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Agenda Item: Dinitrochlorobenzene

DR. VIDRA: Good morning.

As previously mentioned, my name is Dr. Jim Vidra, review chemist from the Division of Dermatologic and Dental Drug Products.

This chemical has several names; however, the easiest name to pronounce might be DNCB. The generic chemical name is 1-chloro-2,4-dinitrobenzene or 2,4-dinitro-1-chlorobenzene. This beige colored chemical has its physical and spectroscopic properties well established since its initial synthesis in 1875.

For you compounding pharmacists, its solubility properties include insoluble in water, slightly soluble in ethanol and soluble in benzene and ether and other organic solvents.

DNCB is considered stable at normal temperature and pressure conditions. During a fire, irritating and toxic fumes may be generated, such as hydrogen chloride, chlorine gas, nitric oxides, carbon monoxide and carbon dioxide.

DNCB is incompatible with strong oxidizing agents and alkaline bases.

Several published synthetic routes exist for DNCB. There are multiple impurities identified in bulk DNCB obtained from various sources. DNCB's impurity and yield may vary depending upon its route of synthesis.

This table from Wilkerson, et al., summarizes the impurities found in DNCB, sold by each of these six commercial sources. To briefly explain this table and using the Aldrich 98 percent pure DNCB as an example, the Aldrich sample contains 1-monochloro, mononitrobenzene isomer, 2-dichloro mononitrobenzene isomers, plus a dinitromonochlorobenzene isomer, other than the DNCB itself.

As a contrast, the ICN 98 percent pure DNCB contains only one isomer. The analytical method used was a gas chromatography mass spec analytical procedure. This method could not differentiate between the ortho, meta or para isomers, simply due to the method of the mass spec itself.

To summarize the chemistry in Assessment 1, DNCB is well characterized physically and spectroscopically. It is stable under normal use conditions. The acceptability of any DNCB lot for compounding should be based upon knowledge of these two specific impurities, the 1-chloro-4-nitrobenzene, as well as the 1-chloro-2-nitrobenzene. These impurities could present carcinogenicity concerns.

The DNCB used in compounding could vary significantly from the DNCB used in literature studies due to its varying concentrations and types of impurities present. Altered clinical properties and toxicities could result from these variations.

Thank you.

DR. BROWN: My name is Paul Brown and I am a pharmacologist from the Division of Dermatologic and Dental Drug Products. And I will summarize safety information available from the literature on dinitrochlorobenzene.

Dinitrochlorobenzene and some of its possible impurities are mutagenic in the Ames assay and this mutagenicity appears to be due to direct interaction of dinitrochlorobenzene with DNA, since metabolic activation is not required. Dinitrochlorobenzene also induces -- is also genotoxic in human skin fibroblasts in vitro at low doses, similar to those that would be used in vivo.

Dinitrochlorobenzene did not induce tumors in rats or mice in an 18 month feeding study, although the dose of dinitrochlorobenzene in this study had to be decreased after four months for mice and two months for rats because of toxicity.

The carcinogenicity of dinitrochlorobenzene by the clinically relevant topical route has not been assessed and this is an important point since the outcome of carcinogenicity by the topical route may be very different than the outcome from the oral route.

Two possible precursors of dinitrochlorobenzene did cause significant elevations of tumors in mice in the same study in which dinitrochlorobenzene was evaluated.

Dinitrochlorobenzene is absorbed through human skin. For example, in one study, approximately 53 percent of radiolabeled dinitrochlorobenzene applied topically to humans was recovered in the urine over five days. In animal studies, dinitrochlorobenzene was shown to be irritating to the skin and cause the depletion of the important cellular protectant, glutathione in the skin.

In one study, it was shown that dinitrochlorobenzene activated the long terminal repeat promoter of the human immunodeficiency virus in transgenic mice, carrying this promoter.

