Topical Antifungals for T. Pedis Labeling Issues

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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 Dollars
• OTC 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 2003
Ingredient 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. Pedis
400,000
24.5
300,000
15.3
Uses
11.9
200,000
10.8
8.6
100,000
0
Naftifine
Econazole
Clotrimazole/ Betamethasone
Ciclopirox
Terbinafine
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
4,741 Total AEs for 15 Active Ingredients 1,663
(35) Lack of Efficacy

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

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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 lt 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 LabelingIndications 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 LabelingDirections 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 Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 athletes 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.
Uses ? cures most athletes foot (tinea pedis) ? relieves itching, burning, cracking, and scaling
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OTC Monograph Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 athletes 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.
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 athletes 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
? use daily for 4 weeks. If condition persist
longer, ask a doctor.
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OTC Monograph Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 athletes 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.
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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.
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 Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) between the toes. Effectiveness on the bottom or sides of foot is unknown. ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 worse Keep 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 athletes 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
Other information XXXXXXX
Inactive ingredients XXXXXXX
Questions or comments? Call 1-800-XXX-XXXX.
Uses ? cures most athletes 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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OTC NDA Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) between the toes. Effectiveness on the bottom or sides of foot is unknown. ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 worse Keep 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 athletes 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
Other information XXXXXXX
Inactive ingredients XXXXXXX
Questions or comments? Call 1-800-XXX-XXXX.
Directions ? adults and children 12 years and older ? wash the affected skin with soap and water and dry completely before applying ? for athletes 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
4
weeks
If condition persists longer, ask a doctor.
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OTC NDA Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) between the toes. Effectiveness on the bottom or sides of foot is unknown. ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 worse Keep 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 athletes 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
Other information XXXXXXX
Inactive ingredients XXXXXXX
Questions or comments? Call 1-800-XXX-XXXX.
Directions ? adults and children 12 years and
older ? wash the affected skin with soap and
water and dry completely before applying ? for
athletes 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
1
week
If condition persists longer, ask a doctor.
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OTC NDA Labeling
Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal
Uses ? cures most athletes foot (tinea pedis) between the toes. Effectiveness on the bottom or sides of foot is unknown. ? relieves itching, burning, cracking, and scaling
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 worse Keep 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 athletes 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
Other information XXXXXXX
Inactive ingredients XXXXXXX
Questions or comments? Call 1-800-XXX-XXXX.
Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When 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 worse Keep 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