Topical tacrolimus and pimecrolimus: cancer, infections--"a clearly unfavorable benefit-risk ratio"-- Prescrire International 2010 ; 19 (110) : 257   English edition.

Le Figaro reports (below French with English translation by Professor David Cohen*) that Astellas Pharma, the Japanese multinational pharmaceutical company has filed a lawsuit in Paris against the independent French medical journal, Prescrire, for  having "denigrated" the use of its anti-eczema ointment, Protopic (Tacrolimus).

Tacrolimus ointment suppresses the immune system and the inflammation by inhibiting an enzyme (calcineurin) crucial for the multiplication of T-cells, cells that are required for activation of the immune system.

FDA Alert to healthcare workers  [3/2005]:

The FDA has issued a public health advisory to inform healthcare professionals and patients about a potential cancer risk from use of Protopic (tacrolimus). This concern is based on information from animal studies, case reports in a small number of patients, and knowledge of how drugs in this class work. It may take human studies of ten years or longer to determine if use of Protopic is linked to cancer. In the meantime, this risk is uncertain, and FDA advises Protopic should be used only as labeled, for patients after other prescription treatments have failed to work or cannot be tolerated.

Updated FDA label warnings (2006) include a boxed warning about a possible risk of cancer. Additionally, the FDA required an FDA-approved, patient Medication Guide to be distributed with each prescription to help ensure that patients using these prescription medicines are aware of this concern.

"The new labeling also clarifies that these drugs are recommended for use as second-line treatments. This means that other prescription topical medicines should be tried first. Use of these drugs in children under 2 years of age is not recommended."

Below we post FDA's Division of Pediatric Drug Development recommendations (Jan. 2005) "based on the totality of scientific information available thus far...The evidence raises serious safety concerns in children regarding the potential for carcinogenicity in humans treated with these agents [Protopic and Elidel]."

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

Prescrire's independent analysis of the data shows "a clearly unfavorable benefit-risk ratio" for use of the ointment "for prevention" of eczema. 

This is not the first time that a pharmaceutical company attempted to bully a medical journal that reported unfavorable findings about a prescription drug.

In 2005, Eli Lilly threatened to sue the BMJ (formerly the British Medical Journal)  when a BMJ news report, that relied on authentic internal Eli Lilly documents, challenged Lilly's claims about the safety of Prozac.

See: http://www.ahrp.org/infomail/05/01/27.php

Let's hope that the French courts will protect the integrity of the medico-scientific journals to publish credible information about the safety of prescription medicines--whether favorable or unfavorable to their manufacturers.

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  AFP

Un laboratoire attaque Prescrire

04/01/2011 | Mise à jour : 20:36 Réactions (7)

Le laboratoire Astellas Pharma a assigné en justice la revue médicale Prescrire pour avoir "dénigré" l'utilisation de l'un de ses produits, le Protopic, dans la prévention d'une maladie, l'eczéma atopique, a indiqué aujourd'hui à l'AFP la revue. L'audience se tiendra demain après-midi devant le tribunal de grande instance de Paris, a précisé l'avocat de la revue médicale indépendante, Me Jean Martin.

 La revue, spécialisée dans l'analyse des bienfaits et des méfaits des médicaments, avait critiqué l'usage du médicament "en prévention" de cette maladie de peau dans son numéro de septembre 2009. Le mensuel notait que le "tacrolimus (nom de la molécule du Protopic) dermique en +prévention+" pour l'eczéma atopique" est "un traitement à écarter". "Gare aux cancers, a fortiori avec un usage au long cours", avertissait l'article.

 Cette pommade pour la peau, toujours dans cet usage préventif, a "une balance bénéfices-risques nettement défavorable", soutenait Prescrire évoquant par ailleurs de possibles "irritations et infections cutanées" (herpès, impétigo, etc.)" liées à cette nouvelle indication du traitement.

 Le laboratoire Astellas Pharma estime que ce "dénigrement" lui porte préjudice et dénonce "le caractère erroné, voire mensonger, de certaines critiques figurant dans l'article litigieux". Pour l'avocat de la revue, "c'est la liberté d'expression et l'exercice de la liberté de critique qui sont en jeu".

The Japanese multinational pharmaceutical company Astellas Pharma has launched a suit in Paris against the independent French medical journal Prescrire for having "denigrated" the use of one of its prescription drugs, Protopic, as a preventive treatment for atopic eczema, according to an Agence France-Presse bulletin published in France's Le Figaro of January 4, 2011. A hearing will be held tomorrow afternoon before the High Court in Paris, according to Jean Martin, attorney for Prescrire.

