Subject: Antifungal, Oral Agents

Status	Drug	PR	PR-QL	PR-AL	ST	M EX‡
P	fluconazole	X	X
P	griseofulvin microsized
P	ketoconazole
P	itraconazole	X
P	nystatin
P	terbinafine	X
P	Lamisil®  (terbinafine)	X
NP	Biostatin®  (nystatin)
NP	Diflucan®  (fluconazole)	X	X
NP	Grifulvin-V®  (griseofulvin microsized)
NP	Gris-peg®  (griseofulvin ultramicrosized)
NP	Nizoral®  (ketoconazole)
FE	Sporanox®  (itraconazole)	X				X
FE	Vfend®  (voriconazole)	X				X
FE	Ancobon®  (flucytosine)					X
FE	Noxafil®  (Posaconazole Susp)	X				X

Policy:

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary, Diflucan, fluconazole, itroconazole, Noxafil,  Sporanox, terbinafine, Vfend and Lamisil are subject to precertification.  If precertification requirements apply Aetna considers Diflucan, fluconazole, itraconazole, Noxafil, Sporanox, terbinafine, Vfend and Lamisil to be medically necessary for those members who meet ANY ONE of the following precertification criteria:

(A AND B) OR E OR (G AND H) - For terbinafine,Lamisil
(A AND B AND C) OR (E AND F) OR (G AND H) OR K- For itraconazole, Sporanox
(A AND B AND C AND D) OR (E AND F) OR (G AND H) OR K OR L-For Diflucan, fluconazole -all strengths except 150mg
I AND J-For Vfend
M -For Noxafil
N- For Diflucan/fluconazole 150mg


A documented

A. Diagnosis of Onychomycosis† confirmed by either a positive KOH stain (potassium ydroxide), positive PAS stain (para-aminosalicylic acid), a positive DTM (dermatophyte test medium), or positive fungal culture

NOTE:  This positive test should be recent (within the last 3-6 months or so) and associated with the current infection. 

AND

B.  One of the following:

• Member is experiencing pain which limits normal activity OR, 
• Member has diabetes OR,
• Member has an iatrogenically-induced or disease-associated immunosuppression, such as that due to AIDS, antirejection treatment for bone marrow or solid organ transplant, or chemotherapy for cancer OR,
• Member has a systemic dermatosis with impaired skin integrity (e.g., pemphigus, ichthyosis) OR, 
• Member has a significant vascular compromise (peripheral)

AND

C.  One of the following:

• Contraindication to terbinafine (Lamisil) OR,
• Intolerance to terbinafine (Lamisil) OR,
• Failure of an adequate trial of 6 weeks of terbinafine (Lamisil) OR,
• Presence of hepatic dysfunction or increased risk for liver disease OR, 
• Fungal culture indicating lack of sensitivity to terbinafine (Lamisil) OR, 
• Non-dermatophyte fungal infection (mixed infection, a mold or yeast infection)

AND
 
D. One of the following:

• Contraindication to itraconazole (Sporanox®) OR,
• Intolerance to itraconazole (Sporanox) OR,
• Failure of an adequate trial of 6 weeks of itraconazole (Sporanox)

†For onychomycosis, new courses of therapy should not be initiated until 32 weeks following the end of therapy unless infection is noted in a previously unaffected nail (since cure rate continues to increase through the 11th month following initiation of a 12 week course of therapy).

OR

E. A documented diagnosis of tinea capitis

AND

F. One of the following:

• Contraindication to the preferred alternative terbinafine (Lamisil) OR
• Intolerance to the preferred alternative terbinafine (Lamisil) OR
• Failure of an adequate trial of two weeks of the preferred alternative terbinafine (Lamisil) OR
• Member requires a liquid dosage form

OR

G.   A documented diagnosis of Cutaneous dermatophyte infection
      [NOTE: tinea pedis (athletes foot), tinea cruris (jock itch), or tinea corporis 
      (ringworm on the body), does NOT include tinea versicolor]
      
AND

H.  One of the following:

• Contraindication to two  formulary alternatives (one of which should be topical) OR
• Intolerance to two  formulary alternatives (one of which should be topical) OR
• Failure of an adequate trial of two weeks each of two  formulary alternatives (one of which should be topical ) OR
• Failure of an adequate trial of two weeks EACH of two oral formulary alternatives if a very large body surface area is being treated and treatment with a topical would be inadequate OR
• Failure of formulary oral terbinafine (Lamisil) (FOR -itraconazole, Sporanox,-ONLY)

OR

I.  A documented diagnosis of one of the following:

• Member has a documented diagnosis of HIV or cancer OR
• Member is being treated for Aspergillosis OR
• Member is being treated for infection with Scedosporium apiospermum OR
• Member is being treated for infection with Fusarium species OR
• Member is being treated for infection with Candida sp. which is RESISTANT to fluconazole/Diflucan-documented by member having already tried and failed Diflucan (at least one week of therapy) OR laboratory evidence of fluconazole resistance

            Note: Candida glabrata, C. krusei, and C. norgegensis are usually resistant to
                 Diflucan-a Trial of Diflucan is NOT required for these organisms.
             
AND
             
J. Member is NOT receiving a contraindicated medication (any of the following):

• Pimozide (Orap)
• Quinidine
• Sirolimus (Rapamune)
• Rifampin
• Carbamazepine
• Long-acting barbiturates(Phenobarbital)
• Rifabutin
• Ergot alkaloids (ergotamine and dihydroergotamine/DHE-45)

 OR

K. Documented Diagnosis of one of the following:

• Member is currently being treated for Blastomycosis OR
• Member is currently being treated for Histoplasmosis OR
• Member is currently being treated for Aspergillosis (FOR -itraconazole, Sporanox-ONLY) OR
• Member is currently being treated for Coccidoidmycosis (valley fever) or Coccidiomeningitis OR
• Member has a documented diagnosis of HIV or cancer OR
• Member has documented diagnosis of tinea versicolor 

          AND
          One of the following    

•  Contraindication to one (1) formulary alternative (oral or topical ketoconazole) OR
•  Intolerance to one (1) formulary alternative (oral or topical ketoconazole) OR
•  Failure of an adequate trial of one (1) course of one (1) formulary alternative (1 week oral ketoconazole  OR  2 weeks topical ketoconazole)

          AND
          One of the following- For Sporanox/itraconazole-ONLY

•  Contraindication to fluconazole single dose [400mg po one time] OR
•  Intolerance to fluconazole single dose [400mg po one time] OR 
•  Failure to fluconazole single dose [400mg po one time]

         OR

• Member has documented diagnosis of febrile neutropenia
  •  Neutrophil count (ANC) <500/mm3  AND EITHER
  •  Single elevation in temperature to >101.3 deg F (38.5 deg C) OR
  •  Three elevations to >100.4 deg F (38 deg C) in a 24 hour period AND Has not responded to at least 7  days of empiric, broad spectrum antibiotics
    

 OR

L. Documented Diagnosis of one of the following:

• Systemic Candidiasis OR
• Bone Marrow Transplant (prophylaxis) OR
• Cryptococcus OR
• Urinary tract infection or Balanitis with Candida OR
• Vulvovaginal candidiasis OR
• Oral (thrush), esophageal, intestinal candidiasis OR
• Mastitis or a candidal infection of the breast (due to breast feeding / oral thrush in the infant) OR
• Chronic cutaneous candidal infection OR
• Fungal Otitis externa AND
  • One of the following:
    • Contraindication to one preferred topical alternatives OR
    • Intolerance to one preferred topical alternative OR
    • Failure of an adequate trial of one week of one preferred topical alternative 

           OR

• Chronic Candidal Paronychia AND
  • One of the following:
    • Contraindication to one (1) formulary alternative (oral or topical ketoconazole) OR
    • Intolerance to one (1) formulary alternative (oral or topical ketoconazole) OR  
    • Failure of an adequate trial of one (1) course of one (1) formulary alternative (1 week oral ketoconazole OR 2 weeks topical ketoconazole)

