FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PEDIATRIC ADVISORY SUBCOMMITTEE
OF THE
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
The Ballrooms
The Hilton Hotel
ATTENDEES
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)
STEVEN E. EBERT, PHARM.D.
Department of Pharmacy
MARY GLODE, M.D.
Professor of Pediatrics
The Children's
University of
DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE MEMBERS: (Voting)
ROSELYN EPPS, M.D.
Chief, Division of Dermatology
Children's
SHARON RAIMER, M.D.
THOMAS TEN HAVE, PH.D.
Department of Biostatistics and
Clinical Epidemiology
University of
SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)
ELIZABETH ANDREWS, M.D.
Vice President
RTI Health Solutions
PATRICIA CHESNEY, M.D., Meeting Chair
Professor of Pediatrics
University of
DAVID DANFORD, M.D.
Associate Professor of Pediatrics
University of
ATTENDEES (Continued)
SPECIAL GOVERNMENT EMPLOYEES-CONSULTANTS: (Voting)
(Continued)
ROBERT FINK, M.D.
Chairman, Department of Allergy and Pulmonary Medicine
Children's
NORMAN FOST, M.D., M.P.H.
University of
RICHARD GORMAN, M.D., FAAP
Pediatrician
Pediatric Partners
VICTOR SANTANA, M.D.
Associate Professor
Dependent of Hematology/Oncology
St. Jude's
Children's
BRUCE SCHNEIDER, M.D.
Associate Professor for Clinical Research
Association of American Medical Colleges
FEDERAL EMPLOYEES: (Voting)
DON MATTISON, M.D.
National Institute of Child Health and
Human Development, NIH
CONSTANTINE STRATAKIS, M.D.
National Institute of Child Health and
Human Development, NIH
BENJAMIN WILFOND, M.D.
Bioethics Research Section
National Institutes of Health
ATTENDEES (Continued)
FOOD AND DRUG ADMINISTRATION STAFF:
SHAAVHREE BUCKMAN, M.D.
DENISE COOK, M.D.
SOLOMON IYASU, M.D.
CLAUDIA KARWOSKI, PHARM.D.
BEVERLY LINDSAY, M.D.
DIANNE MURPHY, M.D.
BINDI NIKHAR, M.D.
THOMAS PEREZ, R.PH., M.P.H., Executive Secretary
JEAN TEMECK, M.D.
ANNE TRONTELL, M.D.
JONATHAN WILKIN, M.D.
ALSO PRESENT:
JERRY ROTH
C O N T E N T S
CLINICAL RISK MANAGEMENT OF HPA AXIS SUPPRESSION
IN CHILDREN WITH ATOPIC DERMATITIS
BEING TREATED WITH TOPICAL CORTICOSTEROIDS
* * *
AGENDA ITEM PAGE
CALL TO ORDER AND INTRODUCTIONS
By Dr. Joan Chesney 7
MEETING STATEMENT
By Mr. Thomas Perez 11
OPENING COMMENTS
By Dr. Dianne Murphy 13
By Dr. Jonathan Wilkin 15
ATOPIC DERMATITIS: ITS CLINICAL COURSE
AND THERAPEUTIC OPTIONS
By Dr. Bindi Nikhar 18
OVERVIEW OF HPA AXIS SUPPRESSION
By Dr. Jean Temeck 30
FDA EXPERIENCE: TOPICAL CORTICOSTEROIDS
AND HPA AXIS SUPPRESSION
By Dr. Denise Cook 46
POST-MARKETING ADVERSE EVENT REPORTS
By Dr. Claudia Karwoski 69
QUESTIONS TO THE SPEAKERS 79
FRAMEWORK FOR RISK ASSESSMENT AND
MANAGEMENT
By Dr. Anne Trontell 106
QUESTIONS TO THE SPEAKER 124
OPEN PUBLIC HEARING PRESENTATION
By Mr. Jerry Roth 147
PRESENTATION OF QUESTIONS TO THE COMMITTEE
By Dr. Dianne Murphy 156
DISCUSSION OF QUESTIONS 157
C O N T E N T S
(Continued)
SECTION 17, BEST PHARMACEUTICALS FOR CHILDREN ACT
ADVERSE EVENT REPORTING
* * *
AGENDA ITEM PAGE
MEETING STATEMENT
By Mr. Thomas Perez 235
ADVERSE EVENT REPORTS PER
SECTION 17 OF BPCA
By Dr. Solomon Iyasu 240
By Dr. ShaAvhree Buckman 252
OPEN PUBLIC HEARING 258
P R O C E E D I N G S
(
DR. CHESNEY: I think we are ready to begin. My name is Joan Chesney, and good morning. I would like to welcome the committee members, the consultants, the guests, and the members of the FDA.
Just briefly, today and tomorrow we will be reviewing two classes of drugs which have been approved for use in the treatment of atopic eczema topically: the topical corticosteroids and the topical immunosuppressants which inhibit the enzyme calcineurin.
Even with topical use often, when used inappropriately, the corticosteroids can cause suppression of the hypothalamic-pituitary axis and the immunosuppressants have been associated with lymphoproliferative disorders when given orally to patients and with lymphoma and follicular cell thyroid adenomas in rodents when given orally, and mouse photocarcinogenicity studies have been associated with cutaneous malignancies.
