Protopic/Elidel Information

PRESCRIPTION DRUGS TREATING SKIN DISEASE PUTS YOU AND PARTICULARLY YOUR CHILDREN AT RISK FOR CANCER

by Larry M. Roth*

Lost in the media and public relations frenzy on Vioxx and other drugs, the FDA with less fanfare has identified a risk for cancer from two currently approved skin disease therapeutic treatments, i.e., atopic dermatitis or atopic eczema. Young children are particularly at risk for serious adverse consequences, including various forms of lymphoma. In March 2005 the FDA decided in agreement with Advisory Committee recommendations that a "Black Box" warning for cancer was required for these approved drugs. This means on the label there must be a "Black Box" with a cancer warning in it so as not to be missed - analogous to a skull and crossbones.

Protopic Elidel

What drugs am I talking about? Protopic, manufactured by Astellas (formerly known as Fujisawa), and Elidel, by Novartis. The FDA first issued a public health advisory about these drugs in February 2005:

The Food and Drug Administration (FDA) today advised health care professionals to prescribe Elidel (pimecrolimus) and Protopic (tacrolimus) only as directed and only after other eczema treatments have failed to work because of a potential cancer risk associated with their use.[1]

However, as early as 2000 investigators for the FDA were concerned about the risk of cancer posed by these topical imunosuppressants.

The Skin Disease

Atopic dermatitis is a form of eczema. It is a disease that results in scales on the skin surface - dermatitis - red blotches, lesions, and oozing sores. Eczema and its variants are:

[g]eneral terms for a group of acute or chronic inflammatory skin disorders characterized by redness, thickening, oozing, and the formation of papules, vesicles, and crusts; often accompanied by itching and burning.[2]

Approximately 20%-25% of the world's population suffers from some form of atopic dermatitis.[3] It is estimated that 15 million people in the U. S. have the disease.[4] Ten to fifteen percent of children less than 5 years of age have this skin disorder.[5] The form of eczema known as atopic dermatitis is a common "chronic disease of young children."[6] It is a recurring and relapsing disease. Forty-eight (48%) percent of children who develop the disease do so before six (6) months of age, and sixty (60%) percent by age one.[7]

Atopic dermatitis has both physical and emotional components. The physical manifestations of the disease are noted above. Itching is a consequence of the skin irritation which then results in open sores and bleeding. The disease can appear in unreachable or sensitive areas such as the ears and genitalia. For the majority of people with age the disease is outgrown. But not always. Statistics indicate 50% of children with atopic dermatitis carry it into adulthood.[8] Particularly with children, atopic dermatitis has emotional components as well. We all can relate to peer group comments and ridicule to which these kids might be subjected. Thus, emotional problems often are a real consequence of the skin disease.

For nearly 50 years eczema-related diseases have been treated with topical corticosteroids.[9] This regimen has proven effective, for the most part, in treating the disease. The scientific community has continuously monitored this form of treatment due to the steroid as an active ingredient and their potential side effects. These products, however, have demonstrated safety and efficacious results particularly with low to mild potency dosages of corticosteroids.[10] Thus, topical corticosteroids are called the "first line of treatment." [11] They do not work, however, for everyone. A person may be allergic to steroids or resistant to their properties. Thus, enter into the market Elidel and Protopic.

Immunosuppressants

Both Elidel and Protopic are topical immunosuppressants.[12] They are touted by their manufacturers as being "steroid free", and this is a high-profile marketing strategy used by both Novartis and Astellas (formerly known as Fujisawa).[13] These drugs are applied as topical medicine, so the manufacturers would say what could be safer - they are not orally ingested. These products' active ingredients - tacrolimus and pimecrolimus - are intended to suppress or block the body's transcription of certain antigens which form in cell creation to cause the disease.[14] Tacrolimus and pimecrolimus have similar chemical structures.[15] However, even their creators do not know how these immunosuppressants actually work.[16] Elidel for Novartis states: "The mechanism of action of pimecrolimus in atopic dermatitis is not known."[17]