This is a table that summarizes safety information about dinitrochlorobenzene, again, bacterial mutagenicity was positive. Mammalian genotoxicity was positive, as measured in human skin fibroblasts. Dinitrochlorobenzene was negative for carcinogenicity for the oral route, while some possible impurities were positive. Topical carcinogenicity hasn't been evaluated, as I mentioned, and information on other aspects of dinitrochlorobenzene toxicity, such as chronic toxicity, reproductive toxicity, photocarcinogenicity have not been reported.

And the Assessment 2 that is in the written review also summarizes this information. Dinitrochlorobenzene is genotoxic and at least two of its potential impurities are carcinogenic in mice. Since other studies have not been conducted, teratogenicity or other toxicities cannot be excluded.

DR. OKUN: My name is Marty Okun. I am a medical reviewer in the Division of Dermatologic and Dental Drug Products. I am here to summarize what is known about the human safety and efficacy data pertaining to DNCB.

This slide has a cartoon of a poison ivy plant because the cutaneous reaction induced by DNCB is analogous to that induced my contact with poison ivy. Typical local side effects associated with DNCB application at the application site include burning, itching, blistering, crusting, urticaria, eczema.

The following systemic side effects have been reported: fever and malaise, painful cervical lymphadenopathy, eczema at distant sites, not where DNCB was directly applied. Case reports also describe edema of eyelid and face requiring hospitalization and dyspnea characterized as of near tracheostomy severity.

There is limited long-term safety data available from use of DNCB. Our review indicates that a published follow-up of longer than six months duration is available for only 135 patients, most of whom were adults. No published reports on pregnancy outcomes are available. No cancer cases have been attributed to DNCB, but the duration and completeness of follow-up is not reported.

Pharmacists, physicians and other health care workers are potentially at risk for DNCB sensitization. Furthermore, although unreported DNCB treatment may sensitize to related compounds, such as nitrobenzenes, which are commonly used in agricultural industries. So, there is the potential for sensitizing workers in those industries.

If applied at home, concerns include the possibility of serious adverse effects from application without proper monitoring and possibly sensitizing of family members.

Our assessment of the human safety is that there are human safety concerns and since there is significant transcutaneous absorption in humans, systemic safety cannot be assured.

Before discussing the effectiveness of DNCB, briefly describing its target diseases as appropriate, we have here a clinical slide of a wart. Warts are scaly papules caused by infection with the human papillomaviruses. They cause cosmetic disfigurement, pain on walking if they are on the feet. They can interfere with manual tasks and are potentially infectious.

Safe, effective treatments are available, such as condylox, podofilin, salicylic acid, cryotherapy, lasers. All practicing dermatologists recognize that despite the availability of these treatments, warts are frequently recalcitrant to any or all of those modalities.

This is a clinical slide of two patients with alopecia areata, which is an immune-mediated non-scarring hair loss disease, which can affect patches of the scalp or the entire scalp, in which case it is called alopecia totalis, or the entire body, in which case it is alopecia universalis.

This disease causes cosmetic disfigurement and can also cause functional impairment, especially if eyebrows or eyelashes are lost.

For treatment of alopecia areata, there are treatments available that are reasonably safe and reasonably effective; corticosteroids administered a variety of routes and, again, a common experience is that despite the availability of these treatments, alopecia areata is frequently recalcitrant to treatment.

Our assessment of the approved alternatives for treatment is that available approved products have been demonstrated to be safe and effective for the treatment of warts and alopecia areata and that some cases are recalcitrant to treatment, despite the availability of these alternatives.

This slide shows the dates of the first reported use and number of reports in the English language literature for a variety of indications that have been treated with DNCB, including warts, alopecia areata, melanoma, immuno-diagnosis and HIV. It is noteworthy, if you look at the year of last report, that the most recent studies of DNCB use for treating warts and alopecia are approximately ten years old.

Most dermatology texts and recent review articles caution against DNCB use, principally because of the positive results on an Ames assay, or warn about the hazards of mutagenesis or generalized sensitization reactions. Other immunogens that are evaluated, such as diphenylcyclopropenone, and squaric acid dibutyl ester rate more favorably.