We are being asked today and tomorrow to provide feedback to the FDA regarding two specific issues. Number one, what are the specific risks of each event associated with each drug? And secondly, how should risk management programs be conducted for, number one, the prevention of HPA suppression with corticosteroids and, number two, with the topical immunosuppressants, how to design long-term registry programs to evaluate the potential cancer risk from exposure to these topical immunosuppressants?
As always, the FDA has provided us with excellent written materials to review and superb consultants to assist us with the discussion of these two questions.
If we could now turn to the introduction of the individual introductions of the people at the table, and I guess we'll start with Dianne.
DR. MURPHY: I'm Dianne Murphy and I'm the Office Director for the Office of Pediatric Therapeutics and also for the Office of Counter-terrorism and Pediatric Drug Development.
DR. WILKIN: I'm Jonathan Wilkin, Director of the Division of Dermatologic and Dental Drug Products.
DR. TRONTELL: I'm Anne Trontell, the Deputy Director of the Office of Drug Safety in the Center for Drugs.
DR. DANFORD: I'm David Danford, a pediatric cardiologist
at the University of Nebraska Medical Center and Creighton University School of
Medicine in
DR. SANTANA: Good morning.
I'm Victor Santana. I'm a
pediatric hematologist/oncologist at St. Jude's Children's
DR. GLODE: I'm Mimi Glode. I'm a member of the subcommittee. My background is pediatric infectious disease, and I work at Children's Hospital, University of Colorado School of Medicine in Denver.
DR. EPPS: I'm Dr. Roselyn Epps, the Chief of the Division of Dermatology at Children's National Medical Center, Washington, D.C.
DR. FOST: Norm Fost, Professor of Pediatrics, general pediatrician, and Director of the Bioethics Program at the University of Wisconsin.
DR. CHESNEY: I'm Joan Chesney. My field is infectious diseases, and I'm at the University of Tennessee in Memphis and St. Jude Children's Research Hospital.
MR. PEREZ: I am Tom Perez, Executive Secretary to this meeting.
DR. EBERT: I'm Steve Ebert. I'm a pharmacist in infectious diseases at Meriter Hospital and Professor of Pharmacy at the University of Wisconsin, Madison.
DR. GORMAN: I'm Rich Gorman. I'm engaged in the private practice of general pediatrics in Ellicott City, Maryland and a member of the subcommittee.
DR. SCHNEIDER: I'm Bruce Schneider. I'm Associate Vice President for Clinical Research at the Association of American Medical Colleges in Washington, D.C. I'm a clinical endocrinologist, formerly a medical officer at FDA, and before that Professor of Medicine at Albert Einstein College of Medicine in New York.
DR. FINK: Bob Fink, pediatric pulmonologist at Children's Medical Center in Dayton, Ohio, and Professor of Pediatrics at Wright State University.
DR. TEN HAVE: Tom Ten Have, Professor of Biostatistics, University of Pennsylvania, and member of the Dermatology Advisory Committee.
DR. ANDREWS: I'm Elizabeth Andrews. I'm a pharmacoepidemiologist. I'm Vice President of RTI Health Solutions at Research Triangle Institute in North Carolina.
DR. RAIMER: I'm Sharon Raimer. I'm a pediatric dermatologist from the University of Texas in Galveston, Texas.
DR. WILFOND: I'm Ben Wilfond. I'm a pediatric pulmonologist with the Department of Clinical Bioethics at the NIH and also with the National Human Genome Research Institute.
DR. MATTISON: Don Mattison. I'm at NICHD. My clinical training is in obstetrics.
DR. CHESNEY: Thank you.
Next on the agenda is the meeting statement by Tom Perez, our Executive Secretary.
MR. PEREZ: Thank you.
The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at the meeting.
The subcommittee will discuss the risk assessment and possible risk management strategies for hypothalamic-pituitary-adrenal axis suppression in children who are treated for skin disorders with topical corticosteroids.
The topic of today's meeting is an issue of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions.
All special government employees have been screened for their financial interests as they may apply to the general topics at hand. Because there have been reported interests in pharmaceutical companies, the Food and Drug Administration has granted a general matters waiver to Dr. Richard Gorman, which permits him to participate in today's discussions.
A copy of the waiver statement may be obtained by submitting a written request to the agency's Freedom of Information Office, room 12A-30 of the Parklawn Building.
Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each member and consultant. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.
In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.
Thank you.
DR. CHESNEY: Thank you.
Our first speakers, who will make opening comments, are Dr. Dianne Murphy and Dr. Wilkin. Dr. Murphy is the Director of the Office of Counter-terrorism and Pediatrics and the Director of the Office of Pediatric Therapeutics. Dr. Wilkin is the Director of the Division of Dermatologic and Dental Drug Products of the FDA. They will be providing us with an introduction and overview.
DR. MURPHY: Good morning and welcome to the lousy weather we have in what should be a glorious autumn, but unfortunately you will mostly be locked up in this room with us. So I guess it doesn't matter as much.
But we are delighted to have the committee meet and help advise us. We have combined the elements of our Pediatric Advisory Subcommittee and members of the Dermatology Advisory Committee, and we look forward to your recommendations to us today.
The good news is that we are bringing these questions to you today because we have conducted trials in children. We had this information brought to us because we asked for these studies to be done. The information, some of it or much of it, is the result of trials that were conducted in response to a written request which the FDA sent to sponsors, and if sponsors respond to these written requests and conduct the trials as we have asked them to do, they are awarded additional marketing exclusivity. This has been a tremendous motivator for the conduct of trials in children, which have been very necessary because, as we all know, the products are being used anyway. So like all things, once you get information, being mostly scientists here, it just tends to generate more questions, and that is exactly what has happened here.