Clinical testing performed by Novartis and Astellas (formerly known as Fujisawa) both demonstrated a host of adverse events (AE), several referred to as serious by the FDA medical examiners. Some of these included asthma, respiratory problems in children, herpes zoster, flu symptoms, headaches, and many others.[18] These symptons occur because of absorption in the blood of these drugs, particularly in children. Protopic, particularly, had a tortured history during the approval process to meet FDA requirements of efficacy and safety.[19] Protopic is dispensed in two strengths. For the stronger dosage of .1%, 48% of the participants developed an infection cluster such as "flu syndrome, herpes simplex, chills, and fever, etc."[20] The lower strength dosage of .03% had 49.4% infection rate. Protopic was only approved for children 2-16 years of age, and only for the .03% dosage level. At both dosages Protopic had an average of about 60% non-application site adverse events.[21]

As far back as March 2000 with Protopic, the FDA was concerned about "the statistically significant increases in pleomorphic lymphomas and undifferentiated lymphomas in topically treated mice, both in the male and female group."[22] The pre-Protopic clinical studies submitted to the FDA demonstrated:[23]

The high and progressively increasing hazard rate of lymphadeopathy in this analysis raised some concerns, especially when considered together with the pre-clinical toxicology studies showing high incidents of lymphomas in mice treated topically with 0.1% Tacrolimus ointment. Further detailed studies of these cases of lymphadeopathy was, therefore, undertaken.

Elidel's clinical studies were not much better. According to the FDA Medical Review only second line therapy was recommended:[24]

[P]reclinical data that suggests an increase incidence of lymphomas, thyroid ademas, and cutaneous malignancies and because of increased incidence of infection over the long-term found in clinical studies.

The studies on adults with Elidel demonstrated a risk for "development of lymphomas and cutaneous malignancies."[25] Infants showed disproportionately adverse events approaching "significant" levels.[26] The Examiner for Elidel recommended that physicians be made aware of the risk to children for lymphadenopathy.[27]

FDA Restrictive Approval

Protopic was approved by the FDA in 2000. Elidel received its NDA in 2001. There were, however, some stringent restrictions placed by the FDA on both products which are significant in understanding. Initially, these products were to be only second line therapies. This meant Protopic and Elidel should not be prescribed by physicians in the first instance. The more traditional and proven topical corticosteroids were to be the first line of therapy. Only if steroids did not work or could not be used, then prescribing Protopic or Elidel was appropriate. Despite this restriction both drug companies have been intentionally marketing these prescribed products to dermatologists and pediatricians for use in the onset of treatment, contrary. FDA investigators concur in this fact:

The increasing use may be related to aggressive and inappropriate advertising with portrayal of these products as safer than steroids and the implication they can be used as first-line therapy and for unlimited periods of time.[28]

Second, these two immunosuppressants were approved only for children between ages 2 - 16 years. This was due in part to the sensitivity of children to reactions and concerns about drug absorption into the blood system. For Protopic dosage levels for these age kids had to be .03% of the active ingredient - tacrolimus - instead of the stronger 0.1% strength authorized for adults.[29] This is again very important to understand. Studies on the drug had found the higher dosage resulted in absorption into the blood of the active suppressive agent, and the more serious adverse events.[30] The NDA medical file on Protopic stated:

Because pediatric patients may absorb more of the Tacrolimus into their blood, and because of the unexpected long term exposure to the Tacrolimus ointment during their life, it seems that there is no sufficient justification for the use of the 0.1% ointment in pediatric patients.[31]

Yet, due to intentional marketing and promotions by Novartis and Astellas (formerly known as Fujisawa), as the prescription data clearly establishes, both drugs are being prescribed indiscriminately from both dosage level and age groups. The manufacturers' marketing efforts were fueling these results, and physicians were not properly told of the risks.