Some pioneers in DNCB use have switched to other topical immunogens, principally because of these safety concerns, but, nonetheless, a few clinicians continue to use DNCB for treating alopecia areata predominantly for patients with more than 50 percent scalp involvement.

Our assessment of historical use is that evidence of widespread use of DNCB is not apparent. Reports of DNCB use have declined in recent years, even in reviews of immunomodulatory treatments.

Typical method of use for alopecia areata and warts involves two phases. The first is a sensitization phase, a relatively concentrated solution; 2 percent in acetone is applied to normal forearm skin. The next phase, the elicitation phase, lower concentrations, ranging from .001 percent to 2 percent, depending upon the report is applied weekly or biweekly to lesional skin.

The concentration is titrated with the goal of inducing a brisk allergic response in lesional skin.

This slide shows a photograph of a hypersensitivity reaction, triggered in non-involved following a topical application of DNCB. You can appreciate the redness, the edema of the skin and microle vesiculation. This is the goal, to induce this kind of brisk allergic reaction.

In considering the efficacy of a proposed treatment for alopecia areata and warts, it is important to keep in mind the natural history of these diseases and, most importantly, that they can resolve spontaneously, depending upon the Lugia(?) Report, warts have been reported to resolve, about two-thirds of them resolve by two years of follow-up without any treatment and alopecia areata, the spontaneous resolution rates range from as low as 38 percent by five years to as high as 94 percent by one year.

Nobody really understands the prognostic features that dictate the probability or the rate of spontaneous resolution of either of these two diseases.

The reviewed studies of DNCB for treatment of these disorders are largely uncontrolled or self or internally controlled or non-compliant patients are the control group. The problem with interpreting these studies is that without a control group of patients, it is very unclear how much improvement can be accredited to treatment effect, rather than to the spontaneous resolution that is possible with these disorders.

Nonetheless, assessing efficacy in alopecia areata, the percentage of patients with cosmetically acceptable response that persists off treatment ranges from 0 percent to 36 percent with a weighted average of approximately 9 percent and the duration of follow-up in these patients ranges from 3 to 18 months. It is unclear whether DNCB is more effective in those patients who are recalcitrant to the other treatments that we already mentioned.

The efficacy in warts, percentage of patients with complete resolution of treated warts ranges from 45 percent to a hundred percent, with a weighted average of 70 percent. Most studies were open label, with all warts treated. In the one internally controlled study where some of the warts on the patients were treated and some were observed, the resolution of the treated warts was not statistically superior to untreated warts.

Again, it is unclear if DNCB is more effective in treatment of warts in patients who are recalcitrant to other treatments. We requested a consultative review by our colleagues in the Oncology Division to evaluate the effectiveness of DNCB in the treatment of recurrent melanoma and they concluded that the available studies are relatively small and non-randomized. They have short follow-up periods. They utilize several application techniques, such as topical or intralesional administration and that they are descriptive or anecdotal in nature.

Of note, no current standard oncology textbook recommends DNCB for treating melanoma. Further, our oncology colleagues reviewed the use of DNCB as an immunodiagnostic agent with the principal purpose of testing immune competence in cancer patients. They concluded that no well conducted randomized trials validating its use have been performed and, frankly, that the prognostic significance of reactivity is unknown.

A consultative review was performed by our colleagues in the Antivirals Division on the effectiveness of DNCB and HIV treatment. Their conclusions were that there was no consistent benefit on CD4, CD8, natural killer cell count or progression to AIDS.

There was a statistically significant reduction in HIV viral load seen in one study of eight patients, but they felt that this was a fairly confusing result because these patients did not have any change in their CD4 count that is typically observed in response to decreased viral load.

They were concerned about potential interactions between DNCB and other approved anti-retroviral therapies and the potential interactions are unknown and potentially of concern.

Our assessment of the evidence of effectiveness is that there is limited evidence that DNCB is effective for the studied indications. With specific regard to alopecia areata, DNCB may provide an increase in hair of variable cosmetic quality, but such hair may be lost despite continued therapy or upon discontinuation of therapy.

