1 Topical Antifungals for T. Pedis Labeling Issues Daiva Shetty, M.D. Division of Over-the-Counter Drug Products (HFD-560) Food and Drug Administration

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Topical Antifungals for T. PedisLabeling Issues

Daiva Shetty, M.D.

Division of Over-the-Counter Drug Products (HFD-560)

Food and Drug Administration

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Outline

• Marketing Data

• Post-marketing Safety Data

• Labeling of Antifungal Drug Products

• Concepts for Efficacy Labeling

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Marketing Data

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Topical Antifungals for T. Pedis

• 11 Rx and OTC NDA active ingredients

• 7 OTC monograph active ingredients

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IMS Health Use Data

• National Sales PerspectivesTM

• National Disease and Therapeutic IndexTM (NDTITM)

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IMS HealthNational Sales PerspectivesTM

• Volume of products• Rx and OTC • Measured in eaches (e.g., tubes or jars)• Does not provide

− demographics − indications− amount of drug used

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IMS Health National Sales PerspectivesTM 2003

Eaches DollarsOTC 20.1 million $82 million

RX 15.7 million $418.6 million

IMS Health, National PerspectivesTM, 2003, Data Extracted April 2004

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National Sales PerspectivesTM 2003Ingredient* 2003 eaches (million)

Clotrimazole/betamethasone (Rx)

Clotrimazole (OTC)

Tolnaftate (OTC)

Miconazole (OTC)

Ciclopirox (Rx)

Terbinafine (OTC)

Clotrimazole (Rx)

Undecylenic acid (OTC)

Econazole (Rx)

Butenafine (OTC)

Butenafine (Rx)

6.1

5.5

5.3

3.6

3.3

3.2

3.1

1.7

1.8

0.7

0.5

*Products approved for tinea pedisIMS Health, National Sales Perspectives™, 2003, Data Extracted April 2004

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IMS Health National Disease and Therapeutic IndexTM

• Drugs mentioned during visits to a panel of physicians• 2,000-3,000 office-based physicians• Prescribing patterns• Includes profiles and trends of

– diagnoses – patients – treatment patterns

• Does not capture patients who self diagnose and purchase OTC products

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National Disease and Therapeutic IndexTM 2003: Most Physician Recommended

Antifungals for T. Pedis24.5%

15.3%11.9% 10.8%

8.6%

Ciclop

irox

Econaz

ole

Clotrim

azole

/

Betam

ethas

one

Terbin

afin

e

Naftif

ine

100,000

0

200,000

300,000

400,000

Use

s

IMS Health, National Disease and Therapeutic IndexTM, 2003, Data extracted April 2004

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Post-Marketing Adverse Event Reporting System (AERS) Data

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AERS Postmarketing Data

• Search of AERS data as of March 16, 2004 for 15 topical antifungal active ingredients (Rx and OTC)– Lack of Efficacy– Cellulitis Cases

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AERS Postmarketing Data

Limitations:• No AE reporting requirements for Monograph

ingredients• Crude number• Ingredients are marketed in multiple formulations• Several indications for use• Causality not assessed

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AERS Data: Lack of Efficacy

• 484 Terbinafine (1992)• 297 Clotrimazole (1975) • 287 Miconazole (1973) • 138 Clotrimazole/betamethasone (1984)

4,741 Total AEs for 15 Active Ingredients

1,663 (35%) Lack of Efficacy

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13 Cases Reported as Cellulitis of 4,741 AEs

Ingredients # of reports

Terbinafine 5

Miconazole 4

Betamethasone + clotrimazole 1

Ketoconazole 1

Tolnaftate 1

Undecylenic Acid 1

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Summary of 13 Cellulitis Cases

Location US (11), Foreign (2)

Age Range 25 to 82 years, median = 43, n = 10

Gender Female (8), Male (5)

Indications Tinea Pedis (8), Tinea Cruris (1), Lupus Flare (1), Vitiligo (1), Dermatophyte (1), NR (1)

Onset Range < 24 hrs to 150 days, median = 1 day, n = 9

Sites Affected Ankle/Foot/Toe (7), Leg (2), Thigh (1), NR (3)

Risk Factors Diabetes (1)

Outcome Hospitalization (7), Death (0)

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Labeling Issues

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Labeling

• Prescription Labeling

• OTC Labeling– Monograph – NDA

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Prescription Labeling

• Targeted at Healthcare Providers• Detailed Information:

– Pharmacology– Microbiology– Preclinical Data– Clinical Efficacy and Safety Data– Indications– Contraindications– Warnings– Dosage and Administration

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Example Prescription Labeling:Indications and Usage

“Indicated for the topical treatment of the following dermal infections: Tinea pedis, tinea cruris and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis due to Candida albicans; and tinea versicolor due to Malassezia furfur.”

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Example Prescription Labeling:Directions for Use

“XXX should be applied to affected and immediately surrounding areas once to twice daily in patients with tinea pedis, tinea corporis, or tinea cruris. Tinea corporis, tinea cruris, and tinea (pityriasis) versicolor should be treated for 2 weeks and tinea pedis for 1 month to reduce the possibility of recurrence.”

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Example Prescription Labeling: Expectations of Treatment

“If a patient shows no clinical improvement after 4 weeks of treatment, the diagnosis should be reviewed.”

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OTC Monograph Labeling

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OTC Monograph LabelingDrug FactsActive ingredient PurposeXXXXXXXXXXXXXX.............................................................................................................Antifungal

Uses cures most athlete’s foot (tinea pedis) relieves itching, burning, cracking, and scaling

WarningsFor external use only Do not use on children under 2 years of age unless directed by a doctorWhen using this product do not get into eyes. If contact occurs, rinse eyes thoroughly with water.Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks.Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

Directions wash the affected area and dry thoroughly. apply a thin layer of the product over affected area twice daily (morning and night) or

as directed by a doctor supervise children in the use of this product. for athlete’s foot: pay special attention to spaces between the toes; wear well-fitting, ventilated shoes,

and change shoes and socks at least once daily. use daily for 4 weeks. If condition persist, longer ask a doctor. this product is not effective on scalp or nails

Other information XXXXXXX

Inactive ingredients XXXXXXX

Questions or comments? Call 1-800-XXX-XXXX.


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and change shoes and socks at least once daily. use daily for 4 weeks. If condition persist, longer ask a doctor. This product is not effective on scalp or nails




Directions wash the affected area and dry thoroughly. apply a thin layer of the product over affected area twice daily (morning and night) or as

directed by a doctor supervise children in the use of this product. for athlete’s foot: pay special attention to spaces between the toes; wear well-fitting, ventilated shoes,


use daily for 4 weeks. If condition persist longer, ask a doctor.

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Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks.

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OTC NDA Labeling

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OTC NDA LabelingDrug FactsActive ingredient PurposeXXXXXXXXXXXXXX.............................................................................................................Antifungal

Uses cures most athlete’s foot (tinea pedis) between the toes. Effectiveness on the bottom

or sides of foot is unknown. relieves itching, burning, cracking, and scaling

WarningsFor external use only Do not use on children under 2 years of age unless directed by a doctorWhen using this product do not get into eyes. If contact occurs, rinse eyes thoroughly with water.Stop use and ask a doctor if too much irritation occurs or gets worseKeep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

Directions adults and children 12 years and older wash the affected skin with soap and water and dry completely before applying for athlete’s foot apply a thin layer over affected area twice daily (morning and night)

for 4 weeks or as directed by a doctor. If condition persists longer, ask a doctor. Supervise children in the use of this product. Pay special attention to spaces between the toes; wear well-fitting, ventilated shoes, and change shoes and socks at least once daily.

wash hands after each use children under 12 years: ask a doctor if condition persist longer, ask a doctor this product is not effective on scalp or nails




Uses cures most athlete’s foot (tinea pedis) between the toes. Effectiveness on

the bottom or sides of foot is unknown. relieves itching, burning, cracking, and scaling

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. wash hands after each use children under 12 years: ask a doctor If condition persist longer, ask a doctor This product is not effective on scalp or nails




Directions adults and children 12 years and older wash the affected skin with soap and water and dry completely before applying for athlete’s foot apply a thin layer over affected area twice daily (morning and

night) for 4 weeks or as directed by a doctor. If condition persists longer, ask a doctor. Supervise children in the use of this product. Pay special attention to spaces between the toes; wear well-fitting, ventilated shoes, and change shoes and socks at least once daily.


If condition persists longer, ask a doctor.

4 weeks

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. wash hands after each use children under 12 years: ask a doctor If condition persist longer, ask a doctor This product is not effective on scalp or nails




Directions adults and children 12 years and older wash the affected skin with soap and water and dry completely before applying for athlete’s foot apply a thin layer over affected area twice daily (morning and night) for

4 weeks or as directed by a doctor. If condition persists longer, ask a doctor. Supervise children in the use of this product. Pay special attention to spaces between the toes; wear well-fitting, ventilated shoes, and change shoes and socks at least once daily.


If condition persists longer, ask a doctor.

1 week

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WarningsFor external use only Do not use on children under 2 years of age unless directed by a doctorWhen using this product do not get into eyes. If contact occurs, rinse eyes thoroughly with water.Stop use and ask a doctor if too much rritation occurs or gets worseKeep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.







WarningsFor external use only Do not use on children under 2 years of age unless directed by a doctorWhen using this product do not get into eyes. If contact occurs, rinse eyes thoroughly with water.Stop use and ask a doctor if irritation too much occurs or gets worseKeep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

Stop use and ask a doctor if too much irritation occurs or gets worse

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Concepts for Efficacy Labeling

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Concepts for Efficacy Labeling

• Most OTC products are indicated for acute symptom relief

• Few have a lag time between the treatment initiation and the expected results

• This information is presented in Drug Facts or in the Package Insert

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Example of Efficacy Labeling: Omeprazole

not intended for immediate relief of heartburn; this drug may take 1 to 4 days for full effect

it may take 1 to 4 days for full effect; although some people get complete relief of symptoms within 24 hours

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Example of Efficacy Labeling: Minoxidil

When using this product it takes time to regrow hair. Results may occur at 2 months with twice a day

usage. For some men, you may need to use this product for at least 4 months before you see results.

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Example of Package Insert Efficacy Labeling: Famotidine

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Considerations for Labeling Revisions

• Should the following be in the label?– Efficacy rates– Time to symptom relief– Expected time to cure– When to see a doctor– Ancillary measures

Documents

1 Topical Antifungals for T. Pedis Labeling Issues Daiva Shetty, M.D. Division of Over-the-Counter Drug Products (HFD-560) Food and Drug Administration