Post-Marketing AE Reports of Post-Marketing AE Reports of Topical Calcineurin InhibitorsTopical Calcineurin InhibitorsPost-Marketing AE Reports of Post-Marketing AE Reports of Topical Calcineurin InhibitorsTopical Calcineurin Inhibitors

Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee

Marilyn R. Pitts, Pharm.D.,Marilyn R. Pitts, Pharm.D.,Safety Evaluator, Office of Drug SafetySafety Evaluator, Office of Drug Safety

October 30, 2003October 30, 2003

Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee

Marilyn R. Pitts, Pharm.D.,Marilyn R. Pitts, Pharm.D.,Safety Evaluator, Office of Drug SafetySafety Evaluator, Office of Drug Safety

October 30, 2003October 30, 2003

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

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OutlineOutline

• Background • Drug Use• Methods• AERS Adverse Event Profile

– Pediatric subgroup– Death/Hospitalized cases– Malignant and non-malignant cases – Infection cases

• Summary

• Background • Drug Use• Methods• AERS Adverse Event Profile

– Pediatric subgroup– Death/Hospitalized cases– Malignant and non-malignant cases – Infection cases

• Summary

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Topical Calcineurin Inhibitors Topical Calcineurin Inhibitors Topical Calcineurin Inhibitors Topical Calcineurin Inhibitors

Pimecrolimus 1%

Tacrolimus 0.03% & 0.1%

Approved: 12/13/2001 12/08/2000

2nd Line Tx: Yes Yes

Indication: Mild to mod. atopic

dermatitis…

Mod. To Severe atopic dermatitis…

Approved for children < 2

No No

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# Prescriptions & Appearances # Prescriptions & Appearances IMS Health National Prescription Audit IMS Health National Prescription Audit PlusPlusTMTM, ,

IMS National Disease & Therapeutic Index AuditIMS National Disease & Therapeutic Index AuditTMTM

# Prescriptions & Appearances # Prescriptions & Appearances IMS Health National Prescription Audit IMS Health National Prescription Audit PlusPlusTMTM, ,

IMS National Disease & Therapeutic Index AuditIMS National Disease & Therapeutic Index AuditTMTM

Since Approval Pimecrolimus

1%

Topical Tacrolimus

0.03%, 0.1%

Total Rx 3,230,000 2,004,000

Appearances0 to 2 yrs 17% 8%

Appearances3 to 16 yrs 36% 29%

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Some Common Elements in Some Common Elements in Product LabelingProduct Labeling

Some Common Elements in Some Common Elements in Product LabelingProduct Labeling

Pimecrolimus 1%

Topical Tacrolimus

0.03% + 0.1%

Varicella zoster Yes Yes

Herpes Simplex Yes Yes

Eczema herpeticum Yes Yes

Lymphadenopathy Yes Yes

Local Skin rxn Yes Yes

Systemic Absorption Yes Yes

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AERS Electronic DatabaseAERS Electronic Database

– Adverse Event Reporting System

• 1969 – SRS

• 1997 – replaced by AERS

• ~ 3 million AE reports for drugs–Medwatch forms

– Adverse Event Reporting System

• 1969 – SRS

• 1997 – replaced by AERS

• ~ 3 million AE reports for drugs–Medwatch forms

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MethodsMethods

Separate search of AERS database:

– All reports with pimecrolimus as suspect agent

– All reports with tacrolimus administered topically as suspect agent

Separate search of AERS database:

– All reports with pimecrolimus as suspect agent

– All reports with tacrolimus administered topically as suspect agent

Pimecrolimus 1% CreamPimecrolimus 1% CreamPimecrolimus 1% CreamPimecrolimus 1% CreamApproved 12/13/2001Approved 12/13/2001

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Pimecrolimus – Overall Findings Pimecrolimus – Overall Findings (Adult and Pediatric, n = 79)(Adult and Pediatric, n = 79)

Pimecrolimus – Overall Findings Pimecrolimus – Overall Findings (Adult and Pediatric, n = 79)(Adult and Pediatric, n = 79)

Location: US (64), Foreign (15)

Gender: Female (53), Males (23), NR (3)

Age: < 2 years (14)2 to 16 years (17)

Adverse Events:

60% - labeled90% - involved the skin

Cases of Interest:

Hospitalization (7)Tumor growth (2)Pediatric (32)

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Demographics of Demographics of Pimecrolimus Pediatric Cases (32) Pimecrolimus Pediatric Cases (32)

Demographics of Demographics of Pimecrolimus Pediatric Cases (32) Pimecrolimus Pediatric Cases (32)

Indications: Atopic or allergic dermatitis (25)

Location: US (23), Foreign (9)

Gender: Male (16), Female (16)

Age: 2 months – 15 years, median = 2 years (n = 30)

< 2 years (14)

AEs Skin reactions predominateNon-malignant tumor (2)Infections (7)

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Hospitalized Pimecrolimus Hospitalized Pimecrolimus Pediatric Cases (n = 4)Pediatric Cases (n = 4)

Hospitalized Pimecrolimus Hospitalized Pimecrolimus Pediatric Cases (n = 4)Pediatric Cases (n = 4)

Ages: 4 months, 6 months, 9 months and 18 months

18 month old Staph aureus + axillary adenitis. Hosp for drainage, irrigation and IV Abx.

9 month old Osteomyelitis, osteitis & soft tissue infection 20 days after starting pimecrolimus.