And our conclusions are that we have concerns about placement of DNCB on the list of bulk drug substances for compounding. And these concerns include concerns related to safety, limited evidence of efficacy and in clinical use, DNCB has largely been supplanted by other topical sensitizers, because of the concerns about mutagenesis.

Thank you.

Agenda Item: Questions From the Committee

DR. JUHL: Do we have questions from the committee, either for Dr. Vidra, Dr. Brown or Dr. Okun?

MR. TRISSEL: One of the statements that was made was that there was a significant remission rate that occurs naturally. Does that include HIV patients, whose immune systems may or may not recover?

DR. OKUN: You are referring specifically to the remission rate of warts?

MR. TRISSEL: Yes. I am sorry.

DR. OKUN: There is no information in the published literature concerning the spontaneous remission rate in HIV patients with warts. The studies I cited to you were actually done before AIDS appeared in the community.

There is actually no published literature concerning the -- although it has been reported for treatment of warts in HIV patients, there is no published literature on the efficacy of DNCB in HIV patients, who have warts.R We looked rather thoroughly for that.

MR. TRISSEL: Elizabeth, do you have any input on that?

DR. MC BURNEY: I agree with Dr. Okun's comments that there are no published data on that and I would really like to reserve my comments to the other immunogens that we are going to be discussing later. I feel at this point that I would like to be able to have the drug available for those few patients. There are two groups. One, the ones that he pointed out with alopecia areata with diffuse, extensive, greater than 50 percent of their hair loss. I think there has been data to show that using some of these topical agents in those patients, that perhaps we may be able to offer them something when they have exhausted all the other means.

That would be my concern for those particular patients. Then the second group of patients are those with very widespread warts, involving all the tips of their fingers, around all their nails, and these are patients that have severe immunosuppression, whether it be due to infection with the AIDS virus or due to iatrogenic inducement of loss of ambient system through chemotherapy agents.

These patients are frequently unresponsive to many -- to all the therapies that were listed. But as far as DNCB particularly, I would rather direct my comments to the other two immunogens that we will be discussing.

DR. LIEBMAN: Randy, we have two physicians or groups of physicians in Baltimore who use it. One of them is a pediatric dermatologist at Johns Hopkins and the other one is a community physician dermatologist, who also teaches on the faculty at the University of Maryland.

The general consensus is why do you use this because no one else seems to be using it. And across the board, the answer is we have exhausted all other possibilities. We have gone through everything that we could have gone through and nothing has been successful. This is my last resort.

It would appear that it is successful because again and again they come up with new patients for it, knowing that it has potential downside, but somehow feeling, again, it is the only other -- if they don't have this, then they have nothing left.

I guess, somewhat with what Elizabeth said, at least they want the opportunity to have a fallback position. Their position is if you take it away, then I have got nothing to offer my patients.

MS. AXELRAD: Dr. Juhl, I was wondering if we could take questions on any of the information that was presented and then hear from the American Academy of Dermatology before we get into a sort of generalized discussion. It was sort of our feeling that the committee might want to hear the information on all three substances and ask questions about that and then discuss all three substances together after it has heard all the presentations, if that is okay?

DR. JUHL: I think that is good. Let's differentiate between items of clarification and questions for discussion. So, are there items of clarification?

MR. TRISSEL: One more.

DR. JUHL: Larry.

MR. TRISSEL: I just have one concern about the use of apparently only published literature to establish use in the community because really you are establishing how much interest there is in publishing on this particular material, rather than how much it might be used. Now, on this case, of course, there are hundreds of papers in the literature. In others, there may be only a few, but rubbing alcohol is widely used, but I doubt if there is a whole lot of published literature in recent years on researching it.

So, I am not sure about the validity of establishing widespread use, using only published research articles.

