Antifungal, Oral Agents

Document Utilities

Pharmacy Clinical Policy Bulletins

Subject: Antifungal, Oral Agents

Class Edit Summary*

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 Lamisil ^® (terbinafine) X

NP Biostatin ^® (nystatin)

NP Diflucan ^® (fluconazole) X X

NP Grifulvin ^® griseofulvin microsized

NP Gris-peg ^® griseofulvin ultramicrosized

NP Nizoral ^® (ketoconazole)

FE Sporanox ^® (itraconazole) X X

FE Vfend ^® (voriconazole) X X

FE Ancobon ^® (flucytosine) X

*P = Preferred; FE = Formulary Excluded; NP = Nonpreferred PR = Precertification; QL = Quantity Limits; AL = Age Limits; ST = Step-Therapy ‡M EX = Medical Exception - This means the physician or health care professional must obtain a medical exception from Aetna, in order for the medication to be eligible for coverage. Medical Exception criteria apply to Formulary Excluded drugs for members enrolled in or covered by closed benefits plans, and also apply to Step-Therapy drugs in cases where a member's physician believes it is medically necessary for the member to use a step-therapy drug in the first instance without a trial of the prerequisite alternative drug(s).

Important Note

This Pharmacy Clinical Policy Bulletin expresses Aetna's determination of whether certain services or supplies are medically necessary. Aetna has reached these conclusions based upon a review of currently available clinical information (including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the technology, evidence-based guidelines of public health and health research agencies, evidence-based guidelines and positions of leading national health professional organizations, views of physicians practicing in relevant clinical areas, and other relevant factors). Aetna expressly reserves the right to revise these conclusions as clinical information changes, and welcomes further relevant information. Each benefits plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their health care providers will need to consult the member's benefits plan to determine if there are any exclusions or other benefit limitations applicable to this service or supply. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (that is, will be paid for by Aetna) for a particular member. The member's benefits plan determines coverage. Some plans exclude coverage for services or supplies that Aetna considers medically necessary. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a state, the federal government or CMS for Medicare and Medicaid members. CMS's Coverage Issues Manual can be found on the following website: http://cms.hhs.gov/manuals/pub06pdf/pub06pdf.asp.

Policy

Precertification Criteria

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


	Diflucan, fluco-nazole	Sporanox itraco-nazole	Vfend	Lamisil

A. Onychomycosis^† Documented diagnosis confirmed by either a positive KOH stain (potassium hydroxide), positive PAS stain (para-aminosalicylic acid), or positive fungal culture AND	X	X		X
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	X	X		X
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	X	X
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)	X

^†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

B. Diagnosis of Blastomycosis	X	X

OR

C. Diagnosis of Histoplasmosis	X	X

OR

D. Diagnosis of Coccidioidomycosis (valley fever)	X	X

OR

E. Diagnosis of Coccidiomeningitis	X	X

OR

F. Diagnosis of Cryptococcus	X

OR

G. 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	X	X

OR

H. Diagnosis of systemic Candidiasis	X

OR

I. Diagnosis of Urinary tract infection or balanitis with candida	X

OR

J. Diagnosis of Vulvovaginal Candidiasis	X

OR

K. Diagnosis of Recurrent vulvovaginal candidiasis (four or more episodes of symptomatic VVC within one year)	X

OR

L. Diagnosis of Oral (thrush), esophageal, intestinal candidiasis	X

OR

M. Diagnosis of Chronic cutaneous candidal infection	X

OR

N. Diagnosis of HIV/AIDS or cancer	X	X	X

OR

O. Diagnosis of Bone marrow transplant (using for prophylaxis)	X

OR

P. Diagnosis of Aspergillosis		X	X

OR

Q. Diagnosis of Fusarium species			X

OR

R. Diagnosis of Scedosporium apiospermum			X

OR

S. Infection with Candida sp which is resistant to fluconazole/ Diflucan® Documented diagnosis of resistant Candida sp AND			X
One of the following: Failure of fluconazole/Diflucan (at least one week of therapy) OR Laboratory evidence of fluconazole resistance AND			X
NOT RECEIVING A CONTRAINDICATED MEDICATION - contraindicated medications can include: pimozide (Orap^®), quinidine, sirolimus (Rapamune^®), rifampin, carbamazepine, long-acting barbiturates (phenobarbital), rifabutin, ergot alkaloids (ergotamine and dihydroergotamine/ DHE-45), ritonavir, efavirenz			X

OR

T. Cutaneous dermatophyte infection [NOTE: tinea pedis (athletes foot), tinea cruris (jock itch), or tinea corporis (ringworm on the body), does NOT include tinea versicolor] Documented diagnosis of cutneous dermatophyte infection AND	X	X		X
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	X	X		X
Failure of formulary oral terbinafine (Lamisil)		X