You will hear over the next two days about two different classes of products that are used in diseases that can be serious, not life-threatening, but for which children need options. So these products, over the next two days, are linked. They are linked because they're treating similar diseases. They are linked because they're topicals, and they're linked because they, again, bring forth questions from the studies that have been conducted. And they're particularly linked ‑‑ and I think this is going to be the challenge to you over the next two days ‑‑ because they are, in essence, options for parents and children and physicians. If one can't use one, one may need to use the other. Yet, what we are asking you to help us with is how do we appropriately advise the people who are both prescribing these products and the parents who are using them when we are not able to clearly delineate the level of risk. That is really what you're going to struggle with over the next two days.
You are going to hear what we think the risk is, but not only what additional studies do we need, but how are we going to develop a risk management program that will not, in essence, limit options and yet clearly inform so that the selection of the product will be that it will be used in the safest manner until we are better informed about what the true risk is. As I said, you will also be asked questions about how to help us identify additional studies that might define this risk. So it's, I think, a very difficult task that you have in the next two days.
You're going to hear about risk management programs that we have and various approaches to risk management, but I think the real quandary to you is we're asking you to help us say when we don't have an absolute certainty on the risk, it is not completely defined, how do we best manage these risk management programs.
Thank you and we look forward to your discussion.
DR. CHESNEY: Dr. Wilkin?
DR. WILKIN: I'd be happy to make my very brief comments from here. I'd like to first echo Dr. Murphy's welcome.
I'd like to point out that we have pediatric dermatologic reviewers in our Division of Dermatologic and Dental Drug Products who will be looking forward to how the committee responds to the questions later in this day, but I would like to point out that they spend a lot of time looking over the transcripts for the entire meeting because what you say and discuss in each section is actually just as meaningful as specific fill-in-the-blank answers that come later in the day.
Dr. Murphy has given an overview of both days. I would like to say just a couple of words about what we'll think about today.
Topical corticosteroids have really been the workhorse for many dermatoses. Most dermatoses are, in fact, inflammatory and many of the dermatoses in children are inflammatory and respond to topical corticosteroids. There has been a lot of success and advantage from this group of products over the last four decades.
We have recognized for many years the potential for adrenal suppression with some of the topical corticosteroids, especially when used over larger body surface areas and in smaller children with a somewhat larger surface-to-volume ratio, and there may be some additional factors also in the younger children.
It's a difficult area to really think about. There is some uncertainty. There aren't many post-marketing reports of adverse events. On the other hand, we have substantial evidence for adrenal suppression with the testing that Dr. Murphy has described that we have been able to obtain from the different products during product development. I think by first principles, the agency has gotten to the stage where we believe that there are certain things we need to say in labeling about risk management, and we'll share with you where we are on this. But we're looking for the committee and for the experts to give us advice on are we where we need to be.
Again, adrenal suppression is silent. It's like hypertension or osteoporosis. I think the usually statement about osteoporosis is the first warning sign is there isn't any. It's a fracture. And that my be the case with adrenal suppression. It's either hidden from view until there is sepsis or some major traumatic event or it's really not detected.
Alvin Feinstein, who coined a lot of words, is the Yale clinical epidemiologist. One word that probably should have gotten picked up more and didn't was he used the word "lanthanic" for these kinds of conditions. It comes from Greek lanthanos, hidden from view, or lanthanine, to escape notice. You may recall from chemistry the lanthanide series of elements, the rare earth elements, the ones that were very difficult to detect. I think that's what we're talking about, a lanthanic kind of condition in Feinstein's terminology.
So, again, there is this kind of uncertainty and we would like to share this uncertainty, the first principles, how we've been thinking about it, how we've been crafting our statements for risk management, and get the sense of the committee, are we on target, are there other things we need to do.
Thank you.
DR. MURPHY: We depend on Jonathan to give us a new word.
(Laughter.)
DR. CHESNEY: I was thinking of laudanum. There must be a derivative there somewhere.
Our first formal presentation is by Dr. Nikhar, and Dr. Nikhar is a medical officer with the Division of Dermatologic and Dental Drug Products and a board certified pediatrician. She will present an overview of atopic dermatitis, its clinical course and therapeutic options.
DR. NIKHAR: Good morning. My talk this morning covers atopic dermatitis, its clinical course and therapeutic options.
Starting off with a brief introduction, atopic dermatitis is a chronic inflammatory disease of the skin, primarily seen in the pediatric age group. It is characterized by dry skin, pruritus, erythema, edema, scaling, excoriations, oozing, and lichenification. However, dry skin and pruritus are invariably present all stages of the disease. It is a multi-faceted disease showing increasing prevalence and rising costs, and together with asthma and allergic rhinitis, it forms part of the atopic triad.
Going on to epidemiology, currently about 10 to 20 percent of children in industrialized countries develop atopic dermatitis, and for reasons that are unclear, this number seems to be increasing. Environmental factors such as urbanization and development may be contributory factors. It is commoner in higher socioeconomic groups and in children from smaller families. The overall clearance is about 50 to 60 percent and 80 percent of children with severe disease continue to have lifelong exacerbations.
Considering morbidity, it has an impact on the quality of life at all ages, and this is due to psychological problems from visible skin lesions due to stigmatization, the itch-scratch cycle that is aggravated during flare-ups, sleeplessness, lack of concentration at school or work, and distress over repeated treatments, time involved, and financial costs.
Atopic dermatitis can cause a considerable drain on financial resources of patients and health services. The costs increase with disease severity and they're highest in the first few years, after which there's a decrease indicating a learning effect in the treatment of patients. And while the FDA does not consider pharmacoeconomic issues in drug approvals, we do recognize that cost is an important factor in drug availability.
Going on to clinical manifestations, atopic dermatitis is a condition of early infancy and in 50 to 75 percent of cases, the age of onset is 6 months or younger. A clearance rate of 60 percent is expected by age 16. However, relapses can occur in adulthood. A worse prognosis is indicated by severe childhood disease, early onset, concomitant or family history of asthma or allergic rhinitis, and a biparental history of atopy.
There are three main age-related stages. Dry skin and pruritus are associated with all stages. The skin barrier function is decreased and this may lead to increased absorption of topically applied treatments. However, this usually improves with adequate treatment.
The infantile phase is from 0 to 2 years of age. The onset can be around 3 months of age, and under 6 months, the face and scalp are commonly involved, while at an older age, the limb folds and hands may be involved. Red, scaly, crusted, weeping patches with excoriations may be seen on both cheeks and extensor surfaces of extremities, and typically the course is chronically relapsing and remitting.
These pictures, courtesy of the University of Erlangen, illustrates the features just described. The infant on the left has typical facial and upper chest involvement and probably has a body surface area involvement of about 20 to 25 percent, while the infant on the right has facial and extensor surface involvement as is again typical in this age group and probably has a body surface area involvement of about 30 to 35 percent.
The childhood phase is from 2 to 12 years of age. Here papular areas in flexural regions are common, and in areas of chronic involvement, persistent rubbing and scratching lead to lichenified plaques and excoriations.
The adult phase is from puberty onwards, and here flexural lichenified eczema with facial involvement in periorbital regions may be seen. The upper trunk, shoulders, and scalp may be affected, with chronic remissions and exacerbations.
In this picture, this young child shows flexural involvement, which is again typical of this age group, and probably has a body surface area involvement of about 35 to 40 percent.
The first picture on the left shows lichenification which is seen in areas of chronic involvement. The picture on the right on the top shows periorbital involvement. The young man on the left in the picture on the bottom shows impetigo, which is a complication that may be seen with atopic dermatitis, while the picture on the right shows typical flexural involvement.
The following are some of the reported immunological features of atopic dermatitis. There is increased IgE production with specific IgE to multiple antigens, increased basophil spontaneous histamine release, decreased CD8 suppressor/cytotoxic number and function, an increased expression of CD23 on mononuclear cells, chronic macrophage activation with increased secretion of granulocyte macrophage colony-stimulating factor, PGE2, and interleukin 10, an expansion of interleukin 4 and 5 secreting Th2-like cells and decreased numbers of interferon-gamma-secreting Th1-like cells.
The diagnosis of atopic dermatitis requires the presence of three or more major and three or more minor criteria, as defined by Hanifin and Rajka, which is a commonly used method. The major criteria include pruritus, lichenification, chronic or chronically relapsing course, and personal or family history of atopy. There are 23 minor criteria that have not been mentioned in this presentation.
As far as the management of atopic dermatitis, there is no single ideal treatment available. Each patient should have a flexible plan tailored for their need taking into account the severity of the illness, the resources available, the compliance of the patient, and so on.
Dietary history is important, but dietary manipulation remains controversial. Infants are most likely to benefit from this, in which case their nutritional status should be closely monitored.
Family education is important regarding atopic dermatitis and its clinical course, while measures to reduce exposure to allergens such as house dust mites, animals, and clothing should be discussed.
Going on to general treatment guidelines, moisturizers are the cornerstone of therapy in atopic dermatitis. Their frequent use, together with avoidance of drying bathing products, is important because atopic dermatitis is often accompanied by dry skin. Creams, ointments, or lotions can be used depending on individual needs.
Itch control is another important aspect. It can be a very distressing symptom leading to skin breakdown, infections, and lack of skin healing. Oral antihistamines, often of the sedating variety, are used to try and break the itch-scratch cycle.
Patients with extensive atopic dermatitis are often colonized with Staph. aureus. A course of oral antibiotics, plus or minus topical antibiotics, may be needed for lichenified, excoriated lesions not responding to treatment. Viral infections, for example, warts, eczema herpeticum, may be seen in these patients and should be appropriately managed.
The selection of treatment depends upon the disease severity, the age, the compliance, the efficacy and safety data, and treatment costs.
The following ‑‑ that is, the first three ‑‑ are some of the prescription treatment options available. Topical corticosteroids are currently the mainstay of first-line therapy of atopic dermatitis and will be discussed further. Topical immunosuppressants. This group of calcineurin inhibitors has been introduced as second-line therapy for treatment of atopic dermatitis and will also be discussed. Systemic corticosteroids are useful for severe, acute cases of atopic dermatitis. However, chronic use can lead to serious side effects and they should be used with caution.
The following are then the off-label and other treatment options available.
Photochemotherapy has been tried mainly in adults.
Cyclosporin was the first in the class of immunosuppressants to be introduced for recalcitrant atopic dermatitis. However, it can lead to serious systemic side effects such as hypertension, renal toxicity, and a propensity for malignant tumors, and this has limited its use.
Azathioprine, thymopentin, and interferon-gamma therapy have all been tried.