DR. ALLEN: I have, I guess, a question. When we look at the conclusions -- and this is just kind of for my information as we look through all of these -- there were safety concerns, limited evidence of efficacy, et cetera, if we look at human safety, I guess I was wondering how that conclusion came because there are limited long term safety, but that is going to be common, you know, with a lot of these things; no published reports on pregnancy outcomes.

There is obviously not going to be any pregnancy studies. No cancer cases were attributed to DNCB. Pharmacists, physicians, other health care workers would be at risk for DNCB sensitization, but that is no different than working with doxyrubin(?), 5FU, et cetera, et cetera. I guess another couple of things, DNCB treatment may sensitize to related compounds. That could be true to other things.

If applied at home, concerns include, you know, family members. I guess my question is at what level are we looking at areas of safety and even efficacy, because there are studies where it has been efficacious, for the conclusions to be drawn that there are safety concerns and limited evidence of effectiveness? Where would be the line for not saying there is limited evidence of effectiveness and what would be the line for -- or what level of safety concern would be acceptable? Does that make sense?

In other words, where did the conclusions come from based upon what we have seen and read in our background materials?

DR. JUHL: Anyone want to comment on how the A led to B?

DR. DeLAP: If I could just comment briefly, and I think this is partly the broader discussion that Jane was just alluding to after we have looked at all the three compounds, I would just like to separate out the issue of whether a compound should be available period versus how it should be available because I think those are two different questions.

I think as we are looking at safety and effectiveness kinds of concerns and when a product becomes a kind of product that you would like to have more widely available with perhaps less safeguards and under the prescription or investigational mechanisms. Those are the kinds of things we have to weight. What do we know about the safety? What do we know about the effectiveness? Is it still really more in the area of an investigational drug? Is there enough safety concern that that alone would make it something that should be out there?

So, these are all kind of judgment issues that we would like to really hear the committee's input on, but, again, I wouldn't want this to be a discussion of whether it is something that should be available or not available, so much as if you think it is worth having, then I think it becomes more of a discussion of how it should be available, as opposed to, you know, a "yes" or "no." Is it appropriate for compounding or is it more appropriate to still be under INDs with all of the things we can do to try and make that as user friendly as possible or should it be -- you know, should it be prescription?

DR. JUHL: Sarah.

DR. SELLERS: I would just like to clarify that this -- for both indications, these are being used chronically, so patients will be seeing long term exposure to this agent potentially.

DR. JUHL: Is that your experience, Dr. McBurney?

DR. MC BURNEY: No, it is not at all. What we usually do is we try to induce, as Dr. Okum showed, 2 percent solution on the skin and induce an allergic reaction or an immune reaction. Then we paint it on the individual lesions, say the warts or the area of loss of hair of alopecia, depending from once a week to as frequently as twice a week or even three times a week in some patients, generally on a once a week basis, until we get a response or until you decide that there is no response.

But this is not done over a year's period. This is done over weeks or months, rather than in terms of years. Then it is usually discontinued. Now, if there is a recurrence, there may be a decision to reuse that therapy later, but it is not like, for instance, you would take a heart medication for the rest of your life or high blood pressure medication. It would be used in a time-limited fashion.

DR. JUHL: Okay. I don't think we will abandon the issues by going on to the next drug. So, let's do that.

Dr. Rodriguez.

DR. RODRIGUEZ: We heard about the drug being, quote, unquote, absorbed from the skin and 53 percent in the urine. How long does it persist in the body? I am just trying to think in terms of the -- we know some drugs that may stay for weeks after that or something like that or is this an acute type sort of exposure and then the drug sort of disappears.

DR. VIDRA: The data that I talked about with the 53 percent, that was in the urine after five days. So, they looked -- in that particular study, they did look over, I think, a 24 hour period. I think the majority of the drug was eliminated early on, like in the first 24 hours, but, again, that is 53 percent in urine. In that particular study, they didn't look at the PCs(?) or anywhere else. They don't know where the other 47 percent is.

Since it does interact covalently, some of it might be bound in tissue and it might not get out in the urine.

