Antifungals, Oral / Noxafil tablet

Antifungals, Oral Therapeutic Class Review (TCR) August 1, 2013 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Provider Synergies, L.L.C. All requests for permission should be mailed to: Attention: Copyright Administrator Intellectual Property Department Provider Synergies, L.L.C. 10101 Alliance Road, Suite 201 Cincinnati, Ohio 45242 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to PSTCREditor@magellanhealth.com. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 1 of 30 August 2013 Antifungals, Topical Therapeutic Class Review (TCR) December 3, 2013 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Provider Synergies, L.L.C. All requests for permission should be mailed to: Attention: Copyright Administrator Intellectual Property Department Provider Synergies, L.L.C. 10101 Alliance Road, Suite 201 Cincinnati, Ohio 45242 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to PSTCREditor@magellanhealth.com. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 1 of 22 December 2013 Antifungals, Topical Review FDA-APPROVED INDICATIONS Tinea pedis Drug benzoic acid/ salicylic acid 1 (Bensal HP®) butenafine (Mentax®) 2 ciclopirox 3,4,5,6 (Loprox®) ciclopirox ® (Ciclodan cream/kit) 7 Tinea cruris Tinea Tinea Cutaneous versicolor corporis candidiasis -- -- -- -- -- X X X X -- X X X X X X X X X X ciclopirox (Ciclodan™ solution) ciclopirox (CNL-8™) 8 9 Other Inflammation and irritation associated with common forms of dermatitis Treatment of insect bites, burns and fungal infections -Seborrheic scalp dermatitis Topical treatment in immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails due to Trichophyton rubrum -- -- -- -- -- clotrimazole 12 (Desenex®) 13 (Lotrimin®) X X X X X -- clotrimazole / betamethasone 14 (Lotrisone®) X X -- X X -- X X X X X -- X -- -- -- -- -- -- -- -- -- -- Seborrheic dermatitis X X X X X Seborrheic dermatitis -- -- -- Seborrheic dermatitis ciclopirox (Pedipirox-4™) ciclopirox (Penlac®) econazole 10 11 15 econazole 16 (Ecoza™) ketoconazole (Extina®) ketoconazole cream 17 18 ketoconazole (Ketodan™) 19 ketoconazole (Nizoral 20 Shampoo®) ketoconazole (Xolegel®) miconazole (Azolen™) 21 22 miconazole (Fungoid®) 23 -- -- X -- -- -- -- -- -- -- -- X -- -- X -- -- X -- -- X -- -- Seborrheic dermatitis Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 2 of 22 December 2013 Antifungals, Topical Review FDA-Approved Indications (continued) Tinea pedis Tinea cruris X -- -- -- -- -- miconazole 25 (Monistat®) X X X X X -- miconazole / zinc oxide / white petrolatum 26 (Vusion®) -- -- -- -- -- X X -- -- -- -- X X -- X -- -- -- -- -- -- X -- Drug miconazole (Fungoid-D) miconazole (Zeasorb®) 24 27 naftifine 28 (Naftin®) nystatin 29 Tinea Tinea Cutaneous versicolor corporis candidiasis Other Diaper dermatitis (adjunctive treatment) nystatin (Pediaderm AF) 30 -- -- -- -- X -- nystatin / triamcinolone 31 -- -- -- -- X -- X X X (cream only) X -- -- 33 X -- -- -- -- -- 34 X X X X -- -- X X X X -- -- X X X X -- -- X X -- X -- Relief of itching , burning, and cracking X -- -- X -- Relief of itching , burning, and cracking X -- -- X -- Relief of itching , burning, and cracking oxiconazole (Oxistat®) 32 sertaconazole (Ertaczo®) sulconazole (Exelderm®) terbinafine (Lamisil®) 35 tolnaftate 36 (Tinactin®) undecylenic acid (Hongo Cura MS) 37 undecylenic acid/ zinc undecylenate (Fungi Nail) 38 undecylenic acid/ zinc undecylenate (Hongo Cura RS) 39 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 3 of 22 December 2013 Antifungals, Topical Review Treatment of tinea versicolor requires a legend topical product while the treatment of tinea pedis, tinea cruris, or tinea corporis may be treated with an over-the-counter (OTC) topical agent. Drug Manufacturer benzoic acid/salicylic acid (Bensal HP) Seven Oaks butenafine (Mentax) Mylan Pharmaceuticals butenafine OTC generic ciclopirox (Ciclodan) Medimetriks ciclopirox (CNL-8) Innocutis Holding ciclopirox (Loprox) generic ciclopirox (Pedipirox-4) Valeant ciclopirox (Penlac) generic clotrimazole (Desenex) OTC Novartis clotrimazole (Lotrimin) generic clotrimazole OTC generic clotrimazole/betamethasone (Lotrisone) generic econazole generic econazole (Ecoza) Quinnova Pharmaceuticals ketoconazole (Extina) Stiefel ketoconazole (Ketodan) Medimetriks ketoconazole (Nizoral Shampoo) generic ketoconazole (Xolegel) Aqua ketoconazole cream generic miconazole (Azolen) OTC Stratus miconazole (Fungoid) OTC Valeant miconazole (Fungoid-D) OTC Valeant miconazole (Monistat) OTC generic miconazole (Nuzole) Vertical Pharmaceuticals miconazole (Zeasorb) OTC Stiefel miconazole / zinc oxide/ white petrolatum (Vusion) Stiefel/Physicians naftifine (Naftin) Merz nystatin generic nystatin (Pediaderm AF) Arbor nystatin/triamcinolone generic oxiconazole (Oxistat) PharmaDerm sertaconazole (Ertaczo) Valeant sulconazole (Exelderm) Ranbaxy Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 4 of 22 December 2013 Antifungals, Topical Review FDA-Approved Indications (continued) Drug Manufacturer terbinafine (Lamisil) OTC generic tolnaftate OTC generic undecylenic acid (Hongo Cura MS) OTC Kramer undecylenic acid/ zinc undecylenate (Fungi Nail) OTC Kramer undecylenic acid/ zinc undecylenate (Hongo Cura RS) OTC Kramer OVERVIEW Tinea cruris, corporis, and pedis, named for the body sites involved, are superficial fungal infections (dermatophytosis) caused by three genera of dermatophytes: Trichophyton, Microsporum, and Epidermophyton. 40 These dermatophytes are a homogenous group of fungi that live on the keratin of the stratum corneum, nails, and hair. The estimated lifetime risk of acquiring tinea infections is between ten and 20 percent.41 Dryness of the skin's outer layer discourages colonization by microorganisms, and shedding of epidermal cells keeps many microbes from establishing residence. With inhibition or failure of the skin's protective mechanisms, cutaneous infection may occur with subsequent pruritus, redness, and scaling. Since dermatophytes require keratin for growth, they are restricted to hair, nails, and superficial skin; therefore, most can be treated with topical antifungal medications. 42 Tinea pedis (athlete's foot) is one of the most common superficial fungal infections of the skin and is most often caused by the dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum. 43 Affected skin is usually pruritic with scaling plaques on the soles extending to the lateral aspect of the feet and interdigital spaces. Tinea cruris is a dermatophyte infection of the groin (jock itch) also caused by T. rubrum, T. mentagrophytes, and E. floccosum. This condition affects the skin of the medial and upper parts of the thighs, usually bilaterally, with severe pruritus. Tinea corporis (ringworm on the skin) refers to tinea anywhere on the body except the scalp, beard, feet, or hands. Trichophyton and Microsporum are usually the causative organisms. Each lesion may have one or several concentric rings with red papules or plaques in the center. As the lesion progresses, the center may clear, leaving post-inflammatory hypopigmentation or hyperpigmentation. Tinea versicolor, a common superficial fungal infection, is caused by Malassezia species (formerly Pityrosporon). 44 This organism is part of the normal flora in most individuals but is capable of becoming pathogenic under certain conditions. The most distinctive clinical feature is the change in pigmentation on the affected sites. Mild scaling and pruritus are usually the only other sequelae. Cutaneous candidiasis, usually caused by Candida albicans, may colonize occluded areas or folds of the skin, producing infection in areas, such as the groin, axillae, and interdigital spaces. Clinical manifestations include erythema, scaling, maceration, vesicles, and pustules. Onychomycosis is a fungal infection of the nailbed (skin beneath the nail plate) with secondary involvement of the nailplate (visible part of the nail on fingers and toes). The main pathogens responsible for onychomycosis are dermatophytes, yeasts, and molds. Despite significant improvements, approximately 20 percent of patients with onychomycosis still fail on antifungal therapy. More common in toenails than fingernails, they often cause the end of the nail to separate Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 5 of 22 December 2013 Antifungals, Topical Review from the nail bed. Additionally, debris (white, green, yellow, or black) may build up under the nail plate and discolor the nail bed. 45 Seborrheic dermatitis is one of the more common cutaneous diseases. 46 One proposed etiology is overgrowth of yeast, which normally inhabits sebaceous skin of the scalp, eyebrows, and central face. The disease typically occurs in three age groups, which are infancy, middle age, and seniors. Seborrheic dermatitis in adults typically involves the scalp, face, neck, mid upper chest, and intertriginous zones (axillae, groin, and submammary). PHARMACOLOGY 47 The mechanism of action of benzoic acid/salicylic acid (Bensal HP) is unknown. It has been demonstrated that benzoic acid/salicylic acid (Bensal HP) reduces methicillin-resistant Staphylococcus aureus (MRSA) protected by biofilms in wounds using porcine models and stimulates reepithelialization of second-degree burns in porcine models. Undecylenic (Hongo Cura MS) and undecylenic/zinc undecylenate (Fungi Nail, Hongo Cura RS) acid are organic unsaturated fatty acids derived from castor oil that have 11 carbons in the fatty acid chain. The exact mechanism of action of undecylenic/undecylenate acid is unknown. It has been demonstrated that undecylenic/undecylenate acid inhibits morphogenesis of Candida albicans by interference with fatty acid biosynthesis, which can inhibit germ tube (hyphae) formation. Medium –chain fatty acids have also been shown to disrupt the pH of the cell cytoplasm by being proton carriers, which interferes with vial replication mechanism in infected cells. The mechanism of action and effectiveness in fatty acid based antifungal is dependent on the number of carbon atoms in the chain. The more carbon atoms in a chain the more effective the fatty acid based antifungal. The other agents in this category can be divided into two principal pharmacologic antifungal groups, the allylamines and the azoles. Butenafine (Mentax) is structurally and pharmacologically related to the allylamine antifungal agents, which include naftifine (Naftin) and terbinafine (Lamisil). The exact mechanisms of the fungicidal action are unknown for these agents. Presumably, they exert antifungal activity by altering cellular membranes resulting in increased cellular permeability and growth inhibition. They may also interfere with sterol biosynthesis at an earlier stage than do the imidazole derivatives. They are active against many fungi and yeasts. Tolnaftate (Tinactin) works in a similar manner to these agents, although it is a thiocarbamate antifungal. Shorter time to cure is usually seen with fungicidal agents. Clotrimazole (Lotrimin, Desenex), econazole (Ecoza), ketoconazole (Extina, Ketodan, Nizoral Shampoo, Xolegel), miconazole (Azolen, Fungoid, Zeasorb, Monistat, Nuzole, Vusion), oxiconazole (Oxistat), sulconazole (Exelderm), and sertaconazole (Ertaczo) are azole antifungals (imidazole derivatives). The imidazole-derivative azole antifungals exert antifungal activity by altering cell membrane permeability by binding with phospholipids in the fungal cell membrane. They are active against many fungi including dermatophytes and yeasts. The azole antifungals, miconazole, clotrimazole, and ketoconazole, are fungistatic and generally require epidermal turnover to shed living fungus from the skin. 48 Ciclopirox (Ciclodan, Pedipirox-4, Loprox, Penlac, CNL-8) is thought to act by chelating polyvalent cations (Fe+3 or Al+3) resulting in the inhibition of the metal dependent enzymes responsible for the Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 6 of 22 December 2013 Antifungals, Topical Review degradation of peroxides within the fungal cell. Ciclopirox is active against many genera of fungi including dermatophytes and yeast. Nystatin Pediaderm AF) exerts its antifungal activity by binding to sterols in the fungal cell membrane. As a result of this binding, the membrane is no longer able to function as a selective barrier, and potassium and other cellular constituents are lost. PHARMACOKINETICS 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 Due to the nature of topical application, all products minimally expose the systemic circulation. Cream: Creams are oil-in-water emulsions and are generally less greasy than ointments. Creams are usually less effective than ointments. Gel: Gels consist of a solid, jelly-like material that is mostly liquid, but contains a substantially dilute crosslinked system that gives the gel the property of thixotropy (the gel is solid until the material is agitated and then becomes liquid). They can also be a highly absorbent drug delivery system with natural or synthetic polymers and can act as reservoirs in topical drug delivery. Lotion: Lotions are diluted creams. Ointment: Ointments are best at delivering drug to the skin and provide a barrier. Solutions: Solutions are typically alcoholic liquids and are especially useful for the scalp because they do not coat the hair. Lacquer: Nail lacquers are topical solutions intended only for use on fingernails and toenails and immediately adjacent skin. Foam: Foam is a topical product that can be used on the scalp, body, and face. It quickly dissolves leaving minimal residue. Powder: Powders are beneficial due to their ease of application but generally are less effective than other formulations. Due to their lack of absorption, they can be used over large areas and sometimes are used preventatively in patients prone to tinea pedis and tinea cruris. CONTRAINDICATIONS/WARNINGS Hypersensitivity to any component of these agents is considered a contraindication for use.63 These are topical agents and not intended for ophthalmic, vaginal, or oral use. 64 Benzoic acid/salicylic acid (Bensal HP) is contraindicated in patients with hypersensitivity type reactions to topical polyethylene glycols. 