# Presentation: 167379

## Topical Antifungals for T. PedisLabeling Issues

- Daiva Shetty, M.D.
- Division of Over-the-Counter Drug Products (HFD-560)
- Food and Drug Administration

## Outline

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

## Marketing Data

## Topical Antifungals for T. Pedis

- 11 Rx and OTC _NDA_ active ingredients
-   7 OTC _monograph_ active ingredients

## IMS Health Use Data 

**IMS Health Use Data **

- National Sales PerspectivesTM
- National Disease and Therapeutic IndexTM (NDTITM)

## IMS HealthNational Sales PerspectivesTM

**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

## IMS Health National Sales PerspectivesTM 2003

**IMS Health ****National Sales Perspectives****TM**** 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

## National Sales PerspectivesTM 2003

**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 pedisIMS Health, National Sales PerspectivesTM, 2003, Data Extracted April 2004

## IMS Health National Disease and Therapeutic IndexTM

**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

## National Disease and Therapeutic IndexTM 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 IndexTM, 2003, Data extracted April 2004

## Post-Marketing Adverse Event Reporting System (AERS) Data

## 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

## 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

## 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

## 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

## 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) |

## Labeling Issues

## Labeling 

- Prescription Labeling
- OTC Labeling
- Monograph
- NDA

## Prescription Labeling 

- Targeted at Healthcare Providers
- Detailed Information:
- Pharmacology
- Microbiology
- Preclinical Data
- Clinical Efficacy and Safety Data
- Indications
- Contraindications
- Warnings
- Dosage and Administration

## 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*.”

## 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.”

## Example Prescription Labeling: Expectations of Treatment

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

## OTC Monograph Labeling

## 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  |
| --- |

## 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.

## 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.

## OTC NDA Labeling

## 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  |
| --- |

## 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

## 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**
-  t**his product is not effective on scalp or nails**

- If condition persists longer, ask a doctor.

- 1

- week

## 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

## Concepts for Efficacy Labeling

##  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

##  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**

##  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.**

## Example of Package Insert Efficacy Labeling: Famotidine

##  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