Third, and most important, neither drug - Protopic nor Elidel - were approved for children under 2 years of age or below. The reason was that tests demonstrated both an unknown effect upon the immune system on such young children and the long term exposure consequences from the drugs. Yet, prescription data in 2004 showed approximately 13% of Elidel and 8% of Protopic were being prescribed for children 2 or under.[32] Novartis and Astellas (formerly known as Fujisawa) know this. It is off label use. Once again, their marketing promotions, presentations made to physicians by the sales forces, and outside paid endorsers saying no safety problem because these are "steroid free" products are believed to be contributing to this, all of which is traceable directly back to the manufacturers.

The second and third points above are referred to as off-label use. Novartis and Astellas' (formerly known as Fujisawa) conduct is irresponsible under recent legislation to this type of intentional off-label promotion.[33] Further, they are doing so with full knowledge of the repercussions of their actions.

Lymphoma From These Immunosuppressants Identified

Evidence began to appear that individuals, including children under the age of 2, were not only using Protopic and Elidel but were developing non-Hodgkins lymphoma, squamous cell disease and malignant lymphomas.[34] As early as the year 2000, lymphoma was identified as a serious AE for these drugs. An FDA Medical Examiner recognized with Protopic:

The high and progressively increasingly hazard rates of lymphodenopathy in this analysis raised some concerns, especially when considered together with the preclinical toxicology studies showing high incidence of lymphoma in mice treated topically with 0.1% Tacrolimus ointment.[35]

Lymphodenopathy is usually an indication of some underlying disease, and can lead to malignancy.[36] The pre-approval studies on Protopic demonstrated the presence of incidences of lymphoma both in animal studies and in trial patients.[37] The manufacturers of Protopic and Elidel, however, have from the outset been marketing these drugs without adequate cancer warnings despite their knowledge of the lymphoma risks. Their PDR references[38] and product inserts for physicians did not contain this type of cancer risk information.

In 2003 an FDA advisory committee recommended that Astellas (formerly known as Fujisawa) and Novartis revise their product inserts to inform patients of the significant adverse events such as cancer risks from these products.[39] A serious adverse risk is defined by the FDA as any experience that resulted in death, was life threatening, required in-patient hospitalization, or prolongation of existing hospitalization, resulting in persistent or significant disability/incapacity or congenital anomaly/birth defect or considered an important medical event.[40]

Accumulating scientific evidence of deaths and serious repercussions, particularly in young children, led the FDA to its March 2005 "Black Box" warning of cancer risks being required for these two topical ointments.

The "Black Box" is the severest of warnings the FDA can mandate. A January 2005 FDA study found:

The immunosuppressive effects of these topical products in animals, manifested primarily as lymphoma formation, are strong, consistent and compelling. The biological relevance of these animals findings to humans exposed to these drugs cannot be excluded. In addition, immunosuppression is the proposed mechanism of action of Protopic and Elidel.[41]

This cancer risk warning was endorsed by the FDA because [b]ased on the totality of scientific information available thus far which includes animal carcinogenicity signal both in mice and monkeys, post-marketing tumor-related adverse event reports coupled with the increased absorption in atopic dermatitis resulting in greater systemic exposure. The evidence raises serious safety concerns in children regarding the potential for carcinogenicity in humans treated with these agents. These products are being widely used to treat atopic dermatitis, a non-life threatening disease, and heavily advertised for use in young children without appreciation by parents and physicians regarding the potential for carcinogenic risk.[42]

Post-Marketing Lymphoma Evidence

Post-marketing evidence of cancer development caused the FDA to take the steps it did in March 2005. Some of the post-marketing adverse effects to young children were very serious. For example, one 2 year old child was diagnosed with lymphoma. Another pediatric patient being treated was an 8 month old male who had developed eczema, and subsequently went into cardiac arrest.[43]

According to the FDA's "Adverse Event Reports Database,"[44] for Elidel through September 22, 2004, less than 3 years after its approval, 54 serious Adverse Event Reports in children less than 2 years of age were reported.[45] The Database found 8 malignancies in all age groups, four of them in children. Although the majority of the serious adverse events for Elidel were skin-related, still this resulted in 15 hospitalizations of children. Overall, 9 tumor cases were reported for Elidel.[46]