DR. MC BURNEY: I would like to just point out one thing that was mentioned in the presentation, that we have safe effective treatments for alopecia areata and they list underneath that corticosteroids intralesionally, meaning they are injected under the skin topically, which would be a lotion or a cream, and then systemically.

I must state concern about it being listed as safe, effective, systemic steroids because we are all familiar with the many side effects and that particularly is a problem with long term use in our pediatric patients of long term use of systemic steroids.

DR. JUHL: Okay. Let's move on to diphenylcyclopropenone. Dr. Hathaway is doing the chemistry and then Dr. Brown and Dr. Okun are back for their presentations.

Agenda Item: Diphenylcyclopropenone

DR. HATHAWAY: Good morning. I have been asked to speak about what is known about the chemistry of diphenylcyclopropenone, also known as DPCP. Diphenylcyclopropenone is a low molecular weight, small ring organic compound, whose physical and spectroscopic properties have been described in a number of published reports in the literature.

It is possible to confirm the identity of the bulk material from various sources by comparison of the properties and the spectra. The stability of diphenylcyclopropenone has been evaluated by examining the known chemical reactivity as published in the literature. DPCP is unstable to heat at temperatures near its melting point, around 120 degrees celsius.

Carbon monoxide is emitted leaving behind diphenylacetyline and other unidentified products. DPCP is also light sensitive and appears to decompose in a manner similar to that of heat. Note that DPCP is affected by light of any type, natural or artificial and including ultraviolet light.

DPCP is unstable in alcohol solutions of base and rapidly decomposes to form a number of products, some of which are unidentified. It appears to be stable in neutral or acidic solutions of alcohol. It is not soluble in water. And DPCP is also chemically reactive, forming addition products with a number of materials.

There are several published synthetic methods for producing DPCP or similar compounds. There is also a second solid form known, the monohydrate, which may come into play regarding identification or amounts. There are also several commercial suppliers. However, it is not known what methods are in use for production of DPCP by these suppliers.

Literature reports are primarily concerned with the methods of synthesis and little or no information has been reported regarding the identification and characterization of any synthetic impurities or degradation products in the bulk chemical.

Lastly, quantitative methods of analysis have not been published in these literature reports. Thus, we are unable to determine how well, if at all, impurities are measured.

This is our assessment for the chemistry. The physical and spectroscopic properties have been adequately established in the published literature. This material is unstable to heat and light under a variety of conditions. It is also known to be unstable in alcohol solutions at basic pH, thus, limiting a choice of compounding material.

It may also be unstable due to reactions with other materials. Numerous sources and methods of production indicate that the impurity profile may differ with the source and the uncertainties of analysis may be a concern here.

Thank you.

DR. BROWN: Now I will summarize some safety information that is available from the literature on diphenylcyclopropenone. Diphenylcyclopropenone is mutagenic in the Ames assay but only in the presence of light. Alpha, alpha-dibromodibenzylketone, which is a synthetic precursor and, therefore, a potential contaminant of DPCP is mutagenic in the Ames assay both with and without metabolic activation.

The potential for absorption of diphenylcyclopropenone is not clear, although diphenylcyclopropenone was not detected in the serum or urine of humans treated topically in the only reported study. The techniques used in that study did not exclude the possibility that diphenylcyclopropenone was rapidly absorbed and metabolized.

This is a table then that summarizes safety information from the literature about diphenylcyclopropenone. Again, it was mutagenic in bacteria with light and, unfortunately, other aspects of toxicity have not been reported in the literature.

Then, again, the Assessment No. 2 in the written review also summarizes the information that diphenylcyclopropenone is photogenotoxic. But given the lack of additional studies, it is not known what toxicities diphenylcyclopropenone may have or whether it may be teratogenic.

This slide shows a list of the recent reports describing side effects associated with the use of DPCP and several are listed here. There have been more published reports of side effects associated with DPCP use and for either DNCB or squaric acid, which will be discussed next.