Traditional Chinese medicine has also been tried. However, liver function abnormalities and interstitial renal fibrosis has limited its use.
Gamma-linoleic acid in the form of evening primrose oil has also been tried.
Now going on to review topical corticosteroids. These were first introduced in the 1950s and are currently the mainstay of prescription therapy for atopic dermatitis. They are safe and effective when used as recommended. The weakest steroid that will keep the eczema under control should be used, and potent steroids should be used in short pulses, generally about 2 to 3 weeks.
The following are some of the factors to consider when prescribing topical corticosteroids. First, the type of preparation, that is, the base and the potency. The base can be an ointment, cream, emulsion, gel, or lotion, and this is important because that can affect the efficacy. The potency is classified from group I, which is the most potent, to group VII, which is the least potent.
Second, acute or chronic eczema.
Third, the age of the child. More potent steroids should be avoided in younger children.
Then the site to be treated, for example, the face and scalp need special attention in choosing potency of steroids.
Next, the extent of eczema. A higher body surface area involvement would lead to increased absorption.
And lastly, the method of application. For example, steroids used under occlusion would lead to increased absorption.
As far as the mechanism of action of topical corticosteroids, there are three effects.
The first is the anti-inflammatory effect. Topical corticosteroids affect inflammatory cells, chemical mediators, and tissue responses which are all responsible for cutaneous inflammation.
Second, the antiproliferative effects. Topical corticosteroids may reduce mitotic activity in the epidermis leading to flattening of the basal cell layer and thinning of the stratum corneum and granulosum.
And thirdly, the atrophogenic effects. Topical corticosteroids can promote atrophy of the dermis through inhibition of fibroblast proliferation, migration, chemotaxis, and protein synthesis.
Now considering the systemic effects of topical corticosteroids. If a topical corticosteroid is absorbed percutaneously in significant quantities, it can cause systemic adverse effects similar to systemically administered corticosteroids. And this is discussed under adverse effects, and so the adverse effects can result from the drug substance or the vehicle which can potentiate problems.
The following are some of the systemic adverse effects of topical corticosteroids. Suppression of hypothalamic-pituitary-adrenal axis, atrogenic Cushing's syndrome, growth retardation in infants and children. And these effects are usually associated with a large body surface area use of potent topical corticosteroids and will be discussed further in the next presentation by Dr. Temeck.
The following are some of the risk factors for systemic adverse effects. Young age, especially infants and children, liver and renal disease, the amount of steroid applied, the extent of skin disease treated, the frequency of application, the length of treatment, the potency of drug, and the use of occlusion. It is not established whether catch-up growth in children will occur when steroids are discontinued.
These are the local side effects of topical corticosteroids. Epidermal atrophy leading to wrinkled skin with prominent vasculature, pseudoscars, striae, or purpura; steroid dependence or rebound; glaucoma and cataracts; and an increased susceptibility to bacterial, fungal and viral infections.
Now going on to the next class of drugs, topical immunosuppressants, these will be discussed in brief today and in further detail tomorrow. This is the newest pharmacological class for atopic dermatitis. These drugs were introduced in this decade. They have a direct immunosuppressive action in diseases with an immunological basis. There are two currently FDA-approved products: tacrolimus, FK506, the trade name being Protopic; and pimecrolimus, SDZ ASM 981, the trade name being Elidel.
Now reviewing their background. Protopic ointment was approved in December of 2000. There are two strengths available. The .03 percent ointment was approved for children 2 to 15 years of age, while the .1 percent ointment was approved for adults. The indication in both age groups is short and intermittent long-term therapy of patients with moderate to severe atopic dermatitis.
Systemic tacrolimus, or Prograf, was first introduced for prevention of allograft rejection and is now used in kidney, liver, and heart transplantation.
Elidel cream 1 percent was approved in December of 2001. It is indicated for patients 2 years of age and older for short and intermittent long-term therapy in the treatment of mild to moderate atopic dermatitis. Both drugs were not approved for use in children less than 2 years of age. And systemic absorption can take place in both adult and pediatric age groups from the topical application of both drugs.
And further, pediatric patients enrolled in clinical studies of tacrolimus and pimecrolimus had an increased frequency of certain adverse events, for example, viral infections compared to vehicle, and currently the effects of topical immunosuppressants on the developing immune system are unknown.
Thus, the indication for use, as mentioned, is second-line therapy in the treatment of atopic dermatitis. Both Protopic and Elidel are indicated for patients in whom the use of alternative, conventional therapies are deemed inadvisable because of potential risks or in the treatment of patients who are not adequately responsive to or are intolerant of alternative, conventional therapies.
Lastly, I wish to acknowledge Diepgen, Yihune, et al., and the Dermatology Online Atlas for the pictures used in this presentation. And that brings me to the end.
DR. CHESNEY: Thank you very much.
I understand we'll have time for asking questions of the speakers after our next three speakers.
Next, Dr. Jean Temeck, who is a medical officer in the Division of Pediatric Drug Development and a board certified pediatrician and pediatric endocrinologist, will present an overview of the hypothalamic-pituitary-adrenal axis suppression secondary to the use of topical corticosteroids.
DR. TEMECK: Good morning and welcome. Thank you all for coming today to help us sort out some very difficult issues.
The topic of my presentation is hypothalamic-pituitary-adrenal axis suppression following topical corticosteroid administration. I'm going to be covering the following topics in this presentation: the regulation of glucocorticoid secretion, the spectrum of hormonal effects of exogenous glucocorticoids on the HPA axis, the spectrum of clinical manifestations of adrenal insufficiency, the importance of diagnosing it, the tests which are used to diagnose it, and the risk factors for HPA axis suppression.