65 Ciclopirox (Ciclodan, CNL-8, Loprox, Pedipirox-4, Penlac,) should be avoided in patients with a history of seizure disorders or immunosuppression.66,67,68 Combination products containing corticosteroids can produce reversible hypothalamic-pituitaryadrenal (HPA) axis suppression if applied over large surface areas, associated with prolonged use, used under occlusive dressings, or used in combination with other topical corticosteroids. If HPA suppression is noted, then if possible, the drug should be discontinued or the application reduced in frequency. 69,70 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 7 of 22 December 2013 Antifungals, Topical Review Xolegel contains 34 percent dehydrated alcohol. Extina and Ecoza contain alcohol and propane/butane. So fire, flame, or smoking during and immediately following application of these products should be avoided.71, 72 Do not store containers in sunlight or expose containers to heat or temperatures above 120oF (49oC) even when empty.73 Effects such as hepatitis, lowered testosterone and ACTH induced corticosteroid serum levels have been seen with oral ketoconazole; however, these adverse events have not been observed with topical ketoconazole.74 Loprox shampoo has had some rare reports of hair discoloration occurring on patients with light colored hair.75 Miconazole (Vusion) should not be used to prevent diaper dermatitis, as in an adult institutional setting. Preventative use may lead to the development of resistance.76 Undecylenic (Hongo Cura MS) and undecylenic/zinc undecylenate (Fungi Nail, Hongo Cura RS) should not be used to treat or prevent diaper rash.77 DRUG INTERACTIONS78,79 Significant drug interactions with the topical agents have not been noted with the exception of econazole. Concomitant administration of warfarin and econazole has resulted in the enhancement of the anticoagulant effect. Monitoring International Normalized Ratio (INR) and /or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion. ADVERSE EFFECTS Drug Burning Itching Application Site Reaction Erythema benzoic acid/salicylic acid 80 (Bensal HP) reported nr nr nr <2 <2 <2 <2 reported reported reported nr 1 nr 1 5 7-34 1-5 1-5 nr reported reported reported reported reported reported reported reported reported reported 3 reported nr nr <1 nr butenafine (Mentax) 81 ciclopirox ® (Ciclodan cream/kit) 82 ciclopirox (Ciclodan solution), CNL-8, Pedipirox-4, 83, 84, 85, 86 Penlac,) ciclopirox (Loprox) 87, 88, 89, 90 clotrimazole 91 (Desenex) 92 (Lotrimin) clotrimazole/betamethasone (Lotrisone) econazole 94 econazole (Ecoza) 95 93 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 8 of 22 December 2013 Antifungals, Topical Review Adverse Effects (continued) Drug Burning Itching Application Site Reaction Erythema 96 10 ≤1 6 ≤1 10 <1 6 <1 nr <3 <3 nr 4 <1 reported <1 5 reported reported nr reported reported reported nr nr nr nr nr nr nr nr nr nr nr nr nr reported reported reported reported 5-6 1-2 2 0.5-2 nr nr reported nr nr nr reported nr reported reported reported nr ketoconazole (Extina) ketoconazole (Ketodan) 97 ketoconazole (Nizoral Shampoo) ketoconazole (Xolegel) ketoconazole cream 98 99 100 miconazole (Monistat) miconazole (Zeasorb) 101 102 miconazole cream (Fungoid-D) miconazole tincture (Azolen, Fungoid) 103, 104 miconazole/zinc oxide/ 105 white petrolatum (Vusion) naftifine (Naftin) nystatin 106 107 nystatin (Pediaderm AF) nystatin/ triamcinolone oxiconazole (Oxistat) 108 109 110 0.7-1.4 0.4-1.6 0.4 0.2 111 reported nr reported nr 112 sertaconazole (Ertaczo) sulconazole (Exelderm) 3 3 reported 1 terbinafine (Lamisil) 113 1-2 1-2 1-2 nr tolnaftate (Tinactin) 114 nr nr reported nr undecylenic acid (Hongo Cura MS) nr nr nr nr undecylenic acid/ zinc undecylenate (Fungi Nail) nr nr nr nr undecylenic acid/ zinc undecylenate (Hongo Cura RS) nr nr nr nr Adverse effects are indicated as percentage occurrence. Adverse effects data are compiled from package inserts and cannot be considered comparative or all inclusive. nr = not reported The incidence of nail disorders, such as shape change, irritation, ingrown toenail, discoloration, and application site reactions were similar between ciclopirox (Ciclodan, CNL-8, Pedipirox-4, Penlac,) and vehicle. SPECIAL POPULATIONS Pediatrics Fungal infections can occur in children and may frequently present as tinea corporis (includes ringworm), diaper dermatitis, and tinea capitis. Infants and young children may experience diaper dermatitis when infected with Candida sp., which may respond rapidly to topical therapy including ciclopirox, nystatin, and several other agents in this class. 115 Drugs which have safety and effectiveness Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 9 of 22 December 2013 Antifungals, Topical Review data for children include clotrimazole, miconazole, tolnaftate, and undecylenic/zinc undecylenate which can be used in patients ages two years and older; Vusion may be used in children four weeks of age and older. 116 In addition, butenafine (Mentax), econazole (Ecoza), ketoconazole gel (Xolegel), ketoconazole foam (Extina, Ketodan), and sertaconazole (Ertaczo) are approved for use in children ages 12 years and older.117 Oxiconazole (Oxistat) cream may be used in pediatric patients for tinea corporis, tinea cruris, tinea pedis, and tinea versicolor; however, these approved indications rarely occur in children less than the age of 12 years. 118 Ciclopirox cream and suspension can be used in patients aged 10 years and older, nail lacquer in patients aged 12 years and older, and gel and shampoo in patients aged 16 years and older. Nystatin (Pediaderm AF) can be used at any age including infancy, while the combination product nystatin/triamcinolone can be used in children two months of age and older. Clotrimazole/betamethasone is not recommended for those less than 17 years of age.119 Safety and effectiveness of econazole, ketoconazole cream, naftifine (Naftin), sulconazole (Exelderm) and terbinafine (Lamisil) for pediatric patients have not been established.120, 121, 122 Pregnancy 123 All agents in this category are Pregnancy Category B with the exception of benzoic acid/salicylic acid (Bensal HP), clotrimazole/betamethasone, econazole (Ecoza), ketoconazole cream, ketoconazole (Extina, Ketodan, Nizoral, Xolegel), miconazole (Azolen, Fungoid, Zeasorb, Monistat, Vusion), nystatin, nystatin/triamcinolone, sertaconazole (Ertaczo), sulconazole (Exelderm), and tolnaftate, which are Pregnancy Category C. Undecylenic/zinc undecylenate has not been assigned a specific FDA pregnancy risk category rating. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 10 of 22 December 2013 Antifungals, Topical Review DOSAGES Drug Frequency of Application Rx Availability benzoic acid/ salicylic acid (Bensal 124 HP) Twice daily for seven days 6%/3% ointment butenafine 125 (Mentax) Once to twice daily for one to four weeks 1% cream ciclopirox (Loprox) 126, 127, 128, 129 Ciclopirox (Ciclodan) 130 OTC Availability -Lotrimin Ultra 1% cream Gel, topical suspension: twice daily for four weeks 0.77% gel Shampoo: Apply 5 mL to scalp as directed twice a 0.77% TS suspension week for four weeks; a minimum of three days should 1% shampoo occur between applications 0.77% cream Cream, kit : twice daily for four weeks 0.77% cream (copackaged with skin cleanser combination TM #23 (Rehyla ) cleanser -- -- ciclopirox 131 (Ciclodan) ciclopirox (Pedipirox132 4) ciclopirox (Penlac) 133 Once daily (preferably at bedtime or eight hours before washing) to all affected nails for 48 weeks; daily 8% nail lacquer topical applications should be made over the previous coat solution and removed with alcohol every seven days -- ciclopirox 134 (CNL-8) clotrimazole Two to four times daily for up to four weeks clotrimazole 135 (Desenex) Two to four times daily for up to four weeks clotrimazole 136 (Lotrimin) Two to four times daily for up to four weeks 1% cream 1% solution clotrimazole / betamethasone 137 (Lotrisone) Twice daily for two to four weeks 1% / 0.05% cream 1% / 0.05% lotion -- Once to twice daily for two to four weeks 1% cream -- econazole 139 (Ecoza) Once daily for four weeks 1% foam ketoconazole 140 (Extina) Twice daily for four weeks 2% foam ketoconazole 141 cream Cream: once daily for two to six weeks depending on indication; apply twice daily for four weeks or until clinical clearing for seborrheic dermatitis 2% cream econazole 138 -- AF 1% cream 2% powder 2% liquid spray -- 2% aero powder 2% powder 2% liquid spray Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 AF 1% cream AF 1% solution ---Page 11 of 22 December 2013 Antifungals, Topical Review Dosages (continued) Drug Frequency of Application ketoconazole (Ketodan) Twice daily for four weeks 142 Daily for two weeks ketoconazole (Nizoral Shampoo 2%: use as directed twice a week for four 144 weeks Shampoo) Shampoo 1%: use every three to four days for up to eight weeks miconazole 145 miconazole (Azolen, Fungoid 146 tincture) miconazole / zinc oxide / white petrolatum 150 (Vusion) Apply at each diaper change for seven days nystatin 152 A-D 1% shampoo -- Twice daily for two to four weeks 151 2% shampoo Apply thin layer twice a day (morning and night) on skin, under nails and surrounding cuticle areas. miconazole 149 (Zeasorb) Cream: daily for four weeks Gel: twice daily for four weeks 1% cream 2% tincture 2% cream -0.25% / 15% / 81.35% ointment 1% cream 1% gel Cream, ointment: twice daily until healing is complete 100,000 units / gm Powder: two to three times daily until healing is cream complete 100,000 units / gm powder 100,000 units / gm ointment Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 -- -- -- Twice daily for two to four weeks naftifine (Naftin) 2% gel Apply thin layer once to twice daily (morning and/or night) miconazole 147,148 (Monistat) OTC Availability 2% foam 2% foam combo package (co-packaged with skin cleanser combination #23 (Rehyla™) cleanser) ketoconazole 143 (Xolegel) (Fungoid-D) Rx Availability 2% powder (Lotrimin AF) 2% liquid (Lotrimin AF) 2% cream 2% spray 2% gel 2% ointment 2% cream (Nuzole) 2% alcohol-gel 2% powder -- -- -- Page 12 of 22 December 2013 Antifungals, Topical Review Dosages (continued) Drug Frequency of Application nystatin (Pediaderm 153 AF) Twice daily until healing is complete nystatin / 154 triamcinolone Twice daily oxiconazole 155 (Oxistat) Rx Availability OTC Availability Pediaderm AF Complete Kit 100,000 units / gm cream -- 100,000 units / gm / 0.1% cream 100,000 units / gm / 0.1% ointment -- Once to twice daily for two to four weeks 1% cream 1% lotion -- sertaconazole 156 (Ertaczo) Twice daily for four weeks 2% cream sulconazole 157 (Exelderm) Once to twice daily for two to four weeks 1% cream 1% solution terbinafine (Lamisil) 158 -- -- 1% cream 1% spray 1% gel -- 1% cream 1% powder 1% powder spray 1% solution 1% gel 1% liquid spray -- 1% cream 1% powder 1% powder spray 1% gel 1% liquid spray -- 25% spray undecylenic acid/ zinc Twice daily (morning and night) for 4 weeks undecylenate (Fungi Nail) -- 5%-20% ointment undecylenic acid/ zinc Twice daily (morning and night) for 4 weeks undecylenate (Hongo Cura RS) -- 5%-20% cream tolnaftate Cream: twice daily for one to two weeks Spray: once or twice daily for one week Gel: once daily for one week -- Twice daily for two to four weeks tolnaftate 159 (Tinactin) Twice daily for two to four weeks undecylenic acid (Hongo Cura MS) Tinea cruris: twice daily (morning and night) for 2 weeks Tinea pedis and corporis: twice daily (morning and night) for 4 weeks In general, tinea corporis and tinea cruris require treatment for two weeks whereas tinea pedis may require treatment for up to four weeks. 160 Treatment should continue for at least one week after symptoms have resolved. 161 Therapy with ciclopirox (Penlac, CNL-8) is recommended for 48 weeks. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 13 of 22 December 2013 Antifungals, Topical Review CLINICAL TRIALS Search Strategies Studies were identified through searches performed on PubMed and review of information sent by manufacturers. Search strategy included the FDA-approved topical use of all drugs in this class. Studies included for analysis in the review were published in English, performed with human participants, and randomly allocated participants to comparison groups. In addition, studies must contain clearly stated, predetermined outcome measure(s) of known or probable clinical importance, use data analysis techniques consistent with the study question and include follow-up (endpoint assessment) of at least 80 percent of participants entering the investigation. Despite some inherent bias found in all studies including those sponsored and/or funded by pharmaceutical manufacturers, the studies in this therapeutic class review were determined to have results or conclusions that do not suggest systematic error in their experimental study design. While the potential influence of manufacturer sponsorship/funding must be considered, the studies in this review have also been evaluated for validity and importance. Tinea Corporis tolnaftate cream (Tinactin) verses undecylenic/zinc undecylenate cream verses placebo Ninety seven subjects with dermatophytosis of the glabrous skin and groin, were randomly assigned to receive 1% tolnaftate, 3% undecylenic acid and its zinc salt (zinc undecylenate), or placebo cream in a double-blind manner. 