From Protopic's approval date on December 8, 2000 through September 22, 2004, "there [were] 10 reports of serious adverse events in children less than 2 years old, and 17 malignancies in all age groups."[47] Two things are significant about this data. First, Protopic was not approved for children under 2, and second there were already 17 malignancies reported in less than a four year period of time. As of December 2004 the FDA had received 19 incidents of reports linking Protopic with cancer-related adverse events. There were two adult deaths, and eight hospitalizations including two pediatric patients. These 19 cases included "9 lymphomas, 10 cutaneous tumors, which 7 occurred at the site of Protopic application".[48] There were also cases of squamous cell carcinoma, cutaneous sarcoma, malignant melanoma and other tumor formation. Of the initial 17 malignancies reported with Protopic, 3 were in children.

Of course, these are only "reported events" and no one knows how extensive the repercussions are which are not being reported. All scientific data has demonstrated increased use of these topical immunosuppressants results in increased risk of cancer.

A further concern is that with children under two years of age being prescribed and using Protopic and Elidel, directly contrary to the FDA approval, is that no one knows the long term adverse effects of this improper usage. Some scientists believe these repercussions will be evidencing themselves over the next 10 years.[49] The risk exposure is huge. Through November 2004 there were over 8.7M prescriptions for Elidel, and 3.48M for Protopic written. Fourteen (14%) percent and seven (7%) percent respectively were being given to patients 2 years and under.[50] The manufacturers have this prescription data and also know that neither drug is approved for children below 2 years of age.

There is also a larger story to tell, at least as to Astellas (formerly known as Fujisawa). It obtained approval in April 1994 for the drug substance "tacrolimus," used for systemic ingestion by capsule and injection and known as Prograf. This product has been used for liver transplant patients as a prophylaxis against organ rejection. However, it has also been widely known for years that this immunosuppressant, "tacrolimus", as a side effect, causes cancer.[51] In Astellas/Fujisawa's new drug application for Protopic it used tacrolimus from that 1994 drug as the active ingredient for the treatment of atopic dermatitis. Tracking back to the manufacturer's knowledge of the systemic repercussions from immunosuppressants used in transplant cases, the FDA found children "treated with Protopic have had measurable blood levels of the drug, in the range of patients treated with Prograf."[52]

Neither Astellas (formerly known as Fujisawa) nor Novartis' clinical testing was long enough to show whether the drugs were safe. The longest study was 12 months, and only in adults.[53]

The reporting time for the lymphoma in the post-marketing adverse events ranged from median times of 90 to 240 days with the longest being 940 days.[54]

Liability Consequences

Novartis, the German parent, 2004 Annual Report titled "Caring and Curing", listed net sales of $28 Billion.[55] Astellas (formerly known as Fujisawa) had consolidated sales of about $3 B in fiscal year 2004-2005. They sold $21 M of Protopic between 2003-2005.[56] These companies have the resources to defend litigation aggressively to save their product brands. They have for years been marketing these dangerous drugs on the public without any cancer warnings and knowing they are being used for very young children. Sales have been escalating because these companies were using Direct to Consumer (DTC) ads, and aggressive "steroid free" marketing strategy - yet never once telling anyone that they are at risk for cancer. These DTC ads would portray idyllic imagery of safety and serenity, and have now been withdrawn. This "steroid free" mantra has also been the linchpin of the marketing efforts of both Astellas (formerly known as Fujisawa) and Novartis. One can only imagine how aggressive these companies sales reps have been with dermatologists and pediatricians during the on-going athletic steroid scandals. Between June 2003 - May 2004 Protopic sales increased 16%, and Elidel by 46%.[57]

This is part of the potential liability of these companies. They have attacked and criticized the traditional first line treatment regimes of corticosteroids for atopic dermatitis as being too risky because of the steroids. As a consequence they have promoted Protopic and Elidel as steroid-free alternatives to these traditional products so that the immunosuppressants have become too often the first line treatment. Yet, these products were only approved if steroid treatment did not work or if the patient could not be exposed to a steroid. Thus, Elidel and Protopic have become initial substituted drugs instead of a successive or subsequent treatment.

