Basis for Decision

The decision to issue an advisory was based on data from animal studies, case reports from a small number of patients, and information about their mechanism of action that were presented to a hearing of the FDA Pediatric Advisory Committee.¹ It may take 10 years or longer to determine if the use of these calcineurin inhibitors is linked to cancer in humans. In the meantime, because this risk is uncertain, the FDA advised that these drugs should be used only as labeled for patients who have failed treatment with other therapies.

US FDA Recommendations

The FDA recommended that healthcare providers, patients, and caregivers should consider

• using pimecrolimus and tacrolimus only as second-line agents for short-term and intermittent treatment of atopic dermatitis in patients who are unresponsive to or intolerant of other treatments.
• avoiding use of these drugs in children younger than 2 years of age. Their effect on the developing immune system in infants and children is not known. In clinical studies, infants and children younger than 2 years old treated with pimecrolimus had a higher rate of upper respiratory infections than did those treated with placebo cream.²
• using these drugs only for short periods of time, not continuously. Their long-term safety is unknown.
• not using these drugs in children and adults with a weakened or compromised immune system.
• using the minimum amount of pimecrolimus and tacrolimus needed to control the symptoms. In animals there was a dose-related response, i.e., increasing the dose and duration reportedly resulted in higher rates of cancer.²

Data from Animal Studies and Human Case Reports

Animal studies presented at the hearing included data from three species (mice, rats, and monkeys) that developed cancer following exposure to these drugs applied orally or topically. These studies were conducted at doses ranging from 1.5-340 times higher than that generally used by humans.¹ The warning is also based on 29 reports of cancer including 12 lymphomas and 8 skin malignancies (e.g., basal cell carcinomas, squamous cell carcinomas, and Kaposi’s sarcoma) in adults and children previously treated with these immunomodulators. In total there were six reports of cancer in children, the youngest being 2 years of age. Cause and effect have not been established.^1,3

On the basis of the advice from the Pediatric Advisory Committee, the FDA will require labeling changes for pimecrolimus and tacrolimus, including the placement of a boxed warning about the potential cancer risk. In addition, the FDA will work with the commercial sponsors of the drugs to develop and implement a Medication Guide (MedGuide) to provide this information as well as instructions about appropriate use of these drugs to patients, their families, and caregivers. MedGuides are intended to be distributed by pharmacists with each prescription or refill of a medication.

Dermatologist Comments at the Hearings

At the hearing, dermatologist Robert A. Silverman, MD, of Fairfax, Virginia, spoke on behalf of the Academy of American Dermatology (AAD), urging the FDA not to impose a black box warning or other labeling restrictions because such steps could limit access to these medications, or limit treatment options if qualified patients decide not to use these medications because of fear of a cancer risk.⁴

Lawrence Eichenfield, MD, also addressed the Committee, stating that atopic dermatitis places a tremendous burden on individuals and families, and that calcineurin inhibitors have had a great impact on improving their quality of life. Patients and physicians now have a choice in addition to emollients and topical corticosteroids. These products have allowed the ability to mix and match medications and allowed tailoring of treatment to disease severity.¹

AAD Response

After the FDA decision was announced, Clay J. Cockerell, MD, president of the American Academy of Dermatology responded, “The Academy is disappointed that the FDA has taken this action, despite the fact that there is no data that proves proper topical use of these drugs is dangerous in humans. Because these medications are applied to the skin, virtually none of it gets inside the body. It’s not the same as taking a pill. These are valuable medications, and if used properly, they significantly reduce the debilitating impact of eczema and allow millions of our patients to live normal lives.”⁴

CDA Response

The Canadian Dermatology Association (CDA) reported that these drugs have been studied collectively in more than 38,000 subjects, including 14,000 children under the age of 17 years. To date there have been 2 cases of malignancy reported with pimecrolimus (no lymphoma) and no cases reported with tacrolimus in the clinical trials programs. In the spontaneous reporting programs, 6 cases have been reported with pimecrolimus (4 lymphomas) and 19 cases with tacrolimus (10 lymphomas). None of the cases of malignancy were reported in children younger than 2 years of age. The number of lymphomas observed in treated patients is below the expected number of lymphomas in both adult and pediatric populations and for cases where enough information was available they were assessed by external experts as unlikely to be linked to the use of topical calcineurin inhibitors. Thus, the current available information does not support an increased risk for lymphoma development associated with the use of topical calcineurin inhibitors. The CDA believes that topical calcineurin inhibitors are an important therapeutic class for the treatment of atopic dermatitis in children and adults and that the FDA and TPD recommendation for a warning of this nature is not supported by clinical evidence and experience.⁵

Skin Therapy Letter® Poll

In an effort to provide clarification to clinicians and their patients, Skin Therapy Letter® conducted a poll of some of the world’s leading dermatologists:

Has the recent US FDA decision to add a black box warning label for pimecrolimus and tacrolimus altered the way in which you prescribe these drugs?

YES: 3       NO: 13

In the absence of convincing evidence, most of those polled said that these warnings will not alter their prescribing habits. Some stated that they had not changed the way in which they prescribed these drugs, but spent extra time counseling patients.6-8

Would you restrict their use in children?

YES: 3       NO: 13

The majority of respondents said they would not restrict their use in children.

Would you limit their use below 2 years of age?

YES: 7       NO: 9

A slight majority would not limit their use. Some noted that they would limit use of these calcineurin inhibitors to those children whose eczema could not be maintained adequately with topical corticosteroid use.^6-8

Have many of your patients expressed concern about using calcineurin inhibitors?

YES: 9       NO: 7

Because their patients had asked about it, they took the time to reassure them and provide reports of the safety data seen in human clinical trials.