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Pimecrolimus Associated Pimecrolimus Associated Pediatric Infection Cases (7)Pediatric Infection Cases (7)Pimecrolimus Associated Pimecrolimus Associated

Pediatric Infection Cases (7)Pediatric Infection Cases (7)

Location: US (4), foreign (3)

Age Range: 9 months to 15 years, median = 18 months (n = 7)

Outcome: Hospitalization (2)Other (2)

Infections Seen:

Abscess, Bronchitis, Eczema herpeticum + infected eyes, Scarlatina, Soft tissue infection, Staph aureus + adenitis, Strep throat

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Non-Malignant Tumor Growth Non-Malignant Tumor Growth Pimecrolimus Pediatric Cases (2)Pimecrolimus Pediatric Cases (2)

Non-Malignant Tumor Growth Non-Malignant Tumor Growth Pimecrolimus Pediatric Cases (2)Pimecrolimus Pediatric Cases (2)

Onset Type

5 year old 49 days Granulomatous lymphadenitis w/ reactive hyperplasia

Unknown age NR Facial tumor

Topical Tacrolimus OintmentTopical Tacrolimus Ointment0.03%, 0.1%0.03%, 0.1%

Topical Tacrolimus OintmentTopical Tacrolimus Ointment0.03%, 0.1%0.03%, 0.1%Approved 12/08/2000Approved 12/08/2000

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Topical Tacrolimus – Overall Topical Tacrolimus – Overall Findings (Adult and Pediatric, n = 183)Findings (Adult and Pediatric, n = 183)

Topical Tacrolimus – Overall Topical Tacrolimus – Overall Findings (Adult and Pediatric, n = 183)Findings (Adult and Pediatric, n = 183)

Location: US (164), Foreign (19)

Gender: Female (103), Male (74), NR (6)

Age: < 2 years (7)2 to 16 years (29)

Adverse Events:

95% - labeled50% - involved the skin

Cases of Interest:

Death (3), Hosp (18)Pediatric (36)Malignancy (5)Acute Renal Failure (4)

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Topical Tacrolimus Topical Tacrolimus Death Cases (3)Death Cases (3)

Topical Tacrolimus Topical Tacrolimus Death Cases (3)Death Cases (3)

Onset Adverse Event

28 year old

1 months Kaposi’s sarcoma

54 year old

3 months Non-Hodgkin’s lymphoma

3 year old 9 months Streptococcal pneumonia, sepsis

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Demographics of Demographics of Topical Tacrolimus Pediatric Topical Tacrolimus Pediatric

Cases (36) Cases (36)

Demographics of Demographics of Topical Tacrolimus Pediatric Topical Tacrolimus Pediatric

Cases (36) Cases (36)

Indication: Atopic dermatitis

Location: US (35), Foreign (1)

Gender: Male (18), Female (13), NR (5)

Age: < 2 yrs (7)2 to 16 (29)

Product: 0.03% (21), 0.1% (10), NR (5)

AEs Skin and application site rxn predominatedInfections (10)Serum levels (2)

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Topical Tacrolimus Topical Tacrolimus Associated Pediatric Infection Associated Pediatric Infection

Cases (10)Cases (10)

Topical Tacrolimus Topical Tacrolimus Associated Pediatric Infection Associated Pediatric Infection

Cases (10)Cases (10)

Location: US (9), foreign (1)

Age Range: 13 months to 16 years, median = 4 years (n = 10)

Outcome: Death (1), Hospitalization (3)Other (6)

Infections Seen:

Pneumonia/sepsis, eczema herpeticum, staph aureus sepsis, chickenpox, warts, strep sepsis, herpes zoster, herpes simplex keratitis, erythema infectiosum

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Malignancies Associated Malignancies Associated with Topical Tacrolimus (5)with Topical Tacrolimus (5)Malignancies Associated Malignancies Associated

with Topical Tacrolimus (5)with Topical Tacrolimus (5)

Location: US (4), foreign (1)

Age Range: 28 to 56 years, median = 52 years (n = 5)

Outcome: Death (2)Other (3)

Onset: 1 month to 6 months (median = 3.5)

Malignancies Seen:

Anaplastic large cell lymphoma w/mets, B cell lymphoma, Kaposi's sarcoma, non-Hodgkin's lymphoma

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Overall Summary Pimecrolimus & Topical Tacrolimus

Overall Summary Pimecrolimus & Topical Tacrolimus

• AERS Post-Marketing AE Reports

– Serious Outcomes

– Malignancies

– Infections

– Pediatric AE Reports • off label use in children < 2 years old

(pimecrolimus, topical tacrolimus)• adult topical tacrolimus product use in

children

• AERS Post-Marketing AE Reports

– Serious Outcomes

– Malignancies

– Infections

– Pediatric AE Reports • off label use in children < 2 years old

(pimecrolimus, topical tacrolimus)• adult topical tacrolimus product use in

children

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AcknowledgementsAcknowledgementsMark Avigan, M.D., C.M., Acting Director, DDRE,

Office of Drug Safety

Renan Bonnel, Pharm.D., M.Ph., Safety Evaluator, DDRE, Office of Drug Safety

Claudia B. Karwoski, Pharm.D., Team Leader, DDRE, Office of Drug Safety

Division of Dermatological and Dental Drug Products

Office of Counter-Terrorism and Pediatric Drug Development

Mark Avigan, M.D., C.M., Acting Director, DDRE, Office of Drug Safety

Renan Bonnel, Pharm.D., M.Ph., Safety Evaluator, DDRE, Office of Drug Safety

Claudia B. Karwoski, Pharm.D., Team Leader, DDRE, Office of Drug Safety

Division of Dermatological and Dental Drug Products

Office of Counter-Terrorism and Pediatric Drug Development