This slide depicts the regulation of glucocorticoid secretion. The hypothalamus secretes corticotropin-releasing hormone, or CRH, which stimulates the pituitary gland to synthesize and secrete ACTH. The ACTH, in turn, stimulates the adrenal gland to synthesize and secrete cortisol. As cortisol levels rise, they suppress the secretion of ACTH and CRH.
Exogenous glucocorticoids may have variable effects on the HPA axis. They may not suppress the HPA axis at all or they may suppress the secretion of ACTH and CRH, and this is termed secondary or central adrenal insufficiency.
The degree of this suppression is variable. It may be mild or partial or it may be complete. If suppression is mild or if it is short-term, only the pituitary ACTH response to stress may be impaired. Both the basal ACTH and cortisol levels may be normal, as well as the adrenal cortisol response to stress. If suppression is severe or prolonged, then adrenal cortical atrophy may occur, and in this circumstance, the basal cortisol levels are low and the entire HPA axis is suppressed.
The clinical manifestations of adrenal insufficiency are variable. Some patients are asymptomatic but their HPA axis is suppressed by hormonal testing. This hormonal suppression is not just an abnormal laboratory finding. It is clinically relevant because when the HPA axis is suppressed, the patient is at risk for an acute adrenal crisis during periods of stress. Other patients with adrenal insufficiency may be symptomatic and the symptoms are generally nonspecific and subtle, such as weakness, lethargy, or decrease in appetite, and they may be insidious in onset. Other patients with adrenal insufficiency may present with an acute adrenal crisis, and this is generally triggered by stress, stress of a febrile illness, for example, trauma or surgery. It is characterized by fever, severe hypotension and shock which may progress to coma and death unless the patient is treated emergently with supplemental glucocorticoids.
This slide reinforces the concept that all patients with HPA axis suppression, regardless of whether they have symptoms or not, are at risk for an acute adrenal crisis during periods of stress.
The true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, and this may be because of several factors. One, there may be lack of clinical suspicion. There may be failure to recognize that topical corticosteroids are systemically absorbed, and therefore they can cause HPA axis suppression. In addition, because the signs and symptoms of adrenal insufficiency are so subtle and nonspecific, clinical suspicion is not aroused and therefore diagnostic testing is not performed or attribution is made to other causes.
For example, if a child with HPA axis suppression secondary to topical corticosteroid use for atopic dermatitis sustains major trauma from a car accident, the ensuing shock may be attributed solely to the car accident without recognizing the contribution of the adrenal insufficiency to the shock.
Another reason that the true prevalence is not known is if the period of suppression induced by the steroids is short so that the short period of suppression goes undetected.
Finally, if a hormonal test with low sensitivity is used for diagnosis, one may get a false negative test result and therefore the adrenal insufficiency is not diagnosed.
Identifying patients with adrenal insufficiency even if it is mild, is important because these patients are at risk for life-threatening hypotension during periods of stress, and the condition is totally preventable if supplemental glucocorticoids are administered before or early in the course of the stress.
The following slides will describe the tests that are available to make the diagnosis. Basically there are two types of tests which are available: the basal hormonal tests and also the dynamic tests.
The dynamic tests fall into two groups: those which test the integrity of the adrenal gland only and those which test the integrity of the entire HPA axis.
There are two basal hormonal tests which are available for diagnosis: the plasma cortisol level and either single or multiple measurements may be obtained; and also the 24-hour urinary free cortisol test.
Plasma cortisol levels are only helpful if the level is either very low or very high. For example, a level cutoff usually used is less than 3 micrograms per deciliter, which is drawn early in the morning around 8:00 a.m., that is soon after the peak cortisol surge occurs, or if the level is very high, greater than or equal to 20 micrograms per deciliter, and that can be obtained at any time of day. Unfortunately, measurements of plasma cortisol usually fall between these two extremes, and therefore they are not diagnostic.
Likewise, the 24-hour urinary free cortisol level is often non-diagnostic because normal individuals may have low cortisol excretion rates and also there may be difficulty in obtaining a complete 24-hour urine, especially in infants.
Due to the low sensitivity of these basal tests, most patients do require dynamic testing for diagnosis. And the advantage of the dynamic testing is that it provides information regarding the function, the reserve capacity, and hence the ability of the adrenal gland or of the entire HPA axis to respond to stress.
There are four dynamic tests which are available to make this diagnosis. Two of these tests, the high-dose and the low-dose cosyntropin stimulation tests, assess only the ability of the adrenal gland to respond to exogenous ACTH. The other two tests, the insulin tolerance test and the CRH test, assess the ability of the entire HPA axis to respond to stress.
This concept can be described graphically. With the cosyntropin tests, exogenous ACTH is administered and this stimulates the adrenal gland to release cortisol. So the cosyntropin test directly assesses the ability of the adrenal gland to release cortisol.
With the CRH test, exogenous CRH is administered and this directly stimulates the pituitary gland to release ACTH.
With the insulin tolerance test, one administers insulin and then subsequently you get a hypoglycemia. The hypoglycemia is a potent stress stimulus for the release of both CRH and ACTH. So then you can see that the ITT and the CRH tests directly assess the ability of the pituitary gland or also of the hypothalamus to release ACTH and CRH, respectively.