Prescrire is an independent monthly medical journal financed entirely by subscription, and it states that it accepts no grants nor advertising of any sort. It specializes in the analysis of benefits and harms of medications. Prescrire's English language edition is available at: http://english.prescrire.org/en/Summary.aspx

According to Le Figaro, Prescrire had criticized the use of Protopic "for prevention" of eczema in its September 2009 issue. The journal noted that applying "tacrolimus [the generic name of Protopic] as prevention for atopic eczema" is "a treatment to avoid." "Beware cancers, especially with long-term use," warned the journal. It also mentioned the possibility of "cutaneous irritations and infections" such as herpes and impetigo linked to the new approved indication of tacrolimus as a preventive treatment.

As a preventive treatment, the ointment has "a clearly unfavorable benefit-risk ratio," concluded Prescrire. In the United States, since 2006, the Protopic Ointment drug label contains a black-box warning of the possible risk of cancer.

According to the Figaro article, Astellas Pharma believes that this "denigration" is harmful to the company and denounces "the erroneous and untrue nature of certain critiques contained in the litigious article." According to Prescrire's attorney, "freedom of expression and the exercise of the freedom to criticize are at stake."

David Cohen, PhD, LCSW
Professor
Robert Stempel College of Public Health and Social Work
Florida International University

Ph/Fx: 305-348-4599/5312

*Professor Cohen serves as the Secretary of the Alliance for Human Research Protection.

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http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4089b2_01_02_DPDD%20Consult.pdf

Subject: Protopic and Elidel Presentation for Regulatory Briefing on January 14, 2005

Date: January 11, 2005

Reviewer: Dr. Jean Temeck

Acting Medical Team Leader

DPDD, HFD-960

 The Division of Pediatric Drug Development (DPDD) recommends a boxed warning for both Protopic and Elidel. This recommendation is based 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. We believe regulatory action is needed at this time since a definitive answer to the carcinogenic risk of these products will not be known for years and the difficulty of designing a clinical study that will provide a definitive answer to this question

 For background, Protopic Ointment (tacrolimus) and Elidel Cream (pimecrolimus) are indicated for the short-term and intermittent long-term treatment of atopic dermatitis in patients >2 years of age who are either unresponsive or intolerant of alternative, conventional therapies or in whom the use of these therapies is deemed inadvisable due to potential risks. Protopic and Elidel are calcineurin inhibitors and immunosuppressants. Although their exact mechanism of action is not known, they exert direct immunosuppressive effects as evidenced by inhibition of T cell activation and inhibition of various interleukins and interferon gamma.

 Although these products are applied topically, they may be systemically absorbed. Detectable drug levels in the blood are more frequently observed in children than in adults. This higher systemic drug exposure in children may be related to their greater body surface area to mass ratio.

Scientific evidence for systemic immunosuppression from topical application of these products is available in both humans and animals.

 In animals, the carcinogenicity signal is strong, consistent, and dependent on dose and treatment duration. In mice, lymphoma formation was reported with application of Protopic and with Elidel dissolved in ethanol, at 26x and 47x MRHD (maximum recommended human dose) based on AUC comparisons, respectively. In addition, the median time to skin tumor formation was decreased in hairless mice following chronic Protopic administration with concurrent exposure to UV irradiation. Furthermore, the latency time to lymphoma formation was shortened to 8 weeks after administration of Elidel in ethanol to mice at a dose of 179-217x MRHD based on AUC comparisons.

 In humans, post-marketing tumor-related adverse events related to these products continues to be reported. Since marketing approval (12/08/00 for Protopic and 12/13/01 for Elidel), 7 cases of lymphoma have been reported, four with Protopic and three with Elidel. Five of these 7 cases occurred in adults; one, in a 2 year old child; and one in a patient of unreported age. Duration of use is known in 5/7 cases (several weeks, 5 months, 6 months in 2 and 1 ½ years in another); occurrence was reported at the site of drug application in one.