Have pharmacists in your area demonstrated reluctance in filling prescriptions for these drugs?

YES: 1       NO: 15

Only one dermatologist has experienced reluctance on the part of the pharmacists to fill his prescriptions.⁶

Conclusion

After assessing the results of the Skin Therapy Letter® survey and reviewing the reports by the American Academy of Dermatology and the Canadian Dermatology Association, I would suggest that both of these drugs should be monitored and periodic reappraisals of any untoward reports be published. However, new warnings without new evidence will only serve to increase doubt in the minds of the prescriber and reduce patient access to worthwhile drugs.

Experts Polled

1. Kenneth A. Arndt   –   Harvard Medical School, Boston, MA, USA
2. Jim Bergman   –   University of British Columbia, Vancouver, BC, Canada
3. Hugo Degreef   –   Catholic University, Leuven, Belgium
4. Lawrence Eichenfield   –   University of California at San Diego, San Diego, CA, USA
5. Boni Elewski   –   University of Alabama, Birmingham, AL, USA
6. Steven R. Feldman   –   Wake Forest University School of Medicine, Winston-Salem, NC, USA
7. Herald P. Gollnick   –   Otto von Guericke University, Magdeburg, Germany
8. Mark Lebwohl   –   Mt. Sinai Medical Center, New York, NY, USA
9. Harvey Lui   –   University of British Columbia, Vancouver, BC, Canada
10. Howard I. Maibach   –   University of California at San Francisco, San Francisco, CA, USA
11. Jean-Paul Ortonne   –   Hôpital de l’Archet, Nice, France
12. Jason K. Rivers   –   University of British Columbia, Vancouver, BC, Canada
13. J. H. Saurat   –   University of Geneva, Geneva, Switzerland
14. Robert Silverman   –   Georgetown University, Washington, DC, and University of Virginia at Charlottesville, Charlottesville, VA, USA
15. Bruce Strober   –   New York University School of Medicine, New York, NY, USA
16. Klaus Wolff   –   University of Vienna, Vienna, Austria

Acknowledgment

I am very grateful to these world-recognized authorities on calcineurin inhibitors for providing answers to the above questions.

References

1. Transcript of the sixth meeting of the US FDA Pediatrics Advisory Committee.
2. FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. Press release (2005 Mar 10).
3. Elidel and Protopic. Med Lett Drugs Ther 47(1205):25 (2005 Mar 28).
4. American Academy of Dermatology issues statement in response to FDA decision related to two eczema medications. Press release (2005 Mar 10).
5. CDA Position Statement on topical calcineurin inhibitors (2005 Apr). Available from URL:
6. Eichenfield L. Personal communication, April, 2005.
7. Lebwohl M. Personal communication, April, 2005.
8. Bergman J. Personal communication, April, 2005.

There is no drug that has provided as much therapeutic benefit for 12 million acne patients as this retinoid has done in the past 18 years following its introduction. However, it is a retinoid and, therefore, a teratogen. In spite of the elaborate pregnancy prevention program put in place by Hoffman-LaRoche, as well as a tracking program monitored by the Slone Epidemiology Unit in Boston Massachusetts, there are patients taking isotretinoin who still get pregnant. More recently, adverse psychiatric events have surfaced in patients who have taken isotretinoin (Accutane).

Such adverse events triggered these meetings called by the US FDA. On September 18th and 19th a joint meeting of the Dermatologic and Ophthalmic Drug/Pharmaceutical Science
Advisory Committees met to discuss three issues with regard to isotretinoin (Accutane):

• risk management regarding pregnancy and isotretinoin use
• possible link with psychiatric events
• a new formulation (Accutane NF) for which an NDA was submitted by Hoffman-LaRoche in October 1999.

Day 1

On the first day of meetings, risk management options to prevent pregnancy in patients taking Accutane were explored by the Committee. Discussions included Roche’s revised US Pregnancy Prevention Program (Targeted PPP or T-PPP). The Committee recommended that a risk management program for pregnancy prevention should consist of Roche’s T-PPP, a mandatory physician and patient enrollment, as well as establishing a linkage between the pharmacy that dispenses an Accutane prescription and confirmation of negative pregnancy test results for the patient.

Day 2

The second day of meetings focused on risk management options for psychiatric events and Accutane NF, Roche’s new formulation.

In light of the lack of clear linkage between depressive illness and Accutane, an opinion expressed by several FDA Committee members, the Committee defeated a motion to expand the registry to include all patients, and to include questions about psychiatric illness in the registry’s informed consent database. Currently, the registry only includes women in their childbearing years. But, the committee did recommend that Roche and NIH fund additional research in this area including a basic science study on retinoids and retinoid receptors in the adolescent and adult brain, prospective controlled studies, etc.

The Committee supported the new formulation because the dosage is less than the current formulation, and there is a reduced variability of drug absorption when taken with or without food. However, they noted that there could be possible consequences associated with the simultaneous availability of the two formulations for both patients and prescribers. Roche stated that it will be launching Accutane NF in very different packaging than the original formulation and will be providing additional information on the new formulation to prescribers.

Conclusion

By the end of the meetings, the Dermatologic and Ophthalmic Drug/Pharmaceutical Science Advisory Committees supported the new formulation (Accutane NF). The Committee agreed that there was at present no causal link between psychiatric events and
Accutane. In spite of this, they recommended additional research with regard to possible psychiatric connections to Accutane, as well as the establishment of a registry to track women who are in their childbearing years taking Accutane. Challenges await Hoffman-LaRoche and the US FDA in establishing such a registry. It will be interesting to follow their progress.