This explains the high prescription rates for both products. In turn this has led to over prescription without either dermatologists or pediatricians being fully aware of the serious, and potentially deadly, adverse events caused by these immunosuppressants. Consequently, although they are only for short term and intermittent application, Protopic and Elidel are being regularly and routinely used. Atopic dermatitis is a recurring, chronic condition so the drugs continually are being prescribed to patients. The clinical studies predicted this would have to occur:

It may be concluded from these results that patients will need treatment, almost all the time (>85% of the time), to maintain the improvement in their atopic dermatitis signs and symptoms that was achieved by the initial treatment with 0.1% tacrolimus ointment.[58]

For the more serious cases, the use on the total body surface increases which in turn catalysts the absorption into the body the active immunosuppressant ingredients of these drugs. This then exposes the body to wide areas of potential blood absorption of the immunosuppressant's active ingredient, and ultimately an unreasonable risk of lymphoma development particularly in young kids. The body's immune systems become suppressed by the absorption through the abraded skin into the blood system which then systematically transports the potentially harmful ingredients

Conclusion

These companies sold drugs that resulted in the suppression of the body's internal immune system in order to fight an otherwise treatable external disease. Their products' active ingredients, known systemically to be linked to cancer does become absorbed into the blood stream. The products, with the knowledge of their makers, are being used for young infants, applied over large body surfaces and for sustained lengths of time - all contrary to the scientific validation to sell the products these manufacturers provided to the FDA. Finally, the products are being aggressively marketed coincident with society's steroid fear and hysteria.

On the human side, think of the parent whose child may be ridiculed or peer-group ostracized by what is an emotionally troubling childhood disease - atopic dermatitis - and who earnestly looks for treatment answers. Think about the overzealous commission sales representative following their sales manager's instructions encouraging treating physicians in promoting Protopic and Elidel as safe because they are "steroid free".

Then think about the parent and the child at the oncologist's office talking about lymphoma. A topical skin disease is a blessing in the face of a potentially deadly cancer. Both the regulatory and legal communities should be outraged. The legal system is the vehicle to right this wrong. The FDA cannot undo what has already occurred. They can only keep the statistics. Individual body counts on a cancer registry coincident with the use of Protopic and Elidel is not an epilogue that we can or should accept.

END NOTES

* Partner, Law Offices of Larry M. Roth, P.A. He has a state-wide and national practice based in Orlando, Florida, and accepts referrals on Protopic and Elidel cases.

