1 Advisory Committee Meeting, 15 February, 2005. FDA Perspective Topical Immunosuppressants Bindi Nikhar, MD. Division of Dermatologic and Dental Drugs

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Advisory Committee Meeting, 15 February, 2005.

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

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

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IntroductionIntroductionIntroductionIntroduction

• 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)

• 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)

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Topical Corticosteroids (TCS)Topical Corticosteroids (TCS)Topical Corticosteroids (TCS)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

• 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

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TacrolimusTacrolimusTacrolimusTacrolimusAdvisory Committee meeting on 11/16/2000 • Second-line therapy in the treatment of atopic

dermatitis (AD)• Not be approved in children < 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

Advisory Committee meeting on 11/16/2000 • Second-line therapy in the treatment of atopic

dermatitis (AD)• Not be approved in children < 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

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TacrolimusTacrolimusTacrolimusTacrolimus

• 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

• 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

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PimecrolimusPimecrolimusPimecrolimusPimecrolimus• 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 March;5(3):643-55, Wolf K, Stuetz A. Pimecrolimus for the treatment of inflammatory skin diseases.

• 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 March;5(3):643-55, Wolf K, Stuetz A. Pimecrolimus for the treatment of inflammatory skin diseases.

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Clinical studies for PimecrolimusClinical studies for PimecrolimusClinical studies for PimecrolimusClinical 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 (%)

• 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 (%)

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Indications for UseIndications for UseIndications for UseIndications 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 < 2 years of age

• 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 < 2 years of age

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Recent ConcernsRecent ConcernsRecent ConcernsRecent Concerns

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


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Proposed mechanisms of actionProposed mechanisms of actionProposed mechanisms of actionProposed 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

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

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PharmacokineticsPharmacokinetics PharmacokineticsPharmacokinetics • 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 -Netherton’s syndrome, generalized erythrodermic skin conditions, eg. GVHD

• 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 -Netherton’s syndrome, generalized erythrodermic skin conditions, eg. GVHD

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AERS reports of systemic AERS reports of systemic exposureexposure

AERS reports of systemic AERS reports of systemic exposureexposure

• Acute renal failure reported in a patient with Netherton’s 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

• Acute renal failure reported in a patient with Netherton’s 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

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Cases of systemic exposureCases of systemic exposureCases of systemic exposureCases 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 Netherton’s syndrome (3-14 years) after treatment with topical tacrolimus.

* Journal of Pediatrics, August 2003, vol 143, number 2** Arch Dermatology 2001, 137: 747-750

• * 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 Netherton’s syndrome (3-14 years) after treatment with topical tacrolimus.

* Journal of Pediatrics, August 2003, vol 143, number 2** Arch Dermatology 2001, 137: 747-750

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Cases of systemic exposureCases of systemic exposureCases of systemic exposureCases 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.

• ** 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.

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Adverse EffectsAdverse EffectsAdverse EffectsAdverse Effects

Local (application site):• Burning, pruritus, erythema, irritation, edema,

urticariaSystemic: • 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)

Local (application site):• Burning, pruritus, erythema, irritation, edema,

urticariaSystemic: • 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)

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Systemic immunosuppression and Systemic immunosuppression and malignanciesmalignancies


• Patients receiving Prograf (systemic tacrolimus) are at an increased risk of developing Hodgkin’s, Non-Hodgkin’s lymphomas, Kaposi’s 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

• Patients receiving Prograf (systemic tacrolimus) are at an increased risk of developing Hodgkin’s, Non-Hodgkin’s lymphomas, Kaposi’s 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

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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 1998;66:1193-200, Jain AB, Yee LD, Nalesnik et al.

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 1998;66:1193-200, Jain AB, Yee LD, Nalesnik et al.

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Systemic immunosuppression & skin Systemic immunosuppression & skin cancers*cancers*

Systemic immunosuppression & skin Systemic immunosuppression & skin cancers*cancers*

• Squamous & basal cell carcinomas account for > 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; 348:1681-91. Skin cancers after organ transplantation.

• Squamous & basal cell carcinomas account for > 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; 348:1681-91. Skin cancers after organ transplantation.

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Systemic immunosuppression and Systemic immunosuppression and lymphomalymphoma

Systemic immunosuppression and Systemic immunosuppression and lymphomalymphoma

• 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

• 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

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Possible mechanisms of topical Possible mechanisms of topical immunosuppressants in causing immunosuppressants in causing

malignancy-related eventsmalignancy-related events

Possible mechanisms of topical Possible mechanisms of topical immunosuppressants in causing immunosuppressants in causing

malignancy-related eventsmalignancy-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

• 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

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Case report of lentigines in area of Case report of lentigines in area of topical tacrolimus usetopical 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

* 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

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• 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.

• 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.

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Case report (cont’d)Case report (cont’d)Case report (cont’d)Case report (cont’d)• 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 ?

• 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 ?

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Concerns in the pediatric age groupsConcerns in the pediatric age groupsConcerns in the pediatric age groupsConcerns 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

• 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

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Expanding useExpanding useExpanding useExpanding 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

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

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Use characteristics Use characteristics Use characteristics 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 < 2 years of age

• How often are they being used first-line?

• Use of both drugs is increasing in the US

• Use is increasing in the pediatric age groups

• Substantial proportion of use is in children < 2 years of age

• How often are they being used first-line?

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Concerns about long-term useConcerns about long-term useConcerns about long-term useConcerns 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

• 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

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October 2003 Pediatric Advisory October 2003 Pediatric Advisory Committee MeetingCommittee Meeting

October 2003 Pediatric Advisory October 2003 Pediatric Advisory Committee MeetingCommittee 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

• 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

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Recent HistoryRecent HistoryRecent HistoryRecent History

AERS malignancy related reports for tacrolimus and pimecrolimus since approval

• 21 with tacrolimus • 9 with pimecrolimus Confounding factors not unusual for AERS events

AERS malignancy related reports for tacrolimus and pimecrolimus since approval

• 21 with tacrolimus • 9 with pimecrolimus Confounding factors not unusual for AERS events

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Recent ConcernsRecent Concerns Recent ConcernsRecent Concerns



Documents

1 Advisory Committee Meeting, 15 February, 2005. FDA Perspective Topical Immunosuppressants Bindi Nikhar, MD. Division of Dermatologic and Dental Drugs