In addition, there is one case of cutaneous Kaposi’s sarcoma which developed at the site of Protopic application and that became metastatic in an HIV positive adult. To date, 6 cases of skin cancer (of which three were recurrences) have been reported in adults, five with Protopic and one with Elidel. In 4/6 cases, the latency time to skin cancer was reported: 1-2 weeks, 3-4 weeks, 8 weeks and 3 months. Of these 6 cases, there was a history of atrophic lichen sclerosis in two cases and occurrence at the site of drug application in 2 different cases. Of note, the incidence of skin papillomas, a risk factor for precancerous lesions and cancer, was reported pre-marketing in children treated with Elidel (in the Adverse Reactions section of the Elidel package insert, the incidence of skin papillomas in the 6-week pediatric study was 0.4% (1/267) with Elidel and 0 (0/136) with vehicle control; in the 1-year safety study, it was 3.3% (9/272) with Elidel and <1% of 75 patients treated with vehicle control ). Post-marketing, 2 cases of papilloma have been reported with Elidel, one in a child and one in an adult. Additional post-marketing tumor-related cases in children include one case each of facial tumor, type unspecified, with Elidel cream, Sezary’s syndrome after three years of Protopic use, hepatoblastoma after one year of Protopic use and one case of sudden increase in size of metastatic angiosarcoma after three months of Protopic use.

Additional supportive evidence of immunosuppression in pediatric patients includes the increased incidence of specific infections that occurred with these products compared to vehicle alone in the pediatric clinical trials conducted pre-marketing. These results are reported in the Pediatric Use and Adverse Reactions sections of the Package Inserts. Of the cases of infections reported post marketing in pediatric patients, the most significant case was that of an 8-month old male who developed eczema herpeticum with pseudomonas sepsis and subsequent cardiac arrest. Protopic ointment was applied over his entire body for 6 months. Of note, the serum tacrolimus level was 3.5 ng/ml two weeks after Protopic had been discontinued. The patient survived.

It is known that oral or parenteral administration of immunosuppressant drugs is associated with an increased incidence of infection and cancer, particularly lymphoma. Tacrolimus injection (Prograf), cyclosporine and azathioprine, all of which include an indication for prevention of organ transplant rejection, contain a boxed warning. Although a systemic preparation of tacrolimus, Prograf, is available, there currently is no marketed systemic preparation of Elidel. Of note, a recent non-human primate study conducted with an oral formulation of Elidel which is under development, demonstrated the occurrence of lymphoma in all dose groups studied, including the lowest dose which represented 30x MRHD for the topical product. Therefore, a NOEL for lymphoma was not established in this study. Of further concern, lymphoma was reported in one of four recovery animals despite discontinuation of treatment. In this study, lymphoma was associated with a latent infection by an Epstein Barr related virus which is the same mechanism described in immunosuppressed humans following transplantation. In addition, three of nine monkeys developed concurrent leukemia.

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

These products are indicated for the intermittent but chronic treatment of a non life-threatening condition, atopic dermatitis. The abraded skin characteristic of atopic dermatitis increases systemic absorption of these drugs and, as noted above, children have higher systemic blood levels of these drugs compared to adults, and, thus, greater systemic drug exposure. Given that these topical products may be applied chronically in a young child over an extensive surface area of abraded skin, there is potential for significant cumulative drug exposure. As demonstrated in the animal carcinogenicity studies, the development of lymphoma was dependent on cumulative drug exposure, being a function of dose and treatment duration. The increasing number of post-marketing tumor-related adverse events is concerning because they too, like the animal carcinogenicity findings and the known carcinogenicity potential with systemic administration of these drugs to humans, relate to the mechanism of action of this drug class, i.e., immunosuppression.

CFR 201.57 provides the Agency with the legal and regulatory authority to require a boxed warning based on serious animal toxicity in the absence of clinical data. FDA has previously exercised this authority. Such was the case for Forteo (teriparatide injection) and Flagyl (metronidazole tablets). Therefore, there is precedent.

A boxed warning is the most effective labeling tool FDA has to convey a potential safety signal or risk. It is also recommended that the PPI for these products inform patients/parents/caregivers of the potential cancer risk based on the animal carcinogenicity findings and the post-marketing adverse events.

The use of these products continues to increase, including use in the very young, although they are not approved in patients less than 2 years of age. For example, from June, 2003-May, 2004, the number of prescriptions dispensed for Protopic, increased by 16% and for Elidel, by 46%, compared to the previous year. In this same time period, patients aged 1-2 years, accounted for 8% and 13% of Protopic and Elidel prescriptions, respectively.

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

A presentation entitled: “ELIDEL Redefining Successful Therapy…A Blockbuster in the Making!” was delivered by Kurt Graves, Chief Marketing Officer, Novartis, on their 2003 R&D day. Included in this presentation were plans to develop the drug for flare prevention among other indications (e.g., chronic hand dermatitis) and to expand usage to infants with atopic dermatitis.

In conclusion, based on the scientific information available to date which raises serious safety concerns regarding the potential for carcinogenicity of these agents in humans, the Division of Pediatric Drug Development recommends that a boxed warning be included in the Package Inserts for Protopic and Elidel