162 Thirty three subjects received 1% tolnaftate cream and twenty one of those subjects were cured clinically and mycologically. Thirty two subjects received 3% undecylenic acid and 20% zinc undecylenate cream of which twenty one subjects were cured clinically and mycologically. In contrast only three of the thirty two subjects that received the placebo cream were cured clinically and mycological. Treatments with tolnaftate and undecylenic/zinc undecylenate appeared safe and effective in dermatophytoses of the glabrous skin. Tinea Cruris and Tinea Corporis butenafine (Mentax) versus clotrimazole (Lotrimin) Eighty patients, diagnosed with tinea cruris or tinea corporis, were randomly assigned to butenafine once daily for two weeks or clotrimazole twice daily for four weeks in a double-blind manner.163 Follow-up was done at one, two, four, and eight weeks. At the end of one week, butenafine recipients exhibited higher clinical cure rate compared to clotrimazole recipients (26.5 versus 2.9 percent, respectively) as well as higher mycological cure (61.7 versus 17.6 percent, respectively); however, this difference was not statistically significant at four and eight weeks of treatment. naftifine (Naftin) versus econazole Patients with tinea cruris or tinea corporis (n=104) were evaluated in a double-blind, randomized study.164 Naftifine 1% cream or econazole 1% cream were applied to affected areas twice daily for four weeks. After one week of treatment, naftifine had an overall cure rate of 19 percent compared with four percent for econazole (p=0.03). Two weeks after the end of treatment, both medications had overall cure rates of approximately 80 percent. A difference in favor of naftifine, although not Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 14 of 22 December 2013 Antifungals, Topical Review statistically significant after the first week, persisted throughout treatment. Three percent of the naftifine patients had adverse effects compared with 13 percent of the econazole subjects. Tinea Pedis econazole foam (Ecoza) versus placebo In two randomized, double-blind, vehicle-controlled, multicenter, clinical trials 505 patients with interdigital tinea pedis were randomized 1:1 to Ecoza 1% topical foam or vehicle.165 The patients ranged in age from 12 to 71 years with 5 subjects less than 18 years of age at baseline. Patients applied the assigned medication once daily for four weeks. The severity of erythema, scaling, fissuring, maceration, vesiculation, and pruritus were graded using a 4-point scale (none, mild, moderate, severe). Patients had KOH (potassium hydroxide) examination and fungal cultures taken to confirm eligibility. A total of 339 subjects with positive fungal cultures were evaluated for efficacy. Efficacy was evaluated on Day 43, two weeks post-treatment with treatment success being defined as complete cure (negative KOH and fungal culture and no evidence of clinical disease). Complete cure rates at two weeks post treatment (Day 43) were 23.2 percent for Ecoza 1% topical foam and 2.4 percent for the foam vehicle in trial 1, and 25.3 percent for Ecoza 1% topical foam and 4.8 percent for the foam vehicle in trial 2. The effective treatment (mycological cure and no or mild erythema and/or scaling with all other signs and symptoms absent) and mycological cure (negative KOH and Fungal culture) rates were also measured two weeks post treatment (Day 43). The effective treatment rates for trial 1 were 48.8 percent for Ecoza 1% foam and 10.8 percent for the foam vehicle, and trial two reflected 48.4 percent for Ecoza and 10.8 percent for the vehicle. The mycological cure rates in trial 1 were 68.3 percent for Ecoza and 15.7 percent for the vehicle, in trial two the rates were 67 percent for Ecoza and 18.1 percent for the vehicle. ketoconazole (Nizoral) versus clotrimazole (Lotrimin) The effects of clotrimazole 1% cream and ketoconazole 2% cream were compared in a double-blind, randomized manner for therapy of interdigital tinea pedis in 106 treated patients. 166 Ketoconazole cream was used twice daily, and clotrimazole cream was administered once daily; both used for four weeks. The number of patients with cure or improvement after four weeks was comparable (62 percent clotrimazole group versus 64 percent ketoconazole group). The mycological response revealed a negative culture and microscopy in 53.1 versus 52.1 percent of the patients after 14 days, in 76 versus 79.2 percent after 28 days, and in 83.7 versus 76.9 percent after 56 days of observation in clotrimazole versus ketoconazole, respectively. The overall score of the development of tinea-related signs and symptoms did not show relevant differences between the two drugs. Better results were obtained under clotrimazole than under ketoconazole for pruritus (97.8 versus 89.6 percent) and burning/stinging (97.5 versus 89.4 percent). Treatments appeared comparably safe and tolerable. terbinafine (Lamisil) versus clotrimazole (Lotrimin) A multicenter, randomized, double-blind, parallel-group study in 256 patients with tinea pedis compared the safety and efficacy of the twice daily application of terbinafine 1% cream for one week (placebo given for the remaining three weeks) with the twice daily application of clotrimazole 1% cream for four weeks. 167 Mycological cure and effective treatment were assessed four and six weeks after commencing therapy. Mycological cure rates at four weeks were 93.5 percent for terbinafine and 73.1 percent for clotrimazole (p=0.0001). Effective treatment rates at four weeks were 89.7 percent for Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 15 of 22 December 2013 Antifungals, Topical Review terbinafine and 58.7 percent for clotrimazole (p=0.0001), and at six weeks were 89.7 percent for terbinafine and 73.1 percent for clotrimazole (p=0.002). In a double-blind, clinical trial, 429 patients with tinea pedis were randomized to receive terbinafine 1% topical solution twice daily for one week followed by a vehicle application for three weeks, or clotrimazole 1% solution for four weeks. 168 Patients were evaluated at baseline and at weeks one, two, four (end of treatment), and eight (end of follow-up). Effective treatment results were similar and were recorded in 83 percent of terbinafine patients and 82 percent of clotrimazole patients. Mycological cure and disappearance of signs and symptoms were similar at each assessment visit in the two groups. The mycological cure rate was 95 percent with terbinafine solution and 91 percent with clotrimazole solution (p=0.05). Mild to moderate adverse events occurred in four to five percent of patients in each group. A multicenter, prospective, randomized, double-blind, parallel-group study compared the efficacy and tolerability of terbinafine 1% cream with clotrimazole 1% cream in the treatment of interdigital tinea pedis.169 Patients received either terbinafine twice daily for one week followed by a placebo cream for five weeks or clotrimazole twice daily for four weeks. Outcome measures were observed at one, four, eight, and 12 weeks after the commencement of the study. Of the 217 patients randomized, 104 had a culture-confirmed dermatophyte infection at baseline. In these patients, 84.6 percent in the terbinafine group were culture-negative after one week compared with only 55.8 percent in the clotrimazole group. Both agents were well tolerated. sertaconazole (Ertaczo) versus placebo A total of 383 patients with tinea pedis were evaluated after receiving either sertaconazole 2% cream twice daily for four weeks or vehicle control in two randomized, double-blind, parallel group, multicenter studies.170 Results demonstrated a 70.3 percent mycologic cure reported in the study group versus 36.7 percent with the vehicle group (p<0.0001). At week six, 46.7 percent of the sertaconazole group had successful treatment outcomes versus 14.9 percent of the vehicle group (p<0.0001). Both treatment arms were well-tolerated. Tinea Versicolor ciclopirox cream (Loprox) versus clotrimazole cream Two randomized, double-blind, parallel-group, multicenter studies assessed the efficacy and safety of ciclopirox 1% cream in patients with tinea versicolor. 171 The first study compared ciclopirox with the placebo cream vehicle, and the second study compared ciclopirox 1% cream to clotrimazole 1% cream. In both studies, treatments were applied topically twice a day for 14 days. Clinical and mycological cure responses were compared at treatment weeks one and two, and then post-treatment weeks one and two. Results from the first study demonstrated 49 percent of the ciclopirox treatment group (n=73) were clinically and mycologically cured after two weeks versus 24 percent of the placebo treatment group (n=72; p<0.001). Results from the second study demonstrated that 77 percent of the patients treated with ciclopirox cream were clinically and mycologically cured after two weeks of treatment versus 45 percent of patients treated with clotrimazole cream (p<0.001). Two weeks post-treatment, the proportion of patients with combined response was slightly greater in the ciclopirox treatment group versus the clotrimazole treatment group (86 percent versus 73 percent, respectively). No adverse effects were observed in either group. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 16 of 22 December 2013 Antifungals, Topical Review sulconazole (Exelderm) versus miconazole (Monistat) Sulconazole 1% cream and miconazole 2% cream were compared in the treatment of tinea versicolor in a double-blind, multicenter, randomized clinical trial enrolling 192 patients. 172 The medications were applied twice daily for three weeks. Of 181 patients analyzed for efficacy at the end of the treatment trial, 93 percent of the sulconazole patients and 87 percent of miconazole patients became KOHnegative. The complete clearing of tinea versicolor lesions occurred in 89 percent of sulconazoletreated patients and 82 percent of miconazole-treated patients. Cutaneous adverse effects, predominantly transient itching, were reported in eight patients receiving sulconazole and in four patients receiving miconazole. No systemic adverse events were reported. Onychomycosis ciclopirox (Penlac) versus placebo Two double-blind, vehicle-controlled multicenter studies were performed in the United States to evaluate the use of ciclopirox 8% nail lacquer to treat mild to moderate toenail onychomycosis caused by dermatophytes.173 A total of 460 patients were randomized to ciclopirox (n=231) or vehicle (n=229). Treatment was applied daily for 48 weeks. At the end of the 48-week treatment period, the mycologic cure rate in study I was 29 percent for ciclopirox and 11 percent for the vehicle group. In study II, mycologic cure rates were 36 and nine percent, respectively. The most common adverse reactions were transient and localized to the site of action (e.g., erythema and application site reaction). Seborrheic Dermatitis ketoconazole foam (Extina) versus ketoconazole cream A total of 1,162 subjects, aged 12 years or older, with mild to severe seborrheic dermatitis were randomized to receive ketoconazole foam (n=427), vehicle foam (n=420), ketoconazole cream (n=210), or vehicle cream (n=105) twice daily for four weeks. 174 The primary endpoint was the proportion of subjects achieving an Investigator’s Static Global Assessment score of 0 or 1 at week four (treatment success). A significantly greater percentage of subjects achieved treatment success using ketoconazole foam than vehicle foam (56 percent and 42 percent, respectively; p<0.0001). Ketoconazole foam was well-tolerated with a low incidence of treatment-related adverse events (14 percent). Ketoconazole foam was shown to be equivalent to ketoconazole cream. ketoconazole gel (Xolegel) versus vehicle A randomized phase 3, vehicle-controlled trial was performed on 459 people to evaluate the efficacy of ketoconazole 2% gel in comparison to the vehicle after two weeks of treatment in moderate to severe seborrheic dermatitis. 175 The primary endpoint was to evaluate the proportion of patients who had either cleared or almost cleared dermatitis after 28 days. Results indicated that 25.3 percent of patients treated with ketoconazole 2% gel experienced successful treatment in comparison to 13.9 percent of patients receiving the vehicle alone (p=0.0014). In addition, ketoconazole 2% gel helped to improve erythema, scaling, and pruritus when compared to the vehicle (p=0.0022). Few adverse events were reported, but the adverse events that were experienced were mild and moderate and similar between both groups. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 17 of 22 December 2013 Antifungals, Topical Review Two studies compared the effectiveness of a combination gel containing ketoconazole 2% and desonide 0.05%, each active gel individually, and a vehicle control in 316 patients with moderate to severe seborrheic dermatitis.176 The primary endpoint was efficacy measured by the proportion of patients who experienced an improvement in scaling and erythema as well as the investigator global assessment scores. A score of 0 or 1, if the baseline was ≥ 3, defined effective treatment in these patients after 28 days. The comparison of the combination gel to its individual components revealed that the efficacy of ketoconazole alone was comparable to the combination gel as well as desonide gel alone for up to two weeks after the end of treatment. META-ANALYSIS A systematic review was conducted to evaluate topical treatments for fungal infections of the skin and nails of the foot. 177 Authors searched the Cochrane Skin Group Specialized Register (January 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE and EMBASE (from inception to January 2005). The study objectives were to assess the effects of topical treatments in successfully treating fungal infections of the skin of the feet and toenails and in preventing recurrence. In conclusion, allylamines and azoles for athlete’s foot consistently produce a much higher percentage of cures than placebo. Allylamines cure slightly more infections than azoles and are now available over-the-counter. SUMMARY Many topical antifungal preparations are available as prescription medications and over-the-counter (OTC) products. Limited data are available regarding comparative efficacy in the treatment of the various fungal infections - tinea cruris, tinea corporis, tinea pedis, and tinea versicolor. In general, tinea corporis and tinea cruris require treatment for two weeks, and tinea pedis may require treatment for four weeks. Treatment should continue for at least one week after symptoms have resolved. Combination therapy (antifungal plus corticosteroid) can be considered when inflammation is present. The safety of the topical agents is inherently limited to local exposure. Limited data are also lacking in comparative efficacy for the treatment of seborrheic dermatitis. Both ciclopirox (Loprox) and ketoconazole (Extina, Xolegel) have been approved for use in this condition, but superiority has not been established for either agent due to the lack of well designed comparative clinical studies. Due to the lack of comparative studies with ciclopirox (Ciclodan, CNL-8, Pedipirox-4, Penlac) for the treatment of onychomycosis, it is difficult to measure its effectiveness versus other indicated products. An oral antifungal, if tolerated, may lead to higher success rates in the treatment of onychomycosis. The combination product miconazole, zinc oxide, and white petrolatum (Vusion) is indicated as adjunctive treatment for diaper dermatitis in patients four weeks and older. The other agents with safety and effectiveness data for children ages two years and older are clotrimazole, miconazole, undecylenic, undecylenic/zinc undecylenate, and tolnaftate. Based on the limited amount of efficacy data available for these various agents in the treatment of dermatologic fungal infections, choice of therapy is mainly based on clinical judgment with regard to prior treatments and complicating conditions such as bacterial growth or intense inflammation. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 18 of 22 December 2013 Antifungals, Topical Review REFERENCES 1 Bensal HP [package insert]. Greenville, SC; HS Pharma; February 2009. 2 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 3 Loprox gel [package insert]. Scottsdale, AZ; Medicis Derm; July 2005. 4 Loprox cream [package insert]. Scottsdale, AZ; Medicis Derm; March 2003. 5 Loprox topical solution [package insert]. Scottsdale, AZ; Medicis Derm; May 2003. 6 Loprox shampoo [package insert]. Scottsdale, AZ; Medicis Derm; September 2011. 7 Ciclodan cream/kit [package insert]. Fairfield, NJ; Medimetriks Pharmaceuticals; June 2012. 8 Ciclodan [package insert]. South Plainfield, NJ;Medimetriks Pharmaceuticals; January 2011. 9 CNL-8 [package insert]. 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Accessed December 4, 2013. 105 Vusion [package insert]. Coral Gables, FL; Stiefel; June 2011. 106 Naftin [package insert]. Greensboro, NC; Merz Pharmaceuticals; February 2009. 107 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 108 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 109 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 110 Oxistat [package insert]. Melville, NY; Pharmaderm, a division of Nycomed US Inc; October 2010. 111 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 112 Exelderm [package insert]. Jacksonville, FL; Ranbaxy; January 2010. 113 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 114 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 115 Gallup E, Plott T; Ciclopirox TS Investigators. A multicenter, open-label study to assess the safety and efficacy of ciclopirox topical suspension 0.77% in the treatment of diaper dermatitis due to Candida albicans. J Drugs Dermatol. 2005; 4(1):29-34. 116 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 117 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 118 Oxistat [package insert]. Melville, NY; Pharmaderm, a division of Nycomed US Inc; October 2010. 119 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 120 Exelderm [package insert]. Jacksonville, FL; Ranbaxy; January 2010. 121 Naftin [package insert]. Greensboro, NC; Merz Pharmaceuticals; February 2009. 122 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 20 of 22 December 2013 Antifungals, Topical Review 123 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 124 Bensal HP [package insert]. Greenville, SC; HS Pharma; February 2009. 125 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 126 Loprox gel [package insert]. Scottsdale, AZ; Medicis Derm; July 2005. 127 Loprox cream [package insert]. Scottsdale, AZ; Medicis Derm; March 2003. 128 Loprox topical solution [package insert]. Scottsdale, AZ; Medicis Derm; May 2003. 129 Loprox shampoo [package insert]. Scottsdale, AZ; Medicis Derm; September 2011. 130 Ciclodan cream/kit [package insert]. Fairfield, NJ; Medimetriks Pharmaceuticals; June 2012. 131 Ciclodan [package insert]. South Plainfield, NJ;Medimetriks Pharmaceuticals; January 2011. 132 Pedipirox [package insert]. Amityville, NY; Hi-Tech Pharmaceuticals; June 2011. 133 Penlac nail lacquer [package insert]. Bridgewater, NJ; Dermik Laboratories; July 2006. 134 CNL-8 [package insert]. Charleston, SC; Innocutis Holding; December 2011. 135 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 136 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 137 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 138 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 139 Ecoza. Available at: http://www.quinnova.com/wp-content/uploads/2014/01/Ecoza%20Indications.pdf. Accessed March 13. 2014. 140 Extina [package insert]. Research Triangle Park, NC; Stiefel Laboratories, Inc; April 2011. 141 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 142 Available at: http://dailymed.nlm.nih.gov. Accessed December 4, 2013. 143 Xolegel [package insert]. Coral Gables, FL; Stiefel Laboratories, Inc.; June 2011. 144 Nizoral 2% Shampoo [package insert]. Raritan, NJ; PriCara; July 2010. 145 Available at: http://dailymed.nlm.nih.gov. Accessed December 4, 2013. 146 Available at: http://dailymed.nlm.nih.gov. Accessed December 4, 2013. 147 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 148 Available at: http://www.webmd.com. Accessed May 6, 2011. 149 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 150 Vusion [package insert]. Coral Gables, FL; Stiefel; June 2011. 151 Naftin [package insert]. Greensboro, NC; Merz Pharmaceuticals; February 2009. 152 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 153 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 154 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 155 Oxistat [package insert]. Melville, NY; Pharmaderm, a division of Nycomed US Inc; October 2010. 156 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 157 Exelderm [package insert]. Jacksonville, FL; Ranbaxy; January 2010. 158 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 159 Available at: http://www.clinicalpharmacology.com. Accessed December 4, 2013. 160 Gupta AK, Einarson TR, Summerbell RC, et al. An overview of topical antifungal therapy in dermatomycoses. A North American perspective. Drugs. 1998; 55:645-674. 161 Fitzpatrick TB, Johnson RA, Wolff K, et al. Cutaneous fungal infections. In: Color atlas and synopsis of clinical dermatology: common and serious diseases. Fitzpatrick TB, et al., Eds. 3d ed. New York: McGraw-Hill, 1997:688-733. 162 Battistini F, CorderoC, Urcuyo FG, et al. The treatment of dermatophytoses of the glabrous skin: a comparison of undecylenic acid and its salt versus tolnaftate. Int J Dermatology. 1983; 22(6):388-9. 163 Singal A, Pandhi D, Agrawal S, et al. Comparative efficacy of topical 1% butenafine and 1% clotrimazole in tinea cruris and tinea corporis: a randomized, double-blind trial. J Dermatolog Treat. 2005; 16(5-6):331-335. 164 Millikan LE, Galen WK, Gewirtzman GB, et al. Naftifine cream 1% versus econazole cream 1% in the treatment of tinea cruris and tinea corporis. J Am Acad Dermatol. 1988; 18(1 Pt 1):52-56. 165 Ecoza. Available at: http://www.quinnova.com/wp-content/uploads/2014/01/Ecoza%20Indications.pdf. Accessed March 13. 2014. 166 Suschka S, Fladung B, Merk HF. Clinical comparison of the efficacy and tolerability of once daily Canesten with twice daily Nizoral (clotrimazole 1% cream vs. ketoconazole 2% cream) during a 28-day topical treatment of interdigital tinea pedis. Mycoses. 2002; 45(3-4):91-96. 167 Evans EG. A comparison of terbinafine (Lamisil) 1% cream given for one week with clotrimazole (Canesten) 1% cream given for four weeks, in the treatment of tinea pedis. Br J Dermatol. 1994;130 Suppl 43:12-14. 168 Schopf R, Hettler O, Brautigam M, et al. Efficacy and tolerability of terbinafine 1% topical solution used for 1 week compared with 4 weeks clotrimazole 1% topical solution in the treatment of interdigital tinea pedis: a randomized, double-blind, multi-centre, 8-week clinical trial. Mycoses. 1999; 42(5-6):415-420. 169 Patel A, Brookman SD, Bullen MU, et al. Topical treatment of interdigital tinea pedis: terbinafine compared with clotrimazole. Australas J Dermatol. 1999; 40(4):197-200. 170 Savin R, Jorizzo J. The safety and efficacy of sertaconazole nitrate cream 2% for tinea pedis. Cutis. 2006; 78(4):268-274. 171 No authors listed. Treatment of tinea versicolor with a new antifungal agent, ciclopirox olamine cream 1%. Clin Ther. 1985; 7(5):574-583. 172 Tanenbaum L, Anderson C, Rosenberg MJ, et al. 1% sulconazole cream v 2% miconazole cream in the treatment of tinea versicolor. A double-blind, multicenter study. Arch Dermatol. 1984; 120(2):216-219. 173 Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000; 43(4 Suppl):S70-S80. 174 Elewski BE, Abramovits W, Kempers S, et al. A novel foam formulation of ketoconazole 2% for the treatment of seborrheic dermatitis on multiple body regions. J Drugs Dermatol. 2007; 6(10):1001-1008. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 21 of 22 December 2013 Antifungals, Topical Review 175 Elewski B, Ling MR, Phillips TJ. Efficacy and safety of a new once-daily topical ketoconazole 2% gel in the treatment of seborrheic dermatitis: a phase III trial. J Drugs Dermatol. 2006; 5(7): 646-650. 176 Swinyer LJ, Decroix J, Langner A. Ketoconazole gel 2% in the treatment of moderate to severe seborrheic dermatitis. Cutis. 2007; 79(6):475-482. 177 Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev. 2007; (3):CD001434. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2003-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 3 Page 22 of 22 December 2013 Antifungals, Oral Review FDA-APPROVED INDICATIONS Drug Manufacturer FDA-Approved Indication(s) for oral use Treatment of oropharyngeal candidiasis To prophylactically reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation Treatment of oropharyngeal, esophageal, and vaginal candidiasis Treatment of Candida urinary tract infections, peritonitis, candida systemic infections including candidemia, disseminated candidiasis, and pneumonia Cryptococcal meningitis Prevention of candidiasis in patients undergoing bone marrow transplantation receiving cytotoxic chemotherapy and/or radiation Used in combination with amphotericin B for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus clotrimazole (Mycelex 1 Troche) generic fluconazole 2 (Diflucan) generic flucytosine 3 (Ancobon) generic griseofulvin 4 suspension generic griseofulvin, 5 microsized generic griseofulvin , ultramicrosized 6 (Gris-PEG) generic itraconazole 7 (Onmel™) Merz Treatment of onychomycosis of the toenail caused by Trichophyton rubrum, or T. mentagrophytes itraconazole 8 (Sporanox) generic ketoconazole 9 (Nizoral) generic miconazole 10 (Oravig™) Par Pharmaceuticals Onychomycosis of the fingernail and/or toenail due to dermatophytes (tinea unguium) in non-immunocompromised patients Treatment in immunocompromised and non-immunocompromised patients with pulmonary and extrapulmonary blastomycosis, histoplasmosis; or patients with aspergillosis intolerant of amphotericin B; or aspergillosis refractory to amphotericin B Blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, paracoccidioidomycosis, only in patients who are intolerant to, or who have failed, other agents* Local treatment of oropharyngeal candidiasis (OPC) in adults Ringworm infections of the body, skin, hair, and nails, namely tinea corporis, tinea pedis, tinea cruris, tinea barbae, tinea capitis, and tinea unguium (onychomycosis) generic Gastrointestinal and oral candidiasis caused by candida albicans posaconazole 12 (Noxafil) Merck terbinafine 13 (Lamisil) generic Delayed-release tablet and oral suspension: Prophylaxis of invasive Aspergillus and Candida infections in patients 13 years and older who are at high risk of developing these infections due to being severely immunocompromised (e.g., hematopoietic stem cell transplant recipient with graft versus host disease [GVHD] or those with hematologic malignancies with prolonged neutropenia from chemotherapy) Oral suspension: Treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole Onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium) terbinafine (Lamisil Granules)14 Novartis Treatment of tinea capitis in patients four years of age and older nystatin 11 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 2 of 30 August 2013 Antifungals, Oral Review FDA-Approved Indications (continued) Drug Manufacturer FDA-Approved Indication(s) for oral use Treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea JSJ terbinafine 15 Pharmaceuticals unguium) (Terbinex™) Treatment of invasive aspergillosis voriconazole generic 16 Serious fungal infections caused by Scedosporium apiospermum and Fusarium solani (Vfend) Treatment of esophageal candidiasis Treatment of candidemia in non-neutropenic patients and disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds * Ketoconazole is no longer to be used as first-line therapy for any fungal infection and should be reserved for only those cases where alternative therapies are unavailable or not tolerated. Please revisit the indications section of the package insert for details. Previously, ketoconazole was indicated for candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, and severe recalcicant cutaneous dermatophyte infections not responding to topical or oral griseofulvin 17 therapy. These indications were removed due to the risk of hepatic toxicity. OVERVIEW The antifungal agents have different spectrums of activity and are FDA-approved to treat a variety of infections. Few trials have been performed to compare safety and efficacy profiles of the drugs. In addition, many of the agents carry black box warnings related to adverse events and/or drug interactions. The Infectious Diseases Society of America (IDSA) 2009 guidelines on the treatment of oropharyngeal candidiasis in adults include clotrimazole troches (Mycelex) or nystatin for mild disease; for moderate to severe disease, fluconazole (Diflucan) is recommended (updated guidelines are projected to be published in the fall of 2014). 18 For fluconazole-refractory disease, itraconazole solution or posaconazole suspension (Noxafil) may be used. In other refractory cases, voriconazole (Vfend) or amphotericin B oral suspension may be administered. Chronic suppressive therapy for patients with human immunodeficiency virus (HIV) is not always necessary. If suppressive therapy is required, fluconazole is recommended. Since highly active antiretroviral therapy (HAART) for the treatment of HIV for infants and children is widely available and utilized in the U.S., routine primary prophylaxis of candidiasis is not indicated (projected guideline update is unknown at this time). 19 Uncomplicated infections can be effectively treated with topical therapy such as clotrimazole troches or nystatin. Troches should not be used in infants. Systemic therapy with fluconazole, ketoconazole, or itraconazole may be considered for the initial treatment of oropharyngeal candidiasis. Fluconazole is more effective than nystatin for infants. Itraconazole has equivalent efficacy to fluconazole for oropharyngeal candidiasis, but it is less well tolerated. Ketoconazole absorption can be variable so it is recommended to use fluconazole or itraconazole solutions, when available. For esophageal candidiasis in adults, fluconazole, oral or IV, is considered first line (next projected update is fall 2014). 20 Fluconazole or itraconazole are preferred for children for the management of esophageal candidiasis.21 Posaconazole, itraconazole, or voriconazole may be used in patients with fluconazole-refractory infections. Onychomycosis is a fungal infection of the nail bed (skin beneath the nail plate) with secondary involvement of the nail plate (visible part of the nail on fingers and toes). Dermatophytes, yeasts, and molds are the primary pathogens associated with onychomycosis. More common in toenails than Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 3 of 30 August 2013 Antifungals, Oral Review fingernails, the disease often causes the end of the nail to separate from the nail bed. The most common clinical presentations are distal and lateral subungual onychomycosis (which usually affects the great or first toe) and white superficial onychomycosis (which generally involves the third or fourth toes). 22 Additionally, debris (white, green, yellow, or black) may build up under the nail plate and discolor the nail bed. Onychomycosis is often chronic, difficult to eradicate, has a tendency to recur, and is found more frequently in the elderly. Opportunistic fungal infections are particularly likely to occur in patients during corticosteroid, immunosuppressant, or antimetabolite therapy, or in patients with Acquired Immunodeficiency Syndrome (AIDS), azotemia, diabetes mellitus, bronchiectasis, emphysema, tuberculosis, lymphoma, leukemia, or burns. Histoplasmosis, coccidioidomycosis, cryptococcosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis are systemic mycoses which can cause disease in both healthy and immunocompromised individuals. In contrast, mycoses caused by opportunistic fungi such as Candida albicans, Aspergillus spp, Trichosporon, Torulopsis (Candida) glabrata, Fusarium, Alternaria, and Mucor are generally found only in an immunocompromised host. PHARMACOLOGY Drug Mechanism of Action Inhibits the action of fungal ergosterol synthesis; interacts with the cytochrome P450 enzyme 14-alpha demethylase; inhibits growth of pathogenic yeasts by altering cell membrane permeability clotrimazole (Mycelex 23 Troche) fluconazole (Diflucan) 24 Highly selective inhibitor of fungal cytochrome P450 sterol C-14 alpha-demethylase, which results in fungistatic activity 25 Enters the fungal cell and is metabolized to 5-fluorouracil, which is extensively incorporated into fungal RNA and inhibits synthesis of both DNA, RNA, and protein synthesis; the result is unbalanced growth and death of the fungal organism flucytosine (Ancobon) griseofulvin 26 Fungistatic amounts are deposited in the keratin precursor cell. The new keratin becomes resistant to fungal invasion. itraconazole (Onmel) 27 Inhibits the cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. itraconazole (Sporanox) ketoconazole (Nizoral) miconazole (Oravig) nystatin 28 29 30 Impairs the synthesis of ergosterol, a vital component of fungal cell membranes Inhibits cytochrome P450-dependent 14-α demethylase in the biosynthetic pathway of ergosterol, an essential component of the fungal cell membrane. 31 Binds to sterols in the fungal cell membranes which leads to fungistatic activity posaconazole (Noxafil) 32 Inhibits cytochrome P450-dependent 14-α demethylase in the biosynthetic pathway of ergosterol which weakens the structure and function of the fungal cell membrane Inhibits squalene epoxidase, a key enzyme in fungal sterol biosynthesis; resulting in cell death due to increased cell membrane permeability; fungicidal in vitro depending on organism and concentration terbinafine (Lamisil, Lamisil Granules, 33,34,35 Terbinex) voriconazole (Vfend) Inhibits the cytochrome P450-dependent synthesis of ergosterol, a vital component of the fungal cell membrane, resulting in increased cellular permeability and therefore leakage of cellular contents 36 Inhibits ergosterol synthesis by interacting with the 14-alpha-lanosterol demethylation step, a cytochrome P450 enzyme Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 4 of 30 August 2013 Antifungals, Oral Review In the Terbinex kit, topical hydroxypropyl chitosan or HPCH (Eco Formula) is a companion topical product designed to enhance nail growth and improve the appearance of dystrophic nails. PHARMACOKINETICS Bioavailability (%) Half-life (hr) Metabolism Excretion (%) CYP 450 Enzyme Inhibition negligible absorption -- The small amount that is absorbed is metabolized by the liver Bile -- >90 20-50 -- 2.4-4.8 Small amount of flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil and reabsorbed Renal: 90 Fecal: <10 -- 9-24 No active metabolites Renal , fecal and perspiration excretion -- 37 Several metabolites; hydroxyitraconazole is the major active one Renal: 35 Fecal: 54 3A4 55 64 Several metabolites; hydroxy-itraconazole is the major active metabolite Renal: 40 Fecal: 3-18 3A4 ketoconazole 43 (Nizoral) miconazole 44 (Oravig) 45 nystatin -(requires acidic pH) 8 Several inactive metabolites -- 24 No active metabolites Renal: <1 2C9, 3A4 poorly absorbed -- -- Predominantly feces -- posaconazole 46 (Noxafil) -(suspension: varies based on fed or fasting state) 54 (tablet) 20-66 (suspension) 26-31 (tablet) No active metabolites Renal: 13 Fecal: 71 3A4 40 200-400 No active metabolites Renal: 70 2D6 -- 9.3-13.8 No active metabolites Renal: 70 2D6 96 dose dependent N-oxide metabolite is inactive; several other inactive metabolites 80-83 2C19, 2C9,3A4 Drug clotrimazole (Mycelex 37 Troche) fluconazole 38 (Diflucan) flucytosine 39 (Ancobon) griseofulvin 40 itraconazole 41 (Onmel) itraconazole 42 (Sporanox) terbinafine (Lamisil, 47, 48 Terbinex) terbinafine (Lamisil 49 Granules) voriconazole 50 (Vfend) 78-89 varies with formulation; absorption increases with a high-fat meal 63 Absorption increases with a high-fat meal Renal: 91 Renal: Bile: Renal: 13 87 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. 2C9, 3A4 3A4 Page 5 of 30 August 2013 Antifungals, Oral Review CONTRAINDICATIONS/WARNINGS clotrimazole (Mycelex) Clotrimazole is not indicated for systemic mycoses including systemic candidiasis. 51 fluconazole (Diflucan) 52 Fluconazole is contraindicated in patients with hypersensitivity to fluconazole or any of its excipients. There is no information regarding cross-hypersensitivity among fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Fluconazole is associated with QT prolongation and is a moderate CYP3A4 inhibitor. Therefore, fluconazole is contraindicated with concurrent administration of drugs that prolong the QT interval and are metabolized via CYP3A4, such as quinidine and pimozide. Avoid concomitant administration of fluconazole and voriconazole, and fluconazole and erythromycin. Fluconazole has been associated with rare reports of anaphylaxis, serious hepatic toxicity, and exfoliative skin disorders during treatment. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. There has been no obvious relationship to total daily dose, duration of therapy, sex, or age of the patients in the known cases of fluconazole-associated hepatotoxicity. Fluconazole hepatotoxicity has usually, but not always, been reversible upon discontinuation. Patients with abnormal liver function tests during fluconazole therapy should be monitored for more severe hepatic injury. Discontinue fluconazole therapy if clinical signs and symptoms of liver disease develop during therapy. flucytosine (Ancobon) Flucytosine is excreted primarily by the kidneys, and renal impairment leads to accumulation of drug. There is a boxed warning associated with flucytosine to use extreme caution in patients with impaired renal function. Monitoring of renal, hepatic, and hematologic status is stressed to prevent progressive accumulation of active drug. 53 In addition, extreme caution in patients with bone marrow depression should be exercised. griseofulvin (microsized, Gris-PEG)54,55 Griseofulvin is contraindicated in patients with porphyria, hepatocellular failure, and in patients with a history of hypersensitivity to griseofulvin.56 Griseofulvin should not be prescribed to pregnant patients. If a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Since griseofulvin has demonstrated harmful effects in vitro on the genotype in bacteria, plants, and fungi, males should wait at least six months after completing griseofulvin therapy before fathering a child. Lupus erythematosus or lupus-like syndromes have been reported in patients receiving griseofulvin, as well as exacerbating the condition of those with Systemic Lupus erythematosus (SLE) or lupus-like syndrome. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 6 of 30 August 2013 Antifungals, Oral Review Photosensitivity skin reactions have been associated with griseofulvin therapy. Patients should be warned to avoid exposure to intense natural or artificial sunlight. Severe skin reactions, (e.g., StevensJohnson syndrome, toxic epidermal necrolysis, and erythema multiforme), have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. If severe skin reactions occur, griseofulvin should be discontinued. Elevated liver function tests and jaundice have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. Patients should be monitored for hepatic adverse events and discontinuation of griseofulvin considered, if warranted. Griseofulvin is produced by a species of Penicillium; patients with penicillin hypersensitivity theoretically could exhibit a cross-sensitivity to griseofulvin. However, patients with penicillin hypersensitivity have been treated with griseofulvin without adverse affects. Similar warnings may apply to patients with cephalosporin hypersensitivity or carbapenem hypersensitivity because of the structural similarity of cephalosporins and carbapenems to penicillin. Concomitant use of griseofulvin and oral contraceptives has been reported to reduce the efficacy of the oral contraceptive and cause breakthrough bleeding. Patients who experience breakthrough bleeding while receiving these drugs together should notify their prescribers. An alternate or additional form of contraception should be used during concomitant treatment and should be continued for one month after griseofulvin discontinuation. Additionally, patients taking non-oral combination contraceptives, estrogens, or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary. itraconazole (Sporanox, Onmel)57,58 Itraconazole should not be administered to women considering pregnancy or who are pregnant. Simvastatin and lovastatin, which are metabolized by CYP 3A4, are contraindicated with itraconazole. Itraconazole should not be administered with ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine, and methylergometrine (methylergonovine). Additionally, co-administration with pimozide, quinidine, oral midazolam, cisapride, triazolam, lev-acetylmethadol (levomethadyl), and dofetilide are contraindicated as concomitant use may result in elevated plasma concentrations of those drugs leading to potentially serious adverse events. Itraconazole is contraindicated in patients with ventricular dysfunction as evidenced by congestive heart failure (CHF) or a history of CHF. A black box warning associated with itraconazole stresses that itraconazole should not be used for onychomycosis in patients with evidence of ventricular dysfunction or CHF due to the risk of pulmonary edema and/or CHF. Negative inotropic effects have been observed with intravenous itraconazole. Serious cardiovascular events, including QTc prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred when itraconazole is co-administered with inhibitors of CYP450 3A4 isoenzyme. Such patients should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole, discontinue administration. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when coadministering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and nisoldipine is contraindicated. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 7 of 30 August 2013 Antifungals, Oral Review Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped but can persist in some patients. Itraconazole capsules and oral solution should not be used interchangeably as the drug exposure is greater with the oral solution than with the capsules when the same dose of drug is administered. Only the oral solution has demonstrated efficacy for oral and/or esophageal candidiasis. Serious hepatotoxicity, including liver failure and death, has been associated with itraconazole. Some patients did not have an underlying medical condition or pre-existing liver disease. Hepatotoxicity may develop as early as the first week of treatment. If signs or symptoms develop that are consistent with liver disease, itraconazole therapy should be discontinued and liver function testing performed. itraconazole (Sporanox) and terbinafine (Lamisil, Lamisil Granules)59,60 Both itraconazole and terbinafine prescribing information recommend, “Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.” A warning for both terbinafine and itraconazole states that neither agent should be used in patients with pre-existing liver disease, and rare cases of liver failure have occurred during use of either product. ketoconazole (Nizoral) 61,62,63 Ketoconazole should not be administered with terfenadine, astemizole, cisapride, or triazolam as concurrent administration has resulted in cardiovascular adverse events. A black box warning states that ketoconazole has been linked to hepatic toxicities and fatalities. Use in patients with hepatic disease is contraindicated. The presence of viral hepatitis and liver function tests should be assessed prior to therapy, and monitoring of hepatic function is recommended weekly during therapy. Adrenal insufficiency has also been reported due to the inhibition of production of corticosteroids. Monitor adrenal function in those patients with existing adrenal concerns while they are utilizing oral ketoconazole therapy. A medication guide outlining the risks associated with oral ketoconazole use has been approved for distribution by the FDA. miconazole (Oravig)64 Miconazole is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to miconazole, milk protein concentrate, or any other component of the product. Allergic reactions, including anaphylactic reactions and hypersensitivity, have been reported with the administration of miconazole products, including Oravig. Discontinue miconazole immediately at the first sign of hypersensitivity. nystatin65 Nystatin suspension contains significant amounts of sucrose; it should be used cautiously in patients with diabetes mellitus. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 8 of 30 August 2013 Antifungals, Oral Review posaconazole (Noxafil) 66 Posaconazole is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to posaconazole, any other component of the product, or hypersensitivity to any other azole antifungal. Posaconazole is contraindicated in coadministration with sirolimus (sirolimus toxicity) and ergot alkaloids (ergotism). Posaconazole is also contraindicated in coadministration with the CYP3A4 substrates, pimozide, halofantrine, or quinidine, since this may result in increased plasma concentrations of these agents leading to QTc prolongation and rare occurrences of torsades de pointes. Posaconazole is contraindicated with HMG-coA reductase inhibitors primarily metabolized through CYP3A4 due to risk of rhabdomyolysis. Infrequent cases of hepatic reactions such as mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis have been reported with posaconazole. Liver enzyme elevations were generally reversible upon discontinuation or, in some cases, normalized without drug interruption, and rarely require drug discontinuation. More serious hepatic reactions including cholestasis or hepatic failure including fatalities have been reported in patients with serious underlying medical conditions, such as hematologic malignancy during treatment with posaconazole. Posaconazole 800 mg daily has been associated with the more severe hepatic reactions. Liver function tests should be evaluated at therapy initiation and during the course of posaconazole therapy. If abnormal liver function tests occur during posaconazole therapy, monitor for the development of more severe hepatic injury. Posaconazole should be discontinued if worsening of liver function tests continues. Elevated cyclosporine levels resulting in rare serious adverse events including nephrotoxicity, leukoencephalopathy, and death were reported in clinical efficacy trials for posaconazole. Dose reduction and more frequent monitoring of cyclosporine and tacrolimus should be performed when posaconazole therapy is initiated. Posaconazole significantly increases the Cmax and AUC of tacrolimus. Reduce tacrolimus dose by approximately one-third of the original dose on initiation of posaconazole treatment. Frequent monitoring of tacrolimus trough concentrations should be performed during and at discontinuation of posaconazole treatment. Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole. Posaconazole has been known to prolong the sedative/hypnotic effects of midazolam, the serum concentration of midazolam may be increased five fold. Monitor those patients taking concomitant midazolam. In the event signs or symptoms of prolonged hypnosis/sedation signs are noted, have benzodiazepine receptor antagonists available for administration. terbinafine (Lamisil, Lamisil Granules, Terbinex) 67,68,69 Terbinafine is contraindicated in patients with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. Severe hepatic injury, including liver failure, with some leading to death or liver transplantation, has occurred with the use of oral terbinafine. Assessment of serum transaminases are advised before Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 9 of 30 August 2013 Antifungals, Oral Review initiation of treatment with terbinafine. Terbinafine should be discontinued if biochemical or clinical evidence of liver injury occurs. Severe neutropenia, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with terbinafine use. If a progressive skin rash occurs, treatment with terbinafine should be discontinued. Depressive symptoms have been reported with terbinafine. Taste disturbance, including taste loss, has been reported with the use of terbinafine. Taste disturbances can be severe enough to result in decreased food intake, weight loss, and depressive symptoms. Resolution of taste disturbance may resolve within several weeks after discontinuation of treatment, but may be prolonged (greater than one year), or permanent. If symptoms of a taste disturbance occur, discontinue terbinafine. In addition, smell disturbance and loss of smell has been reported. The changes may resolve after discontinuation of treatment but may be prolonged and possibly permanent. If symptoms of a smell disturbance occur, discontinue use. voriconazole (Vfend) 70 Coadministration of voriconazole is contraindicated with CYP3A4 substrates including terfenadine, astemizole, cisapride, pimozide, quinidine, rifabutin, sirolimus, or ergot alkaloids because increased plasma concentrations of these drugs can lead to QTc prolongation and rare occurrences of torsades de pointes. Voriconazole should not be given concurrently with sirolimus (increased sirolimus concentrations and decreased voriconazole concentration), rifampin, carbamazepine, and long-acting barbiturates (decreased voriconazole concentrations), high-dose ritonavir 400 mg every 12 hours (decreased voriconazole concentrations), ergotamines, and St. John’s Wort. Use caution when administering efavirenz and voriconazole (decreased voriconazole concentrations and increased efavirenz concentrations). Additionally, voriconazole should not be given with rifabutin as voriconazole concentrations are decreased, and rifabutin concentrations are increased. Ergot alkaloids should not be used with voriconazole. Concurrent administration of oral voriconazole and oral fluconazole has shown to result in an increase in Cmax and AUC of voriconazole by an average of 57 and 79 percent, respectively. Reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or decrease this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole. Voriconazole prescribing information should be consulted for a detailed description of drug interactions and required dosage modifications prior to initiating therapy. Monitoring liver enzymes before and during therapy is recommended. Visual disturbances associated with therapy have not been studied beyond 28 days. Electrolyte disturbances including hypokalemia, hypomagnesemia, and hypocalcemia should be corrected prior to initiation of therapy with voriconazole as electrolyte disturbances increase the risk of cardiac arrhythmias. As with other azole antifungals, hypersensitivity to voriconazole or any of the excipients contraindicates its use. There is no information regarding cross-sensitivity among voriconazole and other azole antifungal agents. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 10 of 30 August 2013 Antifungals, Oral Review Voriconazole is associated with rare cases of serious hepatic reactions including clinical hepatitis, cholestasis, and fulminant hepatic failure with fatalities. Severe hepatic reactions have occurred in patients with serious underlying medical conditions, predominantly hematological malignancy. Hepatic reactions such as hepatitis and jaundice have occurred in patients with no identifiable risk factors. Liver dysfunction was reversible after discontinuation of voriconazole in most cases. Liver function tests should be performed prior to voriconazole therapy and during therapy to monitor for hepatic injury. Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. DRUG INTERACTIONS Numerous drug interactions are associated with antifungal agents. See chart on next page. Due to low systemic absorption, drug interactions with clotrimazole (Mycelex) and nystatin are limited.71,72 Clotrimazole is an inhibitor of hepatic cytochrome P450 (CYP) 3A4, and tacrolimus is metabolized by CYP3A4.73,74 Administration of clotrimazole troches to renal transplant patients receiving tacrolimus caused clinically significant increases in the relative oral bioavailability, Tmax, and trough concentrations of tacrolimus. 75,76 Tacrolimus blood concentrations should be monitored closely whenever clotrimazole therapy is initiated or discontinued. Close monitoring can minimize toxicity due to increased tacrolimus levels or prevent an acute rejection episode due to subtherapeutic tacrolimus levels. Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression. Cytarabine can competitively inhibit flucytosine, antagonizing its antifungal activity. Other bone marrow depressants include carbamazepine, clozapine, phenothiazines, zidovudine, and other blood dyscrasia-causing medications. Posaconazole (Noxafil) is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux.77 Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. The UDP inducers include efavirenz, rifabutin, and phenytoin. The UDP inducers reduce Cmax and area under the curve (AUC) of posaconazole thus reducing bioavailability. Avoid concurrent use with efavirenz, phenytoin, rifabutin, or cimetidine unless the benefit outweighs the risks. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole. In patients taking both posaconazole and digoxin, increased plasma concentrations of digoxin have been noted. Monitor digoxin plasma concentrations of patients taking both agents concomitantly. While some medications that are metabolized through the CYP3A4 system have specific contraindications, any medication that is metabolized through this pathway and is taken concurrently with posaconazole should result in monitoring of the patient for adverse effects and toxicity. Dose adjustment may need to be considered. Patients should be monitored for breakthrough fungal infections while on posaconazole when concurrently taking esomeprazole or cimetidine (due to an increase in gastric pH), as well as metoclopramide (due to an increase in gastrointestinal motility). Esomeprazole and metoclopramide have each shown to reduce Cmax and AUC of posaconazole. Avoid concurrent administration of Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 11 of 30 August 2013 Antifungals, Oral Review posaconazole oral suspension with esomeprazole unless the benefit outweighs the risks. Other PPIs have not been studied in combination with posaconazole. The drug interactions with esomeprazole and metoclopramide do not apply to posaconazole delayed-release tablets. There are no drug interactions or dosage adjustments needed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists, and proton pump inhibitors. No clinically relevant effect on posaconazole bioavailability and/or plasma concentrations was observed when administered with an antacid, glipizide, ritonavir, loperamide, or H2-receptor antagonists other than cimetidine; therefore, no posaconazole dose adjustments are required when used concomitantly with these products. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin. 78 Fentanyl plasma concentrations could be increased or exposure prolonged by concomitant use of itraconazole and may cause potentially fatal respiratory depression. Itraconazole, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, methadone, lev-acetylmethadol (levomethadyl), or quinidine, concomitantly with itraconazole and/or other CYP3A4 inhibitors. Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine), or methadone with itraconazole capsules or oral solution is contraindicated. Ketoconazole is a strong inhibitor of the CYP3A4 system. Due to this, use of this agent is contraindicated with certain other drugs that are metabolized by CYP3A4. Concomitant administration of miconazole (Oravig) and warfarin has resulted in enhancement of anticoagulant effect. Cases of bleeding and bruising following the concomitant use of warfarin and topical, intravaginal, or oral miconazole were reported. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. 79 Although the systemic absorption of miconazole following miconazole (Oravig) administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 and CYP3A4, such as oral hypoglycemics, phenytoin, or ergot alkaloids, cannot be ruled out. Below is a list of common substrates for CYP 450 enzymes affected by oral antifungal agents:    Selected substrates for the 2C9 system: diazepam, phenytoin, S-warfarin Selected substrates for the 2C19 system: phenytoin, thioridazine Selected substrates for the 2D6 system: carvedilol, clozapine, cyclobenzaprine, donepezil, flecainide, fluphenazine, fluoxetine, galantamine, haloperidol, hydrocodone, maprotiline, meperidine, methadone, methamphetamine, metoprolol, mexiletine, morphine, paroxetine, perphenazine, propafenone, propranolol, risperidone, thioridazine, timolol, tramadol, trazodone, and venlafaxine Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 12 of 30 August 2013 Antifungals, Oral Review  Selected substrates for the 3A4 system: triazolam, alprazolam, diazepam, atorvastatin, lovastatin, simvastatin, cyclosporine, tacrolimus, buspirone and pimozide Drug Interactions Table Consult package inserts for detailed information. CYP 450 enzyme inhibition Drug Dose adjustments needed Contraindications fluconazole 80 (Diflucan) 2C9, 3A4 pimozide quinidine voriconazole - Avoid concurrent use renal impairment rifampin celecoxib tacrolimus midazolam triazolam flucytosine 81 (Ancobon) -- -- renal impairment; drugs which reduce GFR griseofulvin (Grifulvin V, Gris82, 83 PEG) -- -- barbiturates itraconazole (Sporanox, 84,85 Onmel) 3A4 oral midazolam pimozide quinidine dofetilide nisoldipine triazolam levomethadyl ergot alkaloids lovastatin simvastatin Triazolam midazolam alprazolam cisapride HMG-CoA reductase inhibitors rifampin pimozide nisoldipine dofetilide ergot alkaloids quinidine eplerenone isoniazid -- Decreases elimination of drugs metabolized by CYP3A4; dosing modification is required ketoconazole 86 (Nizoral) 3A4 miconazole 87 (Oravig) 2C9, 3A4 Monitoring of other drug effects cyclosporine Diflucan warfarin phenytoin sulfonylureas theophylline anti-neoplastic agents bone marrow suppressants warfarin cyclosporine tretinoin, ATRA sunitinib nilotinib See package insert for full details See package insert for complete detailed drug list cyclosporine tacrolimus methylprednisolone See package insert for detailed drug list digoxin warfarin sulfonylureas phenytoin See package insert for full details -- warfarin oral hypoglycemic phenytoin ergot alkaloids Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 13 of 30 August 2013 Antifungals, Oral Review Drug Interactions Table (continued) Drug CYP 450 enzyme inhibition Contraindications Dose adjustments needed Monitoring of other drug effects posaconazole 88 (Noxafil) 3A4 pimozide quinidine rifabutin* phenytoin* efavirenz* cimetidine* esomeprazole*(suspension) ergot alkaloids halofantrine sirolimus HMG-CoA reductase inhibitors vinca alkaloids calcium channel blockers (3A4 inhibitors) cyclosporine tacrolimus midazolam phenytoin cyclosporine tacrolimus midazolam ritonavir atazanavir digoxin metoclopramide terbinafine (Lamisil, Lamisil Granules, 89,90 Terbinex) 2D6 thioridazine TCAs SSRIs beta-blockers monoamine oxidase inhibitors–type b rifampin warfarin cyclosporine caffeine fluconazole theophylline cimetidine voriconazole 91 (Vfend) 2C19, 2C9,3A4 rifampin ritonavir (high dose) carbamazepine Diflucan (Avoid concurrent use) long-acting barbiturates rifabutin sirolimus pimozide quinidine ergot alkaloids St. John’s Wort cyclosporine tacrolimus statins (3A4 inhibitors) benzodiazepines (midazolam, triazolam, alprazolam) calcium channel blockers phenytoin omeprazole vinca alkaloids methadone alfentanil efavirenz NSAIDS warfarin coumarin derivatives sulfonylureas protease inhibitors non-nucleoside reverse transcriptase inhibitors oral contraceptives with ethinyl estradiol and norethindrone ritonavir (low-dose) fentanyl oxycodone and other long acting narcotic analgesics Diflucan *Avoid concomitant use unless benefits outweigh the risks Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 14 of 30 August 2013 Antifungals, Oral Review ADVERSE EFFECTS Drug clotrimazole 92 (Mycelex troche) fluconazole 93 (Diflucan) n=4,048 flucytosine 94 (Ancobon) griseofulvin (microsized, 95, 96 Gris-PEG) itraconazole 97 (Onmel) itraconazole 98 (Sporanox) n=112 200 mg daily X 12 wks ketoconazole 99 (Nizoral) miconazole 100 (Oravig) 101 nystatin posaconazole suspension 102 (Noxafil) fluconazole (oral pharyngeal candidiasis) posaconazole delayed-release 103 tablet (Noxafil) (antifungal prophylaxis) terbinafine (Lamisil, 104, 105 Terbinex) n=465 terbinafine (Lamisil 106 Granules) n=1,042 voriconazole 107 (Vfend) n=1,655 Nausea Headache Rash Vomiting Abd. Pain Diarrhea Pruritus Elevated LFT reported nr nr reported nr nr reported 15 3.7 1.9 1.8 1.7 1.7 1.5 nr reported reported reported reported reported reported reported reported reported reported reported reported reported nr reported nr reported reported reported nr reported reported reported nr reported 3 10 3-4 reported 4 4 reported 4 3 <1 nr 3 1.2 <1 1.5 reported 0.7-6.6 5-7.6 nr 0.7-3.8 1.4-2.5 6-9 nr nr reported nr nr reported reported reported nr nr 9-29 8-20 3-15 7-28 5-18 10-29 3-6 nr 11 9 4 7 6 13 5-10 56 30 34 28 23 61 nr reported 2.6 12.9 5.6 reported 2.4 5.6 2.8 3.3 2 7 2 5 2 3 1 nr 5.4 3 5.3-7 4.4 <2 <2 <2 1.8-12.4 Incidence is reported as a percentage. Adverse events data are obtained from prescribing information and therefore should not be considered comparative or all inclusive. Incidences for placebo indicated in parentheses. nr = not reported Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 15 of 30 August 2013 Antifungals, Oral Review Pyrexia at a rate of 59 percent has been reported with posaconazole delayed-release tablets.108 Voriconazole is reported to be associated with abnormal visual disturbances (21 percent IV and oral therapy) which resolve with discontinuation of therapy. 109 In patients with normal gastrointestinal, renal, and hematologic function, flucytosine is generally associated with few adverse events, although rash, GI discomfort, diarrhea (five to 10 percent), and reversible elevations in hepatic enzymes are occasionally observed. In patients with renal dysfunction or in patients on concomitant amphotericin B, leukopenia, thrombocytopenia, and enterocolitis may occur. Flucytosine is associated with dose-dependent, potentially lethal bone marrow suppression. 110 Itraconazole (Onmel) has been associated with rare cases of hepatoxicity including liver failure and death. SPECIAL POPULATIONS111,112,113,114,115,116,117,118,119,120,121,122 Pediatrics Clotrimazole (Mycelex) troches have been used in children ages three years and older. Nystatin has been used in infants. 123 Terbinafine (Lamisil Granules) is approved for the treatment of tinea capitis for ages four years and older. The safety and efficacy of terbinafine tablets (Terbinex/Lamisil) have not been established in pediatric patients. Eco Formula (component of Terbinex kit) should be kept out of the reach of children. Safety and effectiveness of griseofulvin (Gris-Peg, Grifulvin V) have been established for children over age two years. Fluconazole safety and effectiveness data exist for children older than six months. Intravenous fluconazole has been used in preterm infants; however, efficacy has not been established in infants less than six months of age.124 Safety and effectiveness of posaconazole (Noxafil) oral suspension and delayed-release tablets in pediatric patients less than 13 years of age have not been established. Safety and effectiveness of itraconazole have not been proven in pediatric patients; however, patients aged 6 months to 16 years have been treated with itraconazole with no serious unexpected adverse events. Voriconazole (Vfend) does not have safety and effectiveness data in children less than 12 years old. Pharmacokinetics and safety data were collected in a small trial with intravenous voriconazole in children ages two to 11 years. 125 No studies of flucytosine (Ancobon) in pediatric patients exist; however, published reports of use of flucytosine with and without amphotericin B in doses of 25-200 mg/kg per day are available. No unexpected serious adverse effects were reported. Ketoconazole (Nizoral) tablets have not been studied in children of any age. The oral tablets should not be used in pediatric patients unless the benefits outweigh the risks. Safety and effectiveness of miconazole (Oravig) in pediatric patients less than the age of 16 years have not been established. The ability of pediatric patients to comply with the application instructions has not been evaluated. Use in younger children is not recommended due to potential risk of choking. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 16 of 30 August 2013 Antifungals, Oral Review Pregnancy Terbinafine is Pregnancy Category B. Clotrimazole, flucytosine, posaconazole, fluconazole, itraconazole, ketoconazole, nystatin, miconazole (Oravig), and griseofulvin are Pregnancy Category C. Voriconazole is Pregnancy Category D. Posaconazole, itraconazole (Onmel), and miconazole (Oravig) may cause fetal harm as has been shown in animal data. Nursing mothers should discontinue either nursing or the drug based on importance of the drug to the mother. Two cases of conjoined twins have been reported with first trimester use of griseofulvin. Griseofulvin should not be used in pregnant patients. Griseofulvin therapy should be discontinued if the patient becomes pregnant during treatment, and potential hazards to the fetus should be explained. The FDA issued a safety announcement regarding the use of long-term, high-dose (400 mg-800 mg/day) fluconazole during the first three months of pregnancy (first trimester) may be associated with a rare and distinct set of birth defects in infants. This risk is not associated with a single, low dose fluconazole 150 mg to treat vaginal yeast infection (candidiasis). The FDA categorizes a single 150 mg dose of fluconazole as category C but changed the Pregnancy Category for the use of fluconazole other than for vaginal candidiasis to category D. 126 Elderly Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. Hepatic Impairment For patients with mild to moderate cirrhosis (Child-Pugh Class A and B), use the standard loading dose regimens of voriconazole; however, reduce the maintenance dose of voriconazole by one-half. There is limited data available with itraconazole (Onmel) tablets in patients with hepatic impairment, therefore use with caution. Ketoconazole oral therapy is contraindicated in persons with hepatic impairment. Assess and monitor patients for new and/or worsening of hepatic damage at baseline and weekly during therapy. Renal Impairment Monitor posaconazole oral suspension and delayed-release tablets closely for breakthrough fungal infections in those patients with severe renal impairment. There is limited data available with itraconazole (Onmel) tablets with patients with renal impairment, therefore use with caution. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 17 of 30 August 2013 Antifungals, Oral Review DOSAGES Drug Oral Dosage Forms 10 mg troche clotrimazole 127 (Mycelex Troche) fluconazole (Diflucan) 128 50, 100, 150, 200 mg tablets 10 mg/mL, 40 mg/mL suspension 129 250, 500 mg capsules flucytosine (Ancobon) Microsized: Grifulvin V: 125 mg/5 mL suspension; 250, 500 mg tablets Ultramicrosized: Gris-PEG: 125, 250 mg tablets griseofulvin (Grifulvin V, 130, 131 Gris-PEG) itraconazole (Onmel) 132 200 mg tablet Adult Dosage Treatment: One troche (10 mg) five times per day for 14 consecutive days Prophylaxis: One troche (10 mg) three times per day Oropharyngeal and esophageal candidiasis: 200 mg X 1, then 100 mg daily Vaginal candidiasis: 150 mg orally X 1 Urinary tract infections and peritonitis: 50 to 200 mg daily Cryptococcal meningitis: 400 mg X 1, then 200 mg daily Undergoing bone marrow transplant: 400 mg daily until neutrophils >1,000 cells/m3 for seven days 50 – 150 mg/kg/day in divided doses every six hours Microsized: Onychomycosis: 1 g orally once a day for at least four months (fingernails) or at least six months (toenails) Tinea barbae: 500 to 1,000 mg orally once a day until infection has cleared Tinea capitis: 500 mg orally once a day for four to six weeks Tinea corporis: 500 mg orally once a day for two to four weeks Tinea cruris: 500 mg orally once a day until infection has cleared Tinea pedis: 1 g orally once a day for four to eight weeks Ultramicrosized: Onychomycosis : 750 mg orally in divided doses for at least four months (fingernails) or at least six months (toenails) Tinea barbae: 375 mg orally once a day or 375 to 750 mg in divided doses until infection has cleared Tinea capitis: 375 mg orally once a day or in divided doses for four to six weeks Tinea corporis: 375 mg orally once a day or in divided doses for two to four weeks Tinea cruris: 375 mg orally once a day or in divided doses until infection has cleared Tinea pedis: 750 mg orally in divided doses for four to eight weeks Onychomycosis of the toenail: single 200 mg tablet orally once daily for 12 consecutive weeks. Take with a full meal at the same time each day. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 18 of 30 August 2013 Antifungals, Oral Review Dosages (continued) Drug Oral Dosage Forms itraconazole 133 (Sporanox) 100 mg capsule 10 mg/mL solution ketoconazole 134 (Nizoral) 200 mg tablet miconazole (Oravig) nystatin 136, 137, 138 135 50 mg buccal tablets Variety of dosage forms and strengths First Duke’s mouthwash compounding kit consists of nystatin, diphenhydramine, and hydrocortisone. Adult Dosage Onychomycosis (toenail): 200 mg daily for 12 weeks Onychomycosis (fingernail): two treatment pulses, which consist of 200 mg twice daily for one week. The pulses are separated by a three-week period without itraconazole. Treatment of Blastomycosis or Histoplasmosis: 200 mg once daily. If no evidence of improvement or progressing disease, the dose can be increased by 100 mg, up to 400 mg daily. Doses greater than 200 mg should be given in two divided doses. Treatment of life threatening situations should include a loading dose of 200 mg three times daily for the first three days. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate active fungal infection has subsided. Treatment of Aspergillosis: 200 to 400 mg daily 200 to 400 mg daily One 50 mg buccal tablet to the upper gum region (canine fossa) once daily for 14 consecutive days. Buccal tablet is applied after brushing teeth in the morning. Alternate gum site each day. Note: If the buccal tablet does not adhere or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet still does not adhere, a new tablet should be placed. If the buccal tablet is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied only once. If the buccal tablet falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose. Chewing gum should be avoided. Do not chew, crush, or swallow the tablets. Gastrointestinal candidiasis: − 500,000 to 1,000,000 units three times daily Oral candidiasis: − 400,000 to 600,000 units four times daily First Mary’s mouthwash compounding kit consists of nystatin, diphenhydramine, tetracycline, and hydrocortisone. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 19 of 30 August 2013 Antifungals, Oral Review Dosages (continued) Drug Oral Dosage Forms posaconazole 139 (Noxafil) 40 mg/1 mL oral suspension 100 mg delayed-release tablet Adult Dosage Prophylaxis of invasive fungal Infections: Oral suspension: 200 mg (5 mL) three times daily during or immediately following (within 20 minutes) a full meal or with a liquid nutritional supplement in patients who can not eat a full meal. Delayed-release tablets: Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day. Maintenance dose of 300 mg (three 100 mg tablets) once a day, starting on the second day. Effect of food on posaconazole tablets is not known, however since the oral bioavailability of posaconazole suspension is increased with food, it is also recommended that posaconazole tablets be taken with food. For both dosage forms, duration of therapy is based on recovery from neutropenia or immunosuppression. Oropharyngeal candidiasis: Loading dose of 100 mg (2.5 mL) twice daily on day 1 then 100 mg once daily for 13 days. Oropharyngeal candidiasis refractory to fluconazole and/or itraconazole: 400 mg (10 mL) twice daily. Duration to be determined by patient’s severity of underlying disease and clinical response. terbinafine (Lamisil) 140 terbinafine (Terbinex) voriconazole (Vfend) 141 142 250 mg tablet 250 mg tablet 50, 200 mg tablets 200 mg/5 mL suspension Onychomycosis (toenail): 250 mg daily for 12 weeks Onychomycosis (fingernail): 250 mg daily for six weeks Onychomycosis (toenail): 250 mg daily for 12 weeks Onychomycosis (fingernail): 250 mg daily for six weeks A thin layer of EcoFormula should be applied daily to clean, dry nails preferably before bedtime. IV: (IV load is required to initiate therapy for all infections except esophageal candidiasis) 6 mg/kg every 12 hours X two doses then 3-4 mg/kg every 12 hours Oral: > 40 kg: 200 mg every 12 hours < 40 kg: 100 mg every 12 hours Concurrent phenytoin therapy: IV: 5 mg/kg every 12 hours Oral: > 40 kg: 400 mg every 12 hours < 40 kg: 200 mg every 12 hours Oral voriconazole should be taken one hour before or one hour after a meal. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 20 of 30 August 2013 Antifungals, Oral Review Dosage recommendations for pediatric patients are listed below: Oral Dosage Forms Drug clotrimazole (Mycelex 143 Troche) fluconazole (Diflucan) 144 10 mg troche Ages Pediatric Dosage > three years Oropharyngeal One troche (10 mg) five times per day 50, 100, 150, 200 six months mg tablets to 13 years 10 mg/mL, 40 mg/mL suspension candidiasis: Oropharyngeal candidiasis: 6mg/kg X 1; then 3 mg/kg daily for at least two weeks Esophageal candidiasis: 6 mg/kg X 1; then 3 mg/kg daily for at least three weeks Cryptococcal meningitis: 12 mg/kg X 1; then 6 to 12 mg/kg daily Systemic infections: 6 to 12 mg/kg daily Equivalent dosing Pediatric dose Adult dose 3 mg/kg daily 100 mg daily 6 mg/kg daily 200 mg daily 12 mg/kg daily 400 mg daily Pediatric dose should not exceed 600 mg daily. Griseofulvin (microsized, Gris145,146,147 PEG) ketoconazole 148 (Nizoral) nystatin 149 terbinafine 150 (Lamisil Granules) Microsized: > two years microsized: 125 mg/5 mL suspension; 250, 500 mg tablets Ultramicrosized: Gris-PEG: 125, 250 mg tablets Microsized: Pediatrics: 10-20 mg/kg daily (max: 1 g) given in one to two divided doses Children weighing 30 to 50 pounds – 125 mg to 250 mg daily Children weighing over 50 pounds – 250 mg to 500 mg daily 200 mg tablet > two years Ultramicrosized: Pediatrics: 3.3-7.3 mg/kg/day Children weighing 35-60 pounds - 125 mg to 187.5 mg daily. Pediatric patients weighing over 60 pounds - 187.5 mg to 375 mg daily 3.3-6.6 mg/kg/day various neonates and older Oral 100,000 to 600,000 units four times daily 125 mg packet 187.5 mg packet > four years Tinea capitis: Dose, based on body weight, given once daily for six weeks: < 25 kg 125 mg 25-35 kg 187.5 mg > 35 kg 250 mg candidiasis: Sprinkle contents of pack on a spoonful of pudding or other soft non-acidic food such as mashed potatoes. Do not use apple sauce or fruit-based foods. Swallow entire spoonful without chewing. Take with food. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 21 of 30 August 2013 Antifungals, Oral Review CLINICAL TRIALS Search Strategy Articles were identified through searches performed on PubMed and review of information sent by manufacturers. Search strategy included the FDA-approved use of all drugs in this class. Randomized, controlled, comparative trials of oral agents used in the outpatient setting are considered the most relevant in this category. Many of the more recent studies have focused on inpatient use of the antifungal agents. Studies included for analysis in the review were published in English, performed with human participants, and randomly allocated participants to comparison groups. In addition, studies must contain clearly stated, predetermined outcome measure(s) of known or probable clinical importance, use data analysis techniques consistent with the study question, and include follow-up (endpoint assessment) of at least 80 percent of participants entering the investigation. Despite some inherent bias found in all studies including those sponsored and/or funded by pharmaceutical manufacturers, the studies in this therapeutic class review were determined to have results or conclusions that do not suggest systematic error in their experimental study design. While the potential influence of manufacturer sponsorship/funding must be considered, the studies in this review have also been evaluated for validity and importance. No clinical trials evaluating the Terbinex kit met the inclusion criteria. fluconazole (Diflucan) and voriconazole (Vfend) – esophageal candidiasis In a double-blind, placebo-controlled trial, 256 immunocompromised patients, most of whom were HIV-positive with biopsy-proven esophageal candidiasis, were randomized to voriconazole (400 mg for one dose; then 200 mg twice daily), fluconazole (400 mg for one dose; then 200 mg daily), or placebo. The study evaluated efficacy, tolerability, and safety. 151 Patients were on therapy for at least seven days after clinical signs and symptoms resolved or for a maximum of six weeks. Patients underwent endoscopy at day 43 to determine efficacy. Endoscopy-documented success (98.3 percent versus 95.1 percent, respectively), as well as symptomatic success (88 percent versus 91.1 percent, respectively), was similar between voriconazole and fluconazole. Visual disturbances were reported in 18 percent of voriconazole patients compared to five percent with fluconazole. More patients discontinued voriconazole due to laboratory abnormalities or treatment-related adverse effects. griseofulvin oral suspension and terbinafine granules (Lamisil Granules) – tinea capitis Terbinafine oral granules and griseofulvin oral suspension were compared for efficacy and safety in the treatment of tinea capitis in children ages four to 12 years in two investigator-blinded studies.152 Patients were randomized to terbinafine 5-8 mg/kg daily or griseofulvin 10-20 mg/kg for six weeks of treatment. The 1,549 patients were followed for an additional four weeks. End of study complete cure was defined as a negative fungal culture and microscopy with no symptoms. Mycologic cure was defined as negative fungal culture and microscopy. Clinical cure was the absence of symptoms. The pooled intent-to-treat population consisted of 1,286 patients. Rates of complete cure and mycologic cure were significantly higher for terbinafine than for griseofulvin (45.1 versus 39.2 percent and 61.5 versus 55.5 percent, respectively; each p<0.05). Most griseofulvin patients (86.7 percent) received 10 to 19.9 mg/kg per day; complete cure rate was not found to be higher among patients who received more than griseofulvin 20 mg/kg per day compared with those who received less than 20 mg/kg per day. Complete cure rate was statistically significantly greater for terbinafine compared to griseofulvin Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 22 of 30 August 2013 Antifungals, Oral Review in trial 1 (46.23 versus 34.01 percent, respectively) but not in trial 2 (43.99 versus 43.46 percent, respectively). Clinical cure was similar between the two drugs based on the pooled data. Subgroup analyses revealed that terbinafine was significantly better than griseofulvin for all cure rates among patients with Trichophyton tonsurans but not Microsporum canis (p<0.001). For M. canis, mycologic and clinical cure rates were significantly better with griseofulvin than with terbinafine (p<0.05). Therapies were well tolerated. miconazole (Oravig) versus clotrimazole troches In a randomized, double-blind, double-dummy trial, miconