FDA Perspective

1

• FDA Perspective
• Topical Immunosuppressants
• Bindi Nikhar, MD.
• Division of Dermatologic and Dental Drugs

2
Introduction

• Topical immunosuppressants are the newest class
  of drugs to be approved for atopic dermatitis
  (AD)
• They belong to a class of drugs known as
  macrolactam immunosuppressants, which were first
  introduced in the 1980s for prevention of graft
  rejection in transplant therapy
• Tacrolimus (FK506) (trade name Protopic)
• Pimecrolimus (SDZ ASM 981) (trade name Elidel)

3
Topical Corticosteroids (TCS)

• Antiinflammatory effects
• - TCS inhibit nuclear factor kappa
  B (NFkB), which upregulates cytokines. Inhibition
  done by increasing production of NFkB inhibitor
  (IkB) and directly binding inactivating NFkB
• - Affects leukocytes, lymphocytes, monocytes,
  epidermal Langerhans cells
• - Inhibit phospholipase A2 inhibit
  prostaglandins leukotrienes
• - Vasoconstrictive
• - Antipruritic - Mast cell sensitization IgE
  induced mediator release inhibited
• Antiproliferative Atrophogenic effects

4
Tacrolimus

• Advisory Committee meeting on 11/16/2000
• Second-line therapy in the treatment of atopic
  dermatitis (AD)
• Not be approved in children lt 2 years of age
• Only the lower concentration be approved for 2 to
  15 years
• - 12 week study in pediatric patients
  
• equivalent efficacy for both strengths
• - larger BSA more absorption
• - longer exposure long-term safety unknown

5
Tacrolimus

• Protopic (topical tacrolimus) approved on
  12/8/2000. 0.03 ointment approved for children 2
  to 15 years, 0.1 ointment approved for adults
• Prograf (systemic tacrolimus) approved on
  4/8/1994, first introduced for allograft
  rejection, currently used mainly in kidney and
  liver transplants

6
Pimecrolimus

• Elidel (pimecrolimus) cream 1 approved on
  12/13/2001 for patients 2 years of age and older
• Phase 3 studies higher incidence of adverse
  effects () in Elidel arm vs. vehicle arm URI
  (24/14 ), pyrexia (32/13), otitis media (4/0),
  gastroenteritis (7/3), diarrhea (8/0)
• Currently available only for topical use
• Literature report - oral formulation under
  development for psoriasis and atopic dermatitis
• Expert Opinion on Pharmacotherapy. 2004
  March5(3)643-55, Wolf K, Stuetz A. Pimecrolimus
  for the treatment of inflammatory skin diseases.

7
Clinical studies for Pimecrolimus

• 2-17 years - 1 year safety study,
  nasopharyngitis (26/21), influenza (13/4),
  pharyngitis (8/3), viral infection (7/1), pyrexia
  (13/5), cough (16/11), headache (25/16)
• 3-23 months 6 week study, pyrexia (32/13), URI
  (24/14), nasopharyngitis (15/8), gastroenteritis
  (7/3), otitis media (4/0), diarrhea (8/0)
• 3-23 months 1 year study, pyrexia (30/20), URI
  (21/17), cough (15/9), vomiting (9/4), rhinitis
  (13/9), viral rash (4/0), rhinorrhea (4/0),
  wheezing (4/0)
• all adverse events, Elidel vs. vehicle ()

8
Indications for Use

• Tacrolimus moderate to severe AD
• Pimecrolimus mild to moderate AD
• Both 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
• Neither drug approved for children lt 2 years of
  age

9
Recent Concerns

• UNCERTAIN RISK FOR CANCER
• Biological plausibility
• Emerging signal in AERS
• Difficult to study and answers would be late
• INFORMATIONAL LANDSCAPE
• Suggests first-line
• Steroid-free, Direct-to-consumer advertising
• Other indications
• Peer and non-peer reviewed literature portrays
  safety
• CURRENT PRACTICES
• Overall use increasing
• Use in lt 2 years increasing

10
Proposed mechanisms of action

• Clinical significance of these observations
  in atopic dermatitis are unknown.
• T P bind to FK-binding protein
  (FKBP)
• T/P-FKBP complex inhibits calcineurin
• inhibits T cell activation
• Both inhibit production of
  pro-inflammatory cytokines from mast cells and
  down regulate the production of Th1 and Th2 type
  cytokines

11
Pharmacokinetics

• Systemic absorption can take place in both adult
  and pediatric age groups from the topical
  application of both drugs
• Factors leading to increased absorption include
• Larger body surface areas
• Younger age groups, especially the 3 to 23 month
  age groups due to the larger body surface area to
  mass ratio
• Reduced skin barrier function -Nethertons
  syndrome, generalized erythrodermic skin
  conditions, eg. GVHD

12
AERS reports of systemic exposure

• Acute renal failure reported in a patient with
  Nethertons syndrome secondary to topical
  absorption of tacrolimus. 0.1 ointment used
• for 1 year. On admission, tacrolimus level
  34.4 ng/ml, BUN/creatinine 54/3.4. On
  discharge, tacrolimus level 2.3 ng/ml,
  creatinine 1.9
• Tacrolimus 0.1 ointment was used in a 11 month
  old patient to treat GVHD secondary to BMT.
  Patient died tacrolimus levels were 75 ng/ml at
  time of death

13
Cases of systemic exposure

• Literature report - 7 month patient with BMT
  secondary to SCID. At age 7 months, single
  application of tacrolimus 0.1 on scalp for
  chronic dermatitis tacrolimus level
  24 ng/ml at 20 hours after application. After 7
  days, 0.03 ointment used level 7
  ng/ml at 20 hours after application with
  transient tremor of the upper limbs and jaw.
• Increased tacrolimus levels have been reported
  in 3 patients with ichthyosis and Nethertons
  syndrome (3-14 years) after treatment with
  topical tacrolimus.
• Journal of Pediatrics, August 2003, vol 143,
  number 2
• Arch Dermatology 2001, 137 747-750

14
Cases of systemic exposure

• Literature report - 28 month old patient with
  lamellar ichthyosis, 0.1 tacrolimus ointment
  used over 100 of BSA. 7 weeks later
  tacrolimus level 19.3 ng/ml 3 hours after
  application. 2 weeks later, after decreased
  amount of use level 7.4 ng/ml. 2 weeks
  later, after decreased frequency (twice daily
  every third day) tacrolimus level 5.8
  ng/ml.
• Archives Dermatology, vol 138, Sep. 2002.

15
Adverse Effects

• Local (application site)
• Burning, pruritus, erythema, irritation, edema,
  urticaria
• Systemic
• Respiratory gastrointestinal infections, viral
  skin rashes (herpes simplex and zoster, eczema
  herpeticum), lymphadenopathy, streptococcal
  staphylococcal infections, leg amputation due to
  infection (P - no further information),
  septicemia (T), septic arthritis (P), renal
  failure (T)

16
Systemic immunosuppression and malignancies

• Patients receiving Prograf (systemic tacrolimus)
  are at an increased risk of developing Hodgkins,
  Non-Hodgkins lymphomas, Kaposis sarcomas, and
  in particular skin cancers such as squamous cell
  carcinomas (SCC), basal cell carcinomas (BCC) and
  malignant melanomas
• Literature reports suggest a correlation between
  tumor regression and reduction in
  immunosuppression

17
Systemic immunosuppression and malignancies

• Comparative incidence of de novo
  non-lymphoid malignancies after liver
  transplantation under tacrolimus protocols done
  using SEER data
• 1000 liver transplant patients, median follow-up
  6.5 years, 57 malignancies
• 22/57 (33.3) were skin malignancies 50 SCC,
  40.9 BCC, 9.1 melanomas
• SEER incidence rates not available for SCC BCC
• Malignant melanoma - 1.94 times SEER rates
• Oropharyngeal cancers - 7.6 times SEER rates
• Transplantation 1998661193-200, Jain AB, Yee
  LD, Nalesnik et al.

18
Systemic immunosuppression skin cancers

• Squamous basal cell carcinomas account for gt
  90 of all skin cancers in transplant recipients
  melanomas 6.2 in adults (15 in children)
• Cancers more aggressive, incidence increases with
  duration of immunosuppressive therapy tapering
  therapy usually decreases rate
• Cancers affect 50 or more of white transplant
  patients (genetic difference present)
• Australian study incidence 7 after I year of
  therapy, increased to 82 after 20 years
• Dutch study incidence 0.2 after 1 year and
  long-term incidence 41.
• N Engl J Med 2003 3481681-91. Skin cancers
  after organ transplantation.

