an anti-inflammatory standpoint. It, like dapsone, has an impressive impact on neutrophils, which are central to a lot of diseases like urticaria, like vasculitides, like leukocytoclastic vasculitis, that’s where I’ve tried using, and pyoderma gangrenosum, which is another area in autoimmune blistering diseases.

I was actually quite surprised that some insurance companies won’t pay for it. I thought it’d be dirt cheap and actually have had some issues getting it covered, which would be the 0.6 mg twice a day.

That’s where, once again, go into the literature. You raised the question earlier. “Where do you get this information?” PubMed is a great location. PubMed.gov, using the right search tool. For example, Colchicine and Vasculitis. You will find case reports. You will find case series, some dating back very, very, very far. One of the first reports I remember seeing was from the early ‘80s from the amazing Jeff Callen, MD, who is like a godfather of medical dermatology. Just getting those, getting access to them, printing them out, sending them back with your rebuttal letter or your prior-authorization letter can definitely make a big difference. I’ve been able to turn it around by just simply doing that.

If they’re really pushing, asking for a peer-to-peer, certainly it can help. I know, they take time, I get that. When you’re fighting for a patient who has something like maybe recurrent LCD and they respond well to colchicine, or you haven’t tried it, they may not have other options, or they don’t want to go on a true immunosuppressant, that could be a good option.

It’s important to fight the good fight. Utilize the resources we have. Another I didn’t even mention is make it a team-based effort. Put the onus on the patient to also harass their insurance companies. Use your medical assistants, your nurses, and make them take some ownership on this. Have them be part of that rebuttal process. You’d be surprised how willing they are to be part of that and feel like they’re part of a solution and feeling valued as part of that team. I find engaging them can be very rewarding for everybody.

In terms of access, especially with expensive medications like biologics, that’s where samples can be really, really helpful, especially if you’re trying to supplement for more frequent dosing.

Let’s say you get a patient approved for once-a-month dosing of a biologic. You could give them twice-a-month dosing by supplementing with samples because I find some patients do need more frequent dosing depending on the indication. Utilizing it for diseases that have absolutely no indicated drugs.

A great example is lichen planus, I see a decent amount, and it’s a very disabling disease. Every drug is technically off-label. I have had some success, for example, with interleukin-17 blockers. Those patients are getting samples in order to achieve that relief.

Engaging industry in that way also, not just asking for help of how to rebut and getting papers. That’s another great resource, PubMed but also industry. You can request publications and they can supply you with papers from investigator-initiated studies or case series. That could be a good resource as well.

Then, certainly getting samples has been so integral to success with some of these off-label uses, whether it be using a TNF blocker for lichen planus or ustekinumab for hidradenitis suppurativa, or interleukin-17 blocker for Graham Little-Piccardi-Lassueur syndrome, which is very rare, but I have a patient who’s on IL-17 blocker.

Becoming buddy-buddy with your local rep who can hook you up with those samples is going to be the key to having at least that option to bring up with a patient.

Melissa:  Thank you for time, Dr Friedman. It was a pleasure speaking with you.

Thank you for listening. If you have any questions about using therapies off-label, feel free to email us at dermeditor@hmbglobal.com or submit your question in the comments box [above]. You can submit any feedback in the box as well. Be sure to share this podcast with your friends and colleagues.