________________________________________
[1]. FDA Talk Paper, T05-06, 3/10/05.
[2]. Mellon's Illustrated Medical Dictionary. at 140 (1979).
[3]. American Academy of Allergy, Asthma and Immunology, 6/4/03, www.cmeweb.com/derm/aciaairept.htn
[4]. Nat'l. Inst. Of Arth. & Musculoskeletal & Skin Diseases, niams.nih.gov/hi/topics/dermatitis/#link_a.
[5]. L. Schultz, The Epidemocology of Atopic Dermatitis, 31 Mongr. Allergy, 9-28 (1993).
[6]. M. Boguniewicz, Topical Treatment of Atopic Dermatitis, Immunology and Allergy Clinics of North America, Vol. 24 at 631 (2004).
[7]. University of Kentucky College of Medicine, Am. Acc. of Alleg., Asthma & Immun., 6/4/03, www.cmeweded.com/derm/acaairept.htm.
[8]. Id.
[9]. Maibach & Surber, ed., Topical Corticosteroids, at vii, 1-5 (1992).
[10]. The Pink Sheet, 11/20/00, at 3 (existing treatment regimen of corticosteroids have "established safety profiles.").
[11]. Id. at 3-4.
[12]. Calcineurin Inhibitors May Cause Cancer Risk in Children, Family Practice News, Vol. 34, No. 5, March 1, 2004.
[13]. This is clear from the websites for these two companies products. For example, see www.protopic.com
[14]. See Note 6, supra at 637.
[15]. See Note 7, supra at 6.
[16]. FDA Div. of Pediatric Drug Development, Presentation for Regulatory Briefing, January 11, 2005, DPDD, HFD-90 (Copy on file with author); Clinical Pharmacology, Rx List, Tacrolimus, www.rxlist.com.
[17]. Physician's Desk Reference, at 2250 (58th Ed. 2004).
[18]. Medical Reviews, Center for Drug Evaluation Research, Application NDA 50777, at 132-133 (Copy on file with author).
[19]. The approval file has numerous correspondence from the FDA continuing to ask for more information. (Copy on file with author).
[20]. See Note 18, supra, at 75.
[21]. Id. at 75-76.
[22]. Id. at 5.
[23]. Id. at 115.
[24]. Center for Drug Evaluation and Research Application NDA, 21:302, 11/06/01, at 3 (Copy on file with author).
[25]. Id. at 8.
[26]. Id. at 116.
[27]. Id. at 7.
[28]. See Note 16, supra.
[29]. Dec. 18, 2000, FDA Approvable Letter to Fujisawa, NDA 50-777, at 1.
[30]. See Note 18, at 73, Table 50 at 80.
[31]. Id. at 131.
[32]. The Pink Sheet, 2/10/05, No. 2; Pitts, Post Marketing Cases of Tumors Reported with Topical Immunosuppressants (Calcineurin Inhibitors), Center for Drug Evaluation and Research, 2/15/05, at 17. (Copy on file with author.)
[33]. See D. Arbitblit & W. Fleischman, The Risky Business of Off-Label Use, V. 41 Trial, No. 3, at 46-53 (Mar. 2005)
[34]. Pitts, supra, Note 32, at 8, 9, 12 & 14.
[35]. See Note 18, supra, at 115, 123.
[36]. www.aafp.org/afp/20021201/2103.html;
www.healthsystem.virginia.edu/uvhealth/peds_ent/lymphodenopathy.cfm; The Pink Sheet, 11/27/00, at 21.
[37]. See Note 18, supra, at 115, 123, 133, Addendum 1.
[38]. Physicians' Desk Reference, at 1327-1330 (Protopic); 2250-2252 (Elidel).
[39]. The Pink Sheet, 2/10/05, No. 2, at 1.
[40]. See Note 18, supra, at 24.
[41]. Regulatory Briefing Paper, Note 16, supra, at third page.
[42]. Id., at 1st page.
[43]. Id., at 2nd page.
[44]. B. Black & K. Altman, Deciphering The Adverse Event Reporting System, V. 41 Trial, No. 3, at 36-45 (Mar. 2005).
[45]. The Pink Sheet, 2/10/05, No. 2, at 1.
[46]. Pitts, supra Note 32, at 7, 11, 19.
[47]. Id. at 2.
[48]. Id.
[49]. See Note 12, supra; The Pink Sheet, 11/10/03, at 41 (10 year latency period).
[50]. Pitts, Note 32, supra, at 17. Hardly any citation is necessary to establish drug companies offering perks to doctors to prescribe their products. See 4/21/05 "Drug Companies Pile on Perks for Doctors," www.msnbc.msn.com/id/7575967
[51]. See Note 16, supra, at 2d page; Note 18, supra at 17; FDA Alert for Professionals, 3/20/05, druginfo@cder.fda.gov; Goodman & Gilman's, The Pharmacological Basis of Therapeutics, at 1295 (9th ed.).
[52]. FDA Alert, Note 51, supra.
[53]. See Note 18, supra, at 39 (Protopic); Note 24, supra, at 4 (Elidel).
[54]. Pitts, Note 32, supra, at 7, 11.
[55]. 2004 Annual Report, at 2, 115 (Copy on file with author).
[56]. Fujisawa Press Release, 1/31/05 (Copy on file with author).
[57]. See Note 16, supra, at 3rd page; Pitts, Note 32, supra, at 18.
[58]. See Note 18, supra, at 42.