Remember that secondary adrenal insufficiency, secondary to exogenous glucocorticoid administration, means that the pituitary ACTH reserve capacity is impaired. As I just pointed out, the ITT and the CRH tests directly assess pituitary ACTH reserve, and therefore these tests are very sensitive for diagnosing secondary adrenal insufficiency.
The cosyntropin stimulation test will also be sensitive for diagnosing secondary adrenal insufficiency if it is chronic or longstanding. The chronic ACTH deficiency leads to adrenal gland atrophy and this is the basis for an abnormal cosyntropin test. However, if the ACTH deficiency is of recent onset, then adrenal gland atrophy may not have had time to develop and therefore the cosyntropin test will be normal although secondary adrenal insufficiency is present.
Likewise, if the ACTH deficiency is mild, there may be sufficient secretion of ACTH to prevent involution of the adrenal gland. So then again the cosyntropin test will be normal although secondary adrenal insufficiency is present.
Therefore, if secondary adrenal insufficiency is of mild or recent onset, the cosyntropin stimulation test may yield a false negative result, and additional testing may be needed in such circumstances if the patient is symptomatic or if there is a high index of suspicion of adrenal insufficiency.
The next few slides will describe each of these four dynamic tests which are available to diagnose adrenal insufficiency.
The high-dose cosyntropin test is the one that is most commonly used to make this diagnosis. A supraphysiologic dose of synthetic ACTH is administered either IV or IM. The cosyntropin label states that this dose is usually 250 micrograms, but that a dose of 125 micrograms may be sufficient in a child who is 2 years of age or younger. Serum cortisol levels are obtained at baseline and at the completion of the test. The advantage of this test is that it is simple, fast, and inexpensive. It can be performed at any time of day as an outpatient and you can complete the test in an hour or less.
The cosyntropin label refers to both the 30-minute cosyntropin stimulation test, as well as the 60-minute test. Since as you will hear from Dr. Denise Cook's talk that the clinical studies that were performed generally use the 30-minute test, it's the 30-minute test that we will predominantly focus on now.
There is controversy regarding the criteria that should be used to define a normal cortisol response. The cosyntropin label mentions three criteria. A basal cortisol level should be greater than 5 micrograms per deciliter. The peak cortisol level should be greater than 18 micrograms per deciliter, and the increment, which is the difference between the baseline cortisol and the peak cortisol levels, should be greater than or equal to 7 micrograms per deciliter. However, the label does specify that since this test can be performed at any time of day and since it is only the peak level which is not dependent on the time of day, the peak cortisol level is sufficient in and of itself to make the diagnosis of adrenal insufficiency.
I would also like to mention that use of the increment may be problematic because the increment is inversely proportional to the basal cortisol level, so that the higher the basal cortisol level, the lower the increment. Therefore, most endocrinologist use a peak cortisol level of greater than 18 micrograms per deciliter to denote a normal response to the 30-minute test.
The disadvantage of this test has already been mentioned. You can get a false negative test when the secondary adrenal insufficiency is mild or is of recent onset. Additional testing may be needed if the patient is symptomatic or there is a high index of suspicion of adrenal insufficiency.
The next test for discussion is the low-dose cosyntropin stimulation test. This is a newer test, and a physiologic dose of ACTH, either 0.5 microgram per meter squared or in other circumstances 1 microgram per meter squared ‑‑ those are some of the ACTH doses which have been used as reported in the literature in children ‑‑ is administered intravenously, and then blood samples are obtained at baseline for cortisol measurement and then serially post ACTH administration. Because such a low dose of ACTH is being administered in this test and ACTH has a very short half-life, this test requires frequent, carefully timed blood sampling because you do not want to miss the peak cortisol response.
Some have reported that this is a more sensitive test than the high-dose test to detect mild secondary adrenal insufficiency because you are administering a physiologic dose of ACTH and therefore only mobilizing the cortisol that is available in the immediate release pool. However, results of studies on this issue have been conflicting.
In addition, there is no standard method of performance for this test either with regard to the dose of ACTH that should be administered or the frequency or the timing of the blood samples post ACTH administration.
In addition, this low dose of ACTH is not commercially available, and therefore dilutional errors can occur. There can be variability in the amount of the ACTH that is administered from test to test, and there is at least one report of adherence of part of the ACTH to the plastic tubing of the vein delivery set.
This slide compares the low-dose to the high-dose ACTH test. Again, with the low-dose test, this dose is not commercially available, but the 250 microgram dose is. Low-dose, you're administering a physiologic ACTH dose; with the high-dose test, you're administering a supraphysiologic dose. The low-dose test, as we said, requires frequent, carefully timed venous sampling, while with the high-dose test, only a single cortisol level needs to be obtained at the end of the test and it does not have to be precisely timed. While there is no consensus on method of performance of the low-dose test, the method of performance with the high-dose test has been standardized. And while with the high-dose test there is no consensus regarding what constitutes a normal cortisol response, with the high-dose test, it is generally accepted that a peak cortisol level greater than 18 micrograms per deciliter with a 30-minute test constitutes a normal response. So as you can see, on balance, the high-dose test offers a number of advantages over the low-dose test.
The next two slides will describe the insulin tolerance test. As we mentioned before, hypoglycemia is a potent stress stimulator for the release of CRH and ACTH. This test involves administration of intravenous insulin after an overnight fast. Plasma cortisol and glucose levels are obtained before and at 30, 45, 60, and 90 minutes post insulin administration. A normal response is a peak cortisol level of greater than 18 to 20 micrograms per deciliter at 60 to 90 minutes post insulin administration, with a concomitant serum glucose level of less than 40 milligrams per deciliter.