OR

M. Documented Diagnosis of one of the following:

• Disseminated candidiasis, Severely immunocompromised patients; Prophylaxis OR
• HIV infection -  Oropharyngeal candidiasis OR
• Mycosis ,  immunocompromised patient  AND
  • Documentation of one of the following:
    • Failure of  fluconazole/Diflucan (at least one week of therapy) OR
    • Laboratory evidence of fluconazole resistance

           OR

• Documentation of Disseminated candidiasis, Severely immunocompromised patients; Prophylaxis due to being currently on cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes
  
   OR
  
• Diagnosis of Infection due to Aspergillus species, Severely immunocompromised patients; Prophylaxis resulting from hematopoietic stem cell transplant with Graft versus Host Disease
   
  OR
  
  Diagnosis of oropharyngeal candidiasis (OPC) AND
  • Documentation of one of the following:
    • Failure of  fluconazole /Diflucan  OR  itraconazole/Sporanox (at least one week of therapy) OR
    • Laboratory evidence of fluconazole/Diflucan OR itraconazole/Sporanox resistance

N.Quantity Limits

According to the manufacturer, a single oral dose of Diflucan/fluconazole 150mg tablets is indicated for vaginal candidiasis. Diflucan/ fluconazole can be dosed at interval(s) as indicated in the table below.  A quantity of Diflucan or fluconazole 150mg tablets will be considered medically necessary as indicated in the table below.

Drug	Maximum Daily Dose/ Dosing Interval	Dosage Strength	Quantity Limits
Diflucan, fluconazole	Once daily	150 mg	Up to 1 tablet in 30 days





For coverage of additional quantities, a member's treating physician must request prior authorization through the Pharmacy Management Precertification Unit. A prior authorization will be granted for coverage of additional quantities of fluconazole or Diflucan for those members who meet ANY of the following criteria:

• Member has a diagnosis of vulvovaginal candidiasis, and has tried and failed one tablet of fluconazole/Diflucan 150mg (up to 2 tablets per 30 days can be approved).
  OR 
• Member has a diagnosis of recurrent (4 or more episodes per year) vulvovaginal candidiasis.
  OR 
• Member has a diagnosis of vulvovaginal candidiasis complicated by antibiotic use or an immune compromised state such as HIV/AIDS, diabetes, cancer, or chronic corticosteroid use.
  OR 
• Member has a diagnosis other than vulvovaginal candidiasis and meets precert criteria above [(A AND B AND C AND D) OR (E AND F) OR (G AND H) OR K OR L ], and an appropriate dosing regimen can not be achieved by using other strengths of fluconazole/Diflucan (50mg, 100mg, 200mg).OR
• Member's physician provides documentation (controlled clinical trial) from peer-reviewed medical literature for use of a higher dose.
  



2. Medical Exception Criteria

Ancobon, Noxafil, Sporanox and Vfend are currently listed on the Aetna Formulary Exclusions List.*, Therefore, Ancobon, Noxafil, Sporanox and Vfend are excluded from coverage for members enrolled in prescription drug benefits plans that use a closed formulary, unless a medical exception is granted.  Aetna considers Ancobon, Noxafil, Sporanox and Vfend to be medically necessary for those members who meet any of the following criteria:

For Ancobon,

A. A documented diagnosis of one of the following:

• Cryptococcal meningitis OR
• Candidal endocarditis or peritonitis OR
• Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for other therapeutic use

For Sporanox,

[(A AND B AND C) OR (D AND E) OR (F AND G) OR H] ANDI

A documented

A. Diagnosis of Onychomycosis† confirmed by either a positive KOH stain (potassium ydroxide), positive PAS stain (para-aminosalicylic acid), a positive DTM (dermatophyte test medium), or positive fungal culture

NOTE:  This positive test should be recent (within the last 3 months or so) and associated with the current infection. 

AND

B.  One of the following:

• Member is experiencing pain which limits normal activity OR,
• Member has diabetes OR,
• Member has an iatrogenically-induced or disease-associated immunosuppression, such as that due to AIDS, antirejection treatment for bone marrow or solid organ transplant, or chemotherapy for cancer OR,
• Member has a systemic dermatosis with impaired skin integrity (e.g., pemphigus, ichthyosis) OR,
• Member has a significant vascular compromise (peripheral)

AND

C.  One of the following:

• Contraindication to terbinafine (Lamisil) OR,
• Intolerance to terbinafine (Lamisil) OR,
• Failure of an adequate trial of 6 weeks of terbinafine (Lamisil) OR,
• Presence of hepatic dysfunction or increased risk for liver disease OR,
• Fungal culture indicating lack of sensitivity to terbinafine (Lamisil) OR,
• Non-dermatophyte fungal infection (mixed infection, a mold or yeast infection)

†For onychomycosis, new courses of therapy should not be initiated until 32 weeks following the end of therapy unless infection is noted in a previously unaffected nail (since cure rate continues to increase through the 11th month following initiation of a 12 week course of therapy).

OR

D.   A documented diagnosis of tinea capitis

AND

E.   One of the following:

• Contraindication to the preferred alternative terbinafine (Lamisil) OR
• Intolerance to the preferred alternative terbinafine (Lamisil) OR
• Failure of an adequate trial of two weeks of the preferred alternative terbinafine (Lamisil) OR
• Member requires a liquid dosage form

OR

F. A documented diagnosis of  Cutaneous dermatophyte infection [NOTE: tinea pedis (athletes foot), tinea cruris (jock itch), or tinea corporis (ringworm on thebody), does NOT include tinea versicolor]
      
AND

G.  One of the following:

• Contraindication to two  formulary alternatives (one of which should be topical) OR
• Intolerance to two  formulary alternatives (one of which should be topical) OR
• Failure of an adequate trial of two weeks each of two  formulary alternatives (one of which should be topical) OR
• Failure of an adequate trial of two weeks EACH of two oral formulary alternatives if a very large body surface area is being treated and treatment with a topical would be inadequate. OR
• Failure of formulary oral terbinafine (Lamisil) (itraconazole, Sporanox, ONLY)

OR

H.  Documented Diagnosis of one of the following:

• Member is currently being treated for Blastomycosis OR
• Member is currently being treated for Histoplasmosis OR
• Member is currently being treated for Aspergillosis OR
• Member is currently being treated for Coccidoidmycosis (valley fever) or Coccidiomeningitis OR
• Member has a documented diagnosis of HIV or cancer OR
• Member has documented diagnosis of tinea versicolor AND A documented
  • Contraindication to an adequate trial of two preferred alternatives (ketoconazole - 1 week oral OR 2 weeks topical AND fluconazole single dose [400mg po one time]) OR
  • Intolerance to an adequate trial of two preferred alternatives (ketoconazole - 1 week oral OR 2 weeks topical AND fluconazole single dose [400mg po one time]) OR
  • Failure of an adequate trial of one two preferred alternatives (ketoconazole - 1 week oral OR 2 weeks topical AND fluconazole single dose [400mg po one time]) OR
• Member has documented diagnosis of febrile neutropenia
  • Neutrophil count (ANC) <500/mm3  AND EITHER
    • Single elevation in temperature to >101.3 deg F (38.5 deg C) OR
    • Three elevations to >100.4 deg F (38 deg C) in a 24 hour period AND Has not responded to at least 7 days of empiric, broad spectrum antibiotics

AND

I.  A documented

• Contraindication to the generic equivalent alternative agent OR
• Intolerance to the generic equivalent alternative agent OR
• Allergy to the generic equivalent alternative agent OR
• Failure of an adequate trial of one month of the generic equivalent alternative agent
  

For VFEND,

(A ANDB)

A.  A documented diagnosis of one of the following:

• Member is being treated for Aspergillosis OR
• Member is being treated for infection with Scedosporium apiospermum OR
• Member is being treated for infection with Fusarium species OR
• Member is being treated for infection with Candida sp. which is RESISTANT to fluconazole/Diflucan-documented by member having already tried and failed Diflucan(at least one week of therapy) OR laboratory evidence of fluconazole resistance 
  Note: Candida glabrata, C. krusei, and C. norgegensis are usually resistant to Diflucan-a Trial of Diflucan is NOT required for these organisms.            

AND
             
B.  Member is NOT receiving a contraindicated medication:

• Pimozide (Orap)
• Quinidine
• Sirolimus (Rapamune)
• Rifampin
• Carbamazepine
• Long-acting barbiturates(Phenobarbital)
• Rifabutin
• Ergot alkaloids (ergotamine and dihydroergotamine/DHE-45)

For Noxafil

A.  A documented diagnosis of one of the following:

• Disseminated candidiasis, Severely immunocompromised patients; Prophylaxis OR
• HIV infection -  Oropharyngeal candidiasis OR
• Mycosis ,  immunocompromised patient  AND
  • Documentation of one of the following:
    • Failure of  fluconazole /Diflucan (at least one week of therapy) OR
    • Laboratory evidence of fluconazole resistance        

      OR

• Documentation of Disseminated candidiasis, Severely immunocompromised patients; Prophylaxis due to being currently on cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes

      OR

• Diagnosis of Infection due to Aspergillus species, Severely immunocompromised patients; Prophylaxis resulting from hematopoietic stem cell transplant with Graft versus Host Disease

      OR

• Diagnosis of oropharyngeal candidiasis (OPC) AND
  •  Documentation of one of the following:
    •  Failure of  fluconazole /Diflucan  OR  itraconazole /Sporanox (at least one week of therapy) OR   
    •  Laboratory evidence of fluconazole/Diflucan  OR  itraconazole /Sporanox resistance

 

Table A: Maximum time of approval for some indications  

Indication	Maximum time of approval
Candidiasis, Esophageal, Intestinal	60 days
Candidiasis, Oropharyngeal (oral thrush), Urinary Tract  Balanitis	30 days
Candidiasis, Vulvovaginal  1st or 2nd episode	30 days
Candidasis, Vulvovaginal, Recurrent	6 months
Candidiasis, Vulvovaginal, Complicated	1 year
Candidiasis, resistant to fluconazole	Vfend – 6 months
Cutaneous dermatophyte infection, tinea capitis, tinea versicolor	30 days
HIV/AIDS	may be indefinite
Onychomycosis	6 months (Diflucan/fluconazole)
Onychomycosis- fingernail	6 weeks
Onychomycosis- toenail	12 weeks
Otitis externa	30 days
All other diagnoses	up to 1 year
NOTE: Diflucan	Duration of therapy approved to be consistent with labeled dose regimen for labeled indications; for unlabeled onychomycosis, limit of 6 months

 
 

Special Notes:

Topical Antifungal Agents:
econazole cream 1%  (SPECTAZOLE, ECOSTATIN)  
ketoconazole cream 2%  (NIZORAL)
nystatin cream, ointment, powder 100,000 units/gm
ciclopirox olamine (LOPROX) cream, lotion, solution, shampoo 1%
clotrimazole cream 1% (Lotrimin OTC)
sertaconazole (ERTACZO) cream 2%

Topical Antifungal/Antiinflammatory
clotrimazole-betamethasone cream  (LOTRISONE)

Other
Lamisil Cream (OTC-not covered by plan but may be considered an alternative)
Butenafine cream 1% (LOTRIMIN ULTRA (OTC), MENTAX)
Naftifine (NAFTIN) -
Tolnaftate cream 1% (TINACTIN OTC)

Oral Antifungal Agents:
nystatin  (MYCOSTATIN)
griseofulvin  (FULVICIN, GRIS-PEG)
ketoconazole  (NIZORAL)
clotrimazole troche (MYCELEX)
terbinifine (LAMISIL)
fluconazole (DIFLUCAN)

Place of Service:

Outpatient

The above policy is based on the following references:

1. Product Information Insert Ancobon®, Costa Mesa, California March 2003.
2. Product Information Insert. Grifulvin® , Ortho Pharmaceutical Corporation. Raritan, New Jersey January 1997.
3. Product Information Insert. Mycelex Troches, Bayer Pharmaceuticals Corporation, Mountain View, CA, Feb. 2003.
4. Product Information Insert. Sporanox® Oral Solution. Janssen Pharmaceutical, Raritan, NJ January  2004.
5. Sporanox internet site accessed Dec 15,2003 http://www.sporanox.com/
6. Product Information Vfend®  Pfizer Inc, New York, NY.  April 2004.
7. Product Information Lamisil® Novartis Pharmaceuticals, East Hanover, NJ, March 2004.
8. Product Information Diflucan® Pfizer/Roerig, New York, NY, June 2003
9. Bell-Syer SE, et.al. Oral treatments for fungal infections of the skin of the foot.Cochrane Database Syst Rev. 2002; (2): CD003584.
10. CDC. 2002 Guidelines for treatment of sexually transmitted diseases; recurrent vulvovaginal candidiasis.  MMWR  May 10 2002 ; /Vol. 51/No.RR-6accessed: http://www.cdc.gov/STD/treatment/5-2002TG.htm#VulvovaginalCan
11. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;51(No. RR-6):45-50.
12. Cohen AD, et.al. An independent comparison of terbinafine and itraconazole in the treatment of toenail onychomycosis. J Dermatolog Treat. 2003 Dec; 14(4): 237-42.
13. Crawford F, Young P, Godfrey C, et al.  Oral treatment s for toenail onychomycosis. Arch Dermatol.  2002;138:811-16.
14. Darkes MJ, et. al. Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol. 2003; 4(1): 39-65. Review.
15. De Punzio C - Fluconazole 150 mg single dose versus itraconazole 200 mg per day for 3 days in the treatment of acute vaginal candidiasis: a double-blind randomized study Eur J Obstet Gynecol Reprod Biol  FEB-2003;
16. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clinical Infectious Diseases 2002;34:563-71.
17. Denning DW, Tucker RM, Hanson LH, Stevens DA. Treatment of invasive aspergillosis with itraconazole therapy in aspergillosis: study in 49 patients. J Am Acad Dermatol 1990;23:607-14.
18. FDA issues health advisory regarding the safety of Sporanox products and Lamisil tablets to treat fungal nail infections. FDA Talk Paper T01-22, May 9, 2001. http://www.fda.gov/bbs/topics/answers/2001/ans01083.ht
19. Ferris DG, Nyirjesy P, Sobel JD, et al. Over-the-counter antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstet Gynecol 2002;99:419-25.
20. Gilbert DN, Moellering RC, Sande MA, eds.  The Sanford Guide to Antimicrobial Therapy 2003.  Antimicrobial Therapy Inc. Hyde Park, VT, 2003.
21. Gupta AK - Non-dermatophyte onychomycosis.Dermatol  Clin - APR-2003; 21(2): 257-68. 
22. Gupta AK, Cooper EA, Lynde CW The efficacy and safety of terbinafine in children. Dermatol Clin. 2003 Jul; 21(3): 511-20.
23. IDSA Guidelines for Treatment of Candidiasis Clinical Infectious Diseases    2004;38:161-189  accessed at: http://www.journals.uchicago.edu/CID/journal/issues/v38n2/32301/32301.html
24. Lesher JL. Pityriasis versicolor and candidiasis. American Academy of Dermatology. http://www.aad.org/education/pityriasis.htm. (Accessed January 2004).
25. McEvoy GK, editor. American Hospital Formulary Service First Professional Edition, (online) Bethesda, Maryland 2006.
26. Medical Economics, Inc., Physicians' Desk Reference,online. (Montvale, NJ: Medical Economics, 2006).
27. Olin BR, editor.  Drug Facts and Comparisons (online version).  St Louis: J.B.Lippincott Company, Facts and Comparisons division, 2006.
28. Thomson Micromedex USPDI; (online version thru statref). Montvale, NJ. 2006.
29. Pickering, Larry K. editor, Red Book:American Academy of Pediatrics 26^th edition 2003 accessed via online statref.
30. Product Information. Noxafil®suspension. Schering Corporation, Kenilworth, NJ.  2006.

Copyright Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

August 14, 2007