OR

U. Tinea capitis Documented diagnosis of tinea capitis AND	X	X		X
One of the following: Contraindication to the formulary alternative Lamisil^® OR Intolerance to the formulary alternative Lamisil OR Failure of an adequate trial of two weeks of the formulary alternative Lamisil OR Member requires a liquid dosage form	X

OR

V. Fungal Otitis externa Documented diagnosis of otitis externa AND	X
One of the following: Contraindication to two formulary topical alternatives OR Intolerance to two formulary topical alternatives OR Failure of an adequate trial of one week each of two formulary topical alternatives	X

OR

W. Diagnosis of Chronic Candidal Paronychia	X

OR

X. Diagnosis of tinea versicolor Documented diagnosis of tinea versicolor AND	X	X
One of the following: Contraindication to one formulary alternative (oral or topical ketoconazole) OR Intolerance to one formulary alternative (oral or topical ketoconazole) OR Failure of an adequate trial of one course of one formulary alternative (1 week oral ketoconazole OR 2 weeks topical ketoconazole) AND	X	X
One of the following: 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]

Under some plans, including plans that use an open or closed formulary, fluconazole and Diflucan may be subject to quantity limits.

Quantity limits:

According to the manufacturer, a single oral dose of Diflucan or fluconazole 150mg tablets is indicated for vaginal candidiasis. Diflucan or 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	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 the following criterion:

Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose

Medical Exception Criteria

Sporanox and Vfend are currently listed on the Aetna Formulary Exclusions List.*, Therefore, 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 Sporanox and Vfend to be medically necessary for those members who meet any of the following criteria:

A documented
- Contraindication to one preferred alternative agent OR
- Intolerance to one preferred alternative agent OR
- Allergy to one preferred alternative agent OR
- Failure of an adequate trial of one month of one preferred alternative agent

Ancobon is currently listed on the Aetna Formulary Exclusions List.* Therefore, Ancobon is 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 to be medically necessary for those members who meet any of the following:

Member has a documented diagnosis of cryptococcal meningitis
OR
Member has a documented diagnosis of candidal endocarditis or peritonitis
OR
Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for other therapeutic use.

Table A: Maximum time of approval for some indications


	Indication		Maximum time of approval

	Vaginal candidiasis		Based on the manufacturer and clinical literature, Aetna will cover 1 tablet per 30 days

	Recurrent vulvovaginal candidiasis		6 months

	Oropharyngeal, urinary tract candidiasis, balanitis		30 days

	Esophageal, intestinal candidiasis		60 days

	Onychomycosis		6 months (DIFLUCAN)/FLUCONAZOLE

	Onychomycosis- toenail		12 weeks

	Onychomycosis- fingernail		6 weeks

	Cutaneous dermatophyte infection, tinea capitis		30 days

	Tinea capitis		30 days

	Tinea versicolor		30 days

	Otitis externa		30 days

	HIV/AIDS		may be indefinite

	Candida sp. resistant to fluconazole		Vfend - 6 months

	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 and RVVC, limit of 6 months

Note:

Topical Antifungal Agents:

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)

*Information regarding Aetna's Preferred Drug List, Formulary Exclusions list, Precertification and Step-Therapy lists is available on our website. In addition, members should refer to their plan documents and may call the toll-free telephone number on their ID card for information regarding their benefits. Health care professionals also may obtain information by calling the Pharmacy Management Precertification Unit at 1-800-414-2386, or they can register to use our password-protected provider website. Visit www.aetna.com, select "Doctors & Hospitals" and choose "Physician Self-Service." Once registration is completed, health care professionals may use our online Precertification/medical exception email request form.

The lists above are subject to change. Not all programs - for example step-therapy, precertification, and quantity limits - are available in all service areas (for example, step-therapy does not apply to fully insured New Jersey members).

Many medications on the Preferred Drug List are subject to manufacturer rebate arrangements between Aetna and the manufacturer of those medications. If the member's prescription benefits plan has a deductible or copay levels based on a percentage of Aetna's contracted rate with the participating pharmacy, the contracted rate does not include or reflect any manufacturer rebate arrangements between Aetna and the medication manufacturer. In prescription plans with a deductible or copayment or coinsurance tiers, use of drugs from the Preferred Drug List generally will result in lower costs to members. However, where the prescription plan utilizes a deductible or copayments or coinsurance calculated on a percentage basis, there could be some circumstances in which a preferred drug would cost the member more than a nonpreferred drug because (1) the negotiated pharmacy payment rate for the preferred drug may be more than the negotiated pharmacy payment rate for the nonpreferred drug, and (2) rebates received by Aetna from drug manufacturers are not reflected in the cost of a prescription drug obtained by a member. The Preferred Drug List is subject to change.