Although this test provides a direct and definitive assessment of HPA axis integrity, it is a very high-risk test, and there has been significant neurologic morbidity and also mortality has been reported with conduct of this test in children. Therefore, this test is rarely, if ever, used. Safer diagnostic alternatives are available.
The next three slides will discuss the CRH test. This test is a newer test, and as we said, the physiologic basis for this test is that CRH stimulates the release of ACTH and hence of cortisol.
A 1 microgram per kilogram dose of CRH is administered intravenously, and plasma ACTH and cortisol levels are measured periodically for 90 to 180 minutes post CRH administration. This test has been used to differentiate primary from secondary from tertiary adrenal insufficiency. With primary adrenal insufficiency, basal ACTH levels are high, and they increase with CRH administration but cortisol levels do not. Both secondary and tertiary adrenal insufficiency are characterized by low levels of ACTH basally. With secondary adrenal insufficiency, you get a flat response to CRH administration, while with tertiary adrenal insufficiency, you get an exaggerated ACTH response to CRH. However, I would like to point out that the distinction between secondary and tertiary adrenal insufficiency is not important here because we're talking about adrenal insufficiency secondary to exogenous glucocorticoid administration.
The advantages of this test are several. The CRH test provides a direct and definitive assessment of HPA axis integrity. There are also reports that the CRH test has equivalent diagnostic value to the insulin tolerance test, but unlike the insulin tolerance test, the CRH test is safe and it can be conducted as an outpatient.
There are a number of disadvantages to this test. First, it is expensive and it does require performance of multiple blood samples. There may be errors in blood collection and storage, and this is because ACTH has a short half-life. It's readily inactivated by proteases so that when you're collecting the samples for ACTH, you have to collect them in pre-chilled containers and then the specimen should be kept frozen to minus 20 degrees Centigrade until ready for assay.
In addition, the normal responses of ACTH on cortisol are laboratory-dependent, and so there is no consensus regarding what constitutes a normal response.
Also, FDA has not approved the CRH test as a diagnostic for adrenal insufficiency. It has only approved it for the use of the differential diagnosis of Cushing's syndrome, whether the ACTH hypersecretion is from the pituitary or from an ectopic source.
Additional studies are needed to confirm the usefulness of this test as a diagnostic for adrenal insufficiency.
We'll now discuss risk factors for HPA axis suppression. Again, to remind you, there is individual susceptibility. HPA axis suppression is variable as is time to recovery. Therefore, the diagnosis of adrenal insufficiency does require performance of hormonal testing.
Nevertheless, there are a number of risk factors that may influence the development and the degree of HPA axis suppression. Certainly the higher the potency of the steroid used and the longer the half-life, the greater the risk of suppression. Also, the vehicle or base used, that is, whether the preparation is a cream, a lotion, or an ointment, may also be an influencing factor, and Dr. Cook will discuss this in her talk.
The greater the extent of absorption, the greater the risk of suppression. Absorption of topical corticosteroids is increased by thin stratum corneum such as found in the face in the intertriginous areas. Absorption is also enhanced in areas of heat and moisture, such as found in the intertriginous areas. And likewise, absorption is greater when the steroid is applied to abraded or inflamed skin as opposed to if you had an intact skin barrier.
Also, the greater the amount of steroid used, the greater the risk of suppression. With topical corticosteroids, the dose administered is a function of the concentration of the steroid in the base vehicle and the percent of skin surface area that is covered. We know that infants are particularly susceptible or vulnerable to HPA axis suppression. It's postulated that this is due to the higher ratio of skin surface area to body mass.
In addition, the longer the contact time of the steroid with the skin, the greater the risk of suppression.
The cumulative dose is a function of the dosing interval and the duration of treatment. The more frequent the application, the less the chance of HPA axis recovery between applications so that continuous application would be expected to be more suppressive than intermittent application.
With regard to duration of treatment, if a topical steroid is used for, let's say, a week or 2 or less, one would anticipate less chance of suppression and if it did occur, there would be more rapid recovery.
These next three slides will summarize the main points of this presentation.
First topical corticosteroids are systemically absorbed and therefore they may cause secondary adrenal insufficiency.
The symptoms of adrenal insufficiency may be subtle and nonspecific, and therefore the diagnosis may not be suspected clinically or attribution is made to other causes.
Patients with secondary adrenal insufficiency are at risk for an acute adrenal crisis regardless of the degree of suppression or the presence of symptoms. An acute adrenal crisis is preventable if supplemental glucocorticoids are administered before or early in the course of stress.
Although risk factors for HPA axis suppression may be present, individual susceptibility is variable.
Hormonal testing is required for the diagnosis, and basal hormonal tests are often nondiagnostic. Therefore, the majority of the patients do require dynamic hormonal testing.
Dynamic tests of HPA axis integrity are more sensitive for the diagnosis of mild or recent onset secondary adrenal insufficiency than are tests which measure only adrenocortical reserve.
A negative cosyntropin test may warrant additional testing, particularly if the patient is symptomatic or if there is a high index of suspicion of secondary adrenal insufficiency.
When HPA axis suppression is diagnosed, treatment should follow standard medical practice and the patient should be followed to document full recovery of the axis.
Thank you.
DR. CHESNEY: