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ph-91034

Topical Antifungals, itraconazole, terbinafine Prior Authorization with Quantity Limit Program Summary

Policy Number: PH-91034

This program applies to Blue Partner, Commercial, GenPlus, SourceRx, and Health Insurance Marketplace formularies.

POLICY REVIEW CYCLE

Effective Date	Date of Origin
01-01-2025

FDA LABELED INDICATIONS AND DOSAGE

Agent(s)	FDA Indication(s)	Notes	Ref#
ciclopirox Topical solution	Topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to Trichophyton rubrum		3
Jublia® (efinaconazole) Topical solution	Topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes		13
Kerydin® (tavaborole)* Topical solution	Topical treatment of onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes	*generic available	14
Sporanox® (itraconazole)* Capsule Oral solution	Oral solution: treatment of oropharyngeal and esophageal candidiasis Capsule: 1) Treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: blastomycosis, pulmonary and extrapulmonary histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy onychomycosis of the toenail or fingernail 2) Treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) Onychomycosis of the fingernail due to dermatophytes (tinea unguium)	*generic available	1
terbinafine Tablet	Treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium)		2
Tolsura® (itraconazole) Capsule	Treatment of the following fungal infections in immunocompromised and non-immunocompromised adult patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Limitations of use: Tolsura is not indicated for the treatment of onychomycosis. Tolsura is not interchangeable or substitutable with other itraconazole products due to the difference in dosing with other itraconazole products.		16

See package insert for FDA prescribing information: https://dailymed.nlm.nih.gov/dailymed/index.cfm

CLINICAL RATIONALE

Onychomycosis

Onychomycosis (tinea unguium) is a fungal infection of the fingernails or toenails that causes discoloration, thickening, and separation from the nail bed that occurs in 10% of the general population but is more common in older adults. It is widely believed to be only a cosmetic problem, but it can be uncomfortable and can lead to cellulitis in older adults and foot ulcers in patients with diabetes. Eradication of the infection is key to improving the appearance and avoiding complications. Guidelines recommend consideration of treatment if walking is uncomfortable, abnormal looking nails are causing significant psychological distress, or if the patient has diabetes, vascular disease, or a connective tissue disorder. Treatment may be necessary if the nail infection is the source of a fungal skin infection or if the person is, or may become, severely immunocompromised.(11)

Onychomycosis can be difficult to distinguish from other causes of nail dystrophy and because of slow nail growth (six months for fingernails and twelve months for toenails) evidence of treatment failure may not be apparent for several months or more. If the diagnosis is not confirmed and improvement does not occur, it is impossible to ascertain if treatment failure has occurred or if the initial diagnosis was incorrect. Only 50% of nail problems are caused by onychomycosis, and physical examination alone can be inaccurate. Accurate diagnosis is crucial for successful treatment and requires identification of physical changes and positive laboratory analysis for diagnosis before initiation of treatment. Laboratory analysis of specimens include KOH preparation, fungal cultures, histopathologic examination of nail clippings with a periodic acid-Schiff (PAS) stain, and polymerase chain reaction (PCR) testing. In a study of 1,146 nail clippings comparing PAS histologic examination with KOH light microscopy and culture, PAS staining was the most sensitive test compared with 53% for culture and 48% for KOH microscopy. PCR has been shown to be more accurate than culture, however it is not yet widely available.(11)

The British Association of Dermatologists guidelines for the management of onychomycosis recommends both itraconazole and terbinafine as first line treatments for dermatophyte onychomycosis and generally prefer terbinafine over itraconazole.(15) The American Academy of Family Physicians recommends terbinafine and itraconazole as first-line treatment for onychomycosis due to its tolerability, high cure rate, and low cost. A meta-analysis showed a mycotic cure rate of 76% for terbinafine and 63% for itraconazole with a clinical cure rate of 66% for terbinafine and 70% for itraconazole.(11) Several meta-analyses have found oral terbinafine more effective than oral itraconazole for onychomycosis.(7-10)

Topical agents are recommended for patients who cannot take oral antifungals and in those with less than 50% of the distal nail affected and no lunular involvement. Ciclopirox is considered less effective than systemic therapy, but has no systemic side effects or drug interactions. Additionally, a comparative study showed combination of ciclopirox and oral terbinafine had a higher mycotic cure rate and complete cure rate compared to terbinafine alone.(11) The prescribing information for ciclopirox indicates it is part of a comprehensive management program that includes removal of the unattached, infected nails as frequently as monthly, by a health care professional who has special competence in the diagnosis and treatment of nail disorders, including minor nail procedures.(3)

Safety

Sporanox capsules and solution have a boxed warning for congestive heart failure, cardiac effects, and drug interactions.(1,17)

Congestive Heart Failure and Cardiac Effects

Sporanox should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections.
If signs or symptoms of congestive heart failure occur during administration of Sporanox oral solution, continued use should be reassessed.
When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.

Drug Interactions

Concomitant use with a number of CYP3A4 substrates (methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine [ergonovine], ergotamine, methylergometrine [methylergonovine]), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin.
Colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment.
Eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.
Venetoclax is contraindicated in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome
Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia.

Tolsura has a boxed warning for congestive heart failure and drug interactions.(16)

Congestive Heart Failure: can cause or exacerbate CHF. When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen.

Drug Interactions:

Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs
Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment
Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors
Increased plasma concentrations of some of these drugs caused by co-administration with TOLSURA can lead to QT prolongation and/or ventricular tachyarrhythmias, including occurrences of torsades de pointes, a potentially fatal arrhythmia

Ciclopirox is contraindicated in individuals who have shown hypersensitivity to any of its components.(3)

Jublia and Kerydin have no contraindications of use.(13,14)

Sporanox is contraindicated in the following:(1,17)

Patients who have shown hypersensitivity to itraconazole.
Capsules: should not be administered for the treatment of onychomycosis in to pregnant patients or to women contemplating pregnancy.

Terbinafine is contraindicated in patients with:(2)

Chronic or active liver disease
History of allergic reaction to oral terbinafine because of the risk of anaphylaxis

Tolsura is contraindicated in patients with known hypersensitivity to itraconazole.(16)

REFERENCES

Number	Reference
1	Sporanox capsule prescribing information. Janssen Pharmaceuticals,Inc. February 2024.
2	Terbinafine prescribing information. Bionpharma Inc. December 2023.
3	Ciclopirox solution prescribing information. Medimetriks Pharmaceuticals, Inc. December 2020.
4	Reference no longer used
5	Reference no longer used
6	Reference no longer used
7	Criber BJ, Paul C. Long-term efficacy of antifungals in toenail onychomycosis: a critical review. British Journal of Dermatology/British Journal of Dermatology, Supplement. 2001;145(3):446-452. doi:10.1046/j.1365-2133.2001.04378.x
8	Haugh M, Helou S, Boissel JP, Cribier BJ. Terbinafine in fungal infections of the nails: a meta-analysis of randomized clinical trials. British Journal of Dermatology/British Journal of Dermatology, Supplement. 2002;147(1):118-121. doi:10.1046/j.1365-2133.2002.04825.x
9	Epstein E. How often does oral treatment of toenail onychomycosis produce a Disease-Free Nail? Archives of Dermatology. 1998;134(12). doi:10.1001/archderm.134.12.1551
10	Crawford F, Young P, Godfrey C, et al. Oral treatments for toenail onychomycosis. Archives of Dermatology. 2002;138(6). doi:10.1001/archderm.138.6.811
11	Westerberg DP, Voyack MJ. Onychomycosis: Current trends in Diagnosis and treatment. AAFP. Published December 1, 2013. https://www.aafp.org/pubs/afp/issues/2013/1201/p762.html
12	Reference no longer used
13	Jublia prescribing information. Bausch Health Companies, Inc. March 2022.
14	Kerydin prescribing information. Anacor Pharmaceuticals, Inc. July 2018.
15	Ameen M, Lear JT, Madan V, et al. British Association of Dermatologists’ guidelines for the management of onychomycosis 2014. British Journal of Dermatology/British Journal of Dermatology, Supplement. 2014;171(5):937-958. doi:10.1111/bjd.13358
16	Tolsura prescribing information. Mayne Pharma. April 2022.
17	Sporanox oral solution prescribing information. Janssen Pharmaceuticals, Inc. March 2024.

POLICY AGENT SUMMARY PRIOR AUTHORIZATION

Target Brand Agent(s)	Target Generic Agent(s)	Strength	Targeted MSC	Available MSC	Final Age Limit	Preferred Status
Ciclopirox, Efinaconazole, Tavaborole
Ciclodan	Ciclopirox Solution 8%	8 %	M ; N ; O ; Y	Y
Jublia	efinaconazole soln	10 %	M ; N ; O ; Y	N
Kerydin	tavaborole soln	5 %	M ; N ; O ; Y	O ; Y

POLICY AGENT SUMMARY QUANTITY LIMIT

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	QL Amount	Dose Form	Day Supply	Duration	Addtl QL Info	Allowed Exceptions	Targeted NDCs When Exclusions Exist

Ciclodan	Ciclopirox Solution 8%	8 %	6.6	mLs	30	DAYS
Jublia	Efinaconazole Soln 10%	10 %	4	mLs	30	DAYS
Kerydin	Tavaborole Soln 5%	5 %	4	mLs	30	DAYS

CLIENT SUMMARY – PRIOR AUTHORIZATION

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Ciclodan	ciclopirox solution	8 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx
Ciclodan	Ciclopirox Solution 8%	8 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx
Jublia	efinaconazole soln	10 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx
Kerydin	tavaborole soln	5 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx

CLIENT SUMMARY – QUANTITY LIMITS

Target Brand Agent Name(s)	Target Generic Agent Name(s)	Strength	Client Formulary
Ciclodan	Ciclopirox Solution 8%	8 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx
Jublia	Efinaconazole Soln 10%	10 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx
Kerydin	Tavaborole Soln 5%	5 %	Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; SourceRx

PRIOR AUTHORIZATION CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
ciclopirox, efinaconazole, tavaborole	Jublia (efinaconazole), Kerydin (tavaborole), or ciclopirox will be approved when ALL of the following are met: The patient has a diagnosis of onychomycosis (tinea unguium) AND The patient has ONE of the following: diabetes mellitus, peripheral vascular insufficiency, immune deficiency due to medical condition or treatment (e.g., cancer chemotherapy, HIV/AIDS, anti-rejection therapy post organ transplant), pain limiting normal activity, secondary bacterial infection in the surrounding skin, or systemic dermatosis with impaired skin integrity AND Treatment of the patient’s onychomycosis is medically necessary and not entirely for cosmetic reasons AND The fungal nail infection is confirmed by laboratory testing (KOH preparation, fungal culture, periodic acid-Schiff [PAS] staining, or polymerase chain reaction [PCR] testing) AND ONE of the following: The patient has tried and had an inadequate response to ONE oral antifungal agent (itraconazole, terbinafine) OR The patient has an intolerance or hypersensitivity to ONE oral antifungal agent OR The patient has an FDA labeled contraindication to ALL oral antifungal agents OR The oral antifungal agents are not clinically appropriate AND If the requested agent is ciclopirox 8% topical solution, treatment will include removal of the unattached, infected nail(s) by a health care professional AND If the requested agent is a brand agent, ONE of the following: The patient has a medication history of use within the past 90 days with ONE generic antifungal onychomycosis agent (itraconazole, terbinafine, ciclopirox) OR The patient has an intolerance or hypersensitivity to ONE generic antifungal onychomycosis agent OR The patient has an FDA labeled contraindication to ALL generic antifungal onychomycosis agents AND The patient does NOT have any FDA labeled contraindications to the requested agent Length of Approval: 12 months NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. *Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

Module

Clinical Criteria for Approval

ciclopirox, efinaconazole, tavaborole

Jublia (efinaconazole), Kerydin (tavaborole), or ciclopirox will be approved when ALL of the following are met:

The patient has a diagnosis of onychomycosis (tinea unguium) AND
The patient has ONE of the following: diabetes mellitus, peripheral vascular insufficiency, immune deficiency due to medical condition or treatment (e.g., cancer chemotherapy, HIV/AIDS, anti-rejection therapy post organ transplant), pain limiting normal activity, secondary bacterial infection in the surrounding skin, or systemic dermatosis with impaired skin integrity AND
Treatment of the patient’s onychomycosis is medically necessary and not entirely for cosmetic reasons AND
The fungal nail infection is confirmed by laboratory testing (KOH preparation, fungal culture, periodic acid-Schiff [PAS] staining, or polymerase chain reaction [PCR] testing) AND
ONE of the following:
1. The patient has tried and had an inadequate response to ONE oral antifungal agent (itraconazole, terbinafine) OR
2. The patient has an intolerance or hypersensitivity to ONE oral antifungal agent OR
3. The patient has an FDA labeled contraindication to ALL oral antifungal agents OR
4. The oral antifungal agents are not clinically appropriate AND
If the requested agent is ciclopirox 8% topical solution, treatment will include removal of the unattached, infected nail(s) by a health care professional AND
If the requested agent is a brand agent, ONE of the following:
1. The patient has a medication history of use within the past 90 days with ONE generic antifungal onychomycosis agent (itraconazole, terbinafine, ciclopirox) OR
2. The patient has an intolerance or hypersensitivity to ONE generic antifungal onychomycosis agent OR
3. The patient has an FDA labeled contraindication to ALL generic antifungal onychomycosis agents AND
The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

*Step therapy requirement may not apply if a prior health plan paid for the medication - documentation of a paid claim may be required.

QUANTITY LIMIT CLINICAL CRITERIA FOR APPROVAL

Module	Clinical Criteria for Approval
	Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met: The requested quantity (dose) does NOT exceed the program quantity limit OR The requested quantity (dose) exceeds the program quantity limit AND ONE of the following: BOTH of the following: The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND There is support for therapy with a higher dose for the requested indication OR BOTH of the following: The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit OR BOTH of the following: The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND There is support for therapy with a higher dose for the requested indication Length of Approval: up to 12 months

Module

Clinical Criteria for Approval

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

The requested quantity (dose) does NOT exceed the program quantity limit OR
The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
1. BOTH of the following:
  1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
  2. There is support for therapy with a higher dose for the requested indication OR
2. BOTH of the following:
  1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
  2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does not exceed the program quantity limit OR
3. BOTH of the following:
  1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
  2. There is support for therapy with a higher dose for the requested indication

Length of Approval: up to 12 months

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.