1. 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

2. 2 Outline Marketing Data Post-marketing Safety Data Labeling of Antifungal Drug Products Concepts for Efficacy Labeling

3. 3 Marketing Data

4. 4 Topical Antifungals for T. Pedis 11 Rx and OTC NDA active ingredients 7 OTC monograph active ingredients

5. 5 IMS Health Use Data National Sales Perspectives TM National Disease and Therapeutic Index TM (NDTI TM )

6. 6 IMS Health National Sales Perspectives TM Volume of products Rx and OTC Measured in eaches (e.g., tubes or jars) Does not provide − demographics − indications − amount of drug used

7. 7 IMS Health National Sales Perspectives TM 2003 EachesDollars OTC20.1 million$82 million RX15.7 million$418.6 million IMS Health, National Perspectives TM, 2003, Data Extracted April 2004

8. 8 National Sales Perspectives TM 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 pedis IMS Health, National Sales Perspectives™, 2003, Data Extracted April 2004

9. 9 IMS Health National Disease and Therapeutic Index TM 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

10. 10 National Disease and Therapeutic Index TM 2003: Most Physician Recommended Antifungals for T. Pedis 24.5% 15.3% 11.9% 10.8% 8.6% Ciclopirox Econazole Clotrimazole/ Betamethasone Terbinafine Naftifine 100,000 0 200,000 300,000 400,000 Uses IMS Health, National Disease and Therapeutic Index TM, 2003, Data extracted April 2004

11. 11 Post-Marketing Adverse Event Reporting System (AERS) Data

12. 12 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

13. 13 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

14. 14 AERS Data: Lack of Efficacy 484Terbinafine (1992) 297 Clotrimazole (1975) 287 Miconazole (1973) 138 Clotrimazole/betamethasone (1984) 4,741Total AEs for 15 Active Ingredients 1,663 (35%)Lack of Efficacy

15. 15 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

16. 16 Summary of 13 Cellulitis Cases LocationUS (11), Foreign (2) Age Range25 to 82 years, median = 43, n = 10 GenderFemale (8), Male (5) IndicationsTinea Pedis (8), Tinea Cruris (1), Lupus Flare (1), Vitiligo (1), Dermatophyte (1), NR (1) OnsetRange < 24 hrs to 150 days, median = 1 day, n = 9 Sites AffectedAnkle/Foot/Toe (7), Leg (2), Thigh (1), NR (3) Risk FactorsDiabetes (1) OutcomeHospitalization (7), Death (0)

17. 17 Labeling Issues

18. 18 Labeling Prescription Labeling OTC Labeling –Monograph –NDA

19. 19 Prescription Labeling Targeted at Healthcare Providers Detailed Information: –Pharmacology –Microbiology –Preclinical Data –Clinical Efficacy and Safety Data –Indications –Contraindications –Warnings –Dosage and Administration

20. 20 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.”

21. 21 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.”

22. 22 Example Prescription Labeling: Expectations of Treatment “If a patient shows no clinical improvement after 4 weeks of treatment, the diagnosis should be reviewed.”

23. 23 OTC Monograph Labeling

24. 24 OTC Monograph Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal Uses  cures most athlete’s 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 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. Uses  cures most athlete’s foot (tinea pedis)  relieves itching, burning, cracking, and scaling

25. 25 OTC Monograph Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal Uses  cures most athlete’s 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 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. 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  use daily for 4 weeks. If condition persist longer, ask a doctor.

26. 26 OTC Monograph Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................Antifungal Uses  cures most athlete’s 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 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. 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.

27. 27 OTC NDA Labeling

28. 28 OTC NDA Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................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 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 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 Other information XXXXXXX Inactive ingredients XXXXXXX Questions or comments? Call 1-800-XXX-XXXX. 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

29. 29 OTC NDA Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................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 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 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 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 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 If condition persists longer, ask a doctor. 4 weeks

30. 30 OTC NDA Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................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 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 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 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 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 If condition persists longer, ask a doctor. 1 week

31. 31 OTC NDA Labeling Drug Facts Active ingredient Purpose XXXXXXXXXXXXXX.............................................................................................................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 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 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 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

32. 32 Concepts for Efficacy Labeling

33. 33 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

34. 34 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

35. 35 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.

36. 36 Example of Package Insert Efficacy Labeling: Famotidine

37. 37 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