19
Systemic immunosuppression and lymphoma

• Post transplant lymphoproliferative disorder
  (PTLD) in immunosuppressed patients related to
  Epstein-Barr virus infection is a well-recognized
  complication
• Risk of PTLD appears greatest in young children
  who are at risk for EBV infection while
  immunosuppressed
• Risk appears to be related to the intensity and
  duration of immunosuppression
• Prograf label

20
Possible mechanisms of topical immunosuppressants
in causing malignancy-related events

• Topical immunosuppressants may break local
  immune surveillance resulting in skin cancers
• T P draining from atopic skin into regional
  lymph nodes may result in immunosuppression
• Systemic exposure to these drugs over a course
  of time could lead to the formation of lymphomas
  and skin cancers

21
Case report of lentigines in area of topical
tacrolimus use

• 3 children with severe atopic dermatitis
  were noted at routine follow-up to have developed
  multiple small pigmented macules during long-term
  therapy with topical tacrolimus 0.1.
• 4 year old patient with severe AD, tacrolimus
  0.1 ointment used 6 months after start of
  therapy, multiple lentigines noted over sites of
  continued tacrolimus use.
• 7 year old patient with severe AD, tacrolimus
  0.1 ointment used 5 months after start of
  therapy, multiple lentigines noted especially
  over area of therapy.
• British journal of Dermatology 2005 152,
  152-154

22
Case report of lentigines in area of topical
tacrolimus use

• 11 year old patient with severe AD, tacrolimus
  0.1 ointment used after about 3 and a half
  years of onset of therapy, multiple lentigines
  noted, especially over area of therapy.
• Histology confirmation present in 2 cases,
  treatment discontinued, lesions persisted.
• Lentigines also occurred at sun-protected sites.
• Per report, focal distribution of lentigines to
  sites of tacrolimus use and the temporal
  association between use of tacrolimus and
  development of lesions suggest direct etiology.

23
Case report (contd)

• Simple lentigines are small pigmented macules
  that usually appear in childhood on sun-exposed
  sites.
• They represent the simplest form of melanocytic
  neoplasia and are one end of a spectrum of
  melanocytic maturation that ranges from
  lentigines to junctional, compound and dermal
  naevi.
• Post-inflammatory changes documented in AD, but,
  discrete pigmented macules are not documnted.
• Systemic immunosuppressants reported to cause an
  increase in melanocytic activity.
• Does topical tacrolimus have an effect
  (undefined) on melanocyte biology ?

24
Concerns in the pediatric age groups

• Long-term effects of topical immunosuppressants
  and their effects on the developing immune system
  in infants and children are unknown
• Medications used on an intermittent, long-term
  basis
• About one third of children with moderate to
  severe AD may continue to use these drugs into
  teenage and adult years

25
Expanding use

• Literature reports suggest use in following
  conditions
• Contact dermatitis, chronic hand dermatitis,
  seborrheic dermatitis, rosacea, psoriasis, lichen
  planus, lichen sclerosus et atrophicus, Graft vs.
  Host disease, pyoderma gangrenosum, etc
• Pimecrolimus Patients 3-18 months, atopic
  march study investigating benefits of
  long-term management of AD, starting in infants
  at first sign of disease
• Novartis web site

26
Use characteristics

• Use of both drugs is increasing in the US
• Use is increasing in the pediatric age groups
• Substantial proportion of use is in children lt 2
  years of age
• How often are they being used first-line?

27
Concerns about long-term use

• Both drugs are being widely reported as safe and
  effective with some local side effects, but being
  steroid-free
• In medical and non-medical journals, need for
  long-term safety information and larger patient
  numbers is often ignored

28
October 2003 Pediatric Advisory Committee Meeting

• 5 malignancy related events associated with
  tacrolimus and 2 non-malignant tumors with
  pimecrolimus
• (Newer malignancy related events have since
  been reported)
• Logistics of cancer registry was to be discussed
• Difficult to initiate, answers not available for
  10 to 12 years, inconclusive
• Label revisions, addition of a black box and
  other risk management issues were discussed

29
Recent History

• AERS malignancy related
  reports for tacrolimus and pimecrolimus since
  approval
• 21 with tacrolimus
• 9 with pimecrolimus
• Confounding factors not unusual for AERS
  events

30
Recent Concerns

• UNCERTAIN RISK FOR CANCER
• Biological plausibility
• Emerging signal in AERS
• Difficult to study and answers would be late
• INFORMATIONAL LANDSCAPE
• Suggests first-line
• Steroid-free, Direct-to-consumer advertising
• Other indications
• Peer and non-peer reviewed literature portrays
  safety
• CURRENT PRACTICES
• Overall use increasing
• Use in lt 2 years increasing