In evaluating clinically and therapeutically similar drugs for selection for the Preferred Drug List, Aetna reviews the costs of drugs and takes into account rebates negotiated between Aetna and drug manufacturers. Consequently, a drug may be included on the Preferred Drug list that is more expensive than a nonpreferred alternative before any rebates Aetna may receive from a drug manufacturer are taken into account. In addition, certain drugs may be chosen for "preferred" status because of their clinical or therapeutic advantages or level of acceptance among physicians even though they cost more than nonpreferred alternatives. The net cost to a self-funded plan sponsor for covered prescriptions will vary based on (1) the terms of Aetna's arrangements with participating pharmacies; (2) the amount of the member's copayment, coinsurance or deductible obligation under the terms of the plan; and (3) the percentage, if any, of rebates to which the plan sponsor is entitled under its agreement with Aetna. As a result, a self-funded plan sponsor's actual claim expense per prescription for a particular preferred drug may in some circumstances be higher than for a nonpreferred alternative.

For members in Texas, additions to the 2006 Preferred Drug List will be effective no later than January 1, 2006. In accordance with state law, fully insured members in Texas who are receiving coverage for medications that are removed from the Preferred Drug List during the plan year will continue to have those medications covered at the same benefit level until their plan's renewal date.

This definition of precertification is not the same as the definition used by Texas law. Our use of the term "precertification" relates to the prior authorization of your services by Aetna, based on our decision of whether the service is medically necessary. Precertification is not a guarantee of payment or "verification" as defined by Texas law.

California HMO members enrolled in a closed formulary benefits plan who are receiving coverage for medications that are moved to the Formulary Exclusions List, and California HMO members who are receiving coverage for medications added to the Precertification or Step-Therapy lists, will continue to have those medications covered, for as long as the treating physician continues prescribing them. This coverage, in accordance with state law, is only provided when the drug is appropriately prescribed and is considered safe and effective for treating the member's medical condition.

Nothing in this section shall preclude the prescribing health care professional from prescribing another drug covered by the plan that is medically appropriate for the enrollee, nor shall anything in this section be construed to prohibit generic drug substitutions.

Place of Service:

Outpatient

The above policy is based on the following references:

Product Information Insert Ancobon®, Costa Mesa, California March 2003.
Product Information Insert. Grifulvin® , Ortho Pharmaceutical Corporation. Raritan, New Jersey January 1997.
Product Information Insert. Mycelex Troches, Bayer Pharmaceuticals Corporation, Mountain View, CA, Feb. 2003.
Product Information Insert. Sporanox® Oral Solution. Janssen Pharmaceutical, Raritan, NJ January 2004.
Sporanox internet site accessed Dec 15,2003 http://www.sporanox.com/
Product Information Vfend® Pfizer Inc, New York, NY. April 2004.
Product Information Lamisil® Novartis Pharmaceuticals, East Hanover, NJ, March 2004.
Product Information Diflucan® Pfizer/Roerig, New York, NY, June 2003
Bell-Syer SE, et.al. Oral treatments for fungal infections of the skin of the foot.Cochrane Database Syst Rev. 2002; (2): CD003584.
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
Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;51(No. RR-6):45-50.
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.
Crawford F, Young P, Godfrey C, et al. Oral treatment s for toenail onychomycosis. Arch Dermatol. 2002;138:811-16.
Darkes MJ, et. al. Terbinafine: a review of its use in onychomycosis in adults. Am J Clin Dermatol. 2003; 4(1): 39-65. Review.
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;
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.
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.
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.html
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.
Gilbert DN, Moellering RC, Sande MA, eds. The Sanford Guide to Antimicrobial Therapy 2003. Antimicrobial Therapy Inc. Hyde Park, VT, 2003.
Gupta AK - Non-dermatophyte onychomycosis.Dermatol Clin - APR-2003; 21(2): 257-68.
Gupta AK, Cooper EA, Lynde CW The efficacy and safety of terbinafine in children. Dermatol Clin. 2003 Jul; 21(3): 511-20.
IDSA Guidelines for Treatment of Candidiasis Clinical Infectious Diseases 2004;38:161-189 accessed at: http://www.idsociety.org/Content/NavigationMenu/Practice_Guidelines/
Guidelines_by_Topic/Practice_Guidelines_by_Topic.htm#Candidiasis
Lesher JL. Pityriasis versicolor and candidiasis. American Academy of Dermatology. http://www.aad.org/education/pityriasis.htm. (Accessed January 2004).
McEvoy GK, editor. American Hospital Formulary Service First Professional Edition , (online) Bethesda, Maryland 2004.
Medical Economics, Inc., Physicians' Desk Reference,online. (Montvale, NJ: Medical Economics, 2004).
Olin BR, editor. Drug Facts and Comparisons (online version). St Louis: J.B.Lippincott Company, Facts and Comparisons division, 2005.
Thomson Micromedex USPDI; (online version thru statref). Montvale, NJ. 2005.
Pickering, Larry K. editor, Red Book:American Academy of Pediatrics 26^th edition 2003 accessed via online statref.

Property of 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.

January 1, 2006