Our assessment of human safety is that there has been limited characterization of human safety. There have been local side effects described, typically a burning, itching, blistering, clustering, urticaria and eczema, analogous to what is seen with the DNCB. A less commonly vitiligo is induced, which sometimes can be persistent and also something called dyschromia in confetti, which is hyper-pigmented areas with islands of hypo-pigmentation. That also can be quite persistent.

In reviewing the literature, the following systemic side effects have been reported, fever and arthralgias, disseminated bullous erythema multiforme, which is a skin disease characterized by a bruise-like blistering, wing-shaped lesions scattered over the body and generalized vitiligo and generalized eczema, vitiligo and eczema not confined to the sites where the DPCP was applied.

Pharmacists, physicians and other health care workers are at risk for DPCP sensitization. There is a report that three out of five medical and nursing staff members developed severe local dermatitis and irrigation of the eye and nose and generalized pruritus from incidental exposure to DPCP.

Apparently, these staff members experienced symptoms simply by entering a room where DPCP had recently been dispensed or mixed up.

If applied at home, sensitization of family members is possible. There is a case report, which attributed incidental exposure of DPCP as the cause of a case of eczema and persistent vitiligo in the wife of an alopecia areata patient being treated with DPCP. In that case report, parenthetically, DPCP was applied in the clinic. So, this was exposure from the material that had rubbed off of a patient after he had gone home and vitiligo had been persistent.

Our assessment of the approved alternatives for treatment, if I may follow up on Dr. McBurney's comment, we agree that a long term systemic, corticosteroid treatment is not safe and it is on this list as reasonably safe when referring to comparatively short burst in papers of a month's duration, which has been used in literature to reverse alopecia areata. Used in that manner, you can avoid many of the side effects associated with long term use, but, clearly, a long term use is not safe.

We have already discussed previously that there are safe, effective treatments available for warts and I will just reiterate that despite the availability of these alternatives, there is no question that some cases are recalcitrant to all of these treatments.

Historical use, our assessment, the first reported use of DPCP for treatment of alopecia areata was 1983. There are at least 18 reports in the literature on using DPCP for alopecia areata. Five reports use this treatment in warts. Evidence of widespread use is not apparent. The point is well-taken that the published literature does not necessarily capture the totality of the clinical experience, but that is the basis of our review. This is a summation of the published reports.

The typical method of use of DPCP is -- it is applied in the provider's office. A relatively concentrated solution is used to sensitize to uninvolved skin and a much more dilute solution is used to sensitize -- after sensitization has occurred, much more dilute solution is applied to trigger reaction in lesional skin.

The largest study characterizing DPCP use in warts, 134 patients were treated for eight weeks and the response rate was 37 percent; all warts resolved, 37 percent of the patients had all their warts go away and 13 percent, at least some of the warts resolved.

This was an open label study.

Assessing the effectiveness of DPCP in alopecia areata, which has recently been reviewed in a review article and their conclusion was that the response rate, which in their assessment included cosmetically acceptable or partial regrowth. The response rate ranged from 9 to 85 percent, with a weighted average response rate of 58 percent.

In the larger study, response rate was 50 percent, but the relapse rate is approximately 50 percent. As with the DNCB, it is unclear if use of DPCP is more effective in patients who are recalcitrant to other treatments.

Most cited review studies were uncontrolled or self or internally controlled. In a randomized, placebo-controlled study, no significant difference in outcomes was observed between patients treated with DPCP and patients treated with placebo.

Our assessment of the evidence of effectiveness is limited evidence that DPCP is effective in the long-term treatment of alopecia areata or warts. Treatment of alopecia areata may provide an increase in hair of variable cosmetic quality during treatment. This hair may be lost if therapy is stopped.

In our conclusions is that there may be variations in the impurity profile of bulk DPCP. There is comparatively limited evaluation of the safety of DPCP, specifically with respect to long term toxicity, dermal and systemic, reproductive toxicity, carcinogenicity and photocarcinogenicity, especially given that there is a positive assay in the presence of light and microsomes.

There is variable effectiveness with limited evidence of long-term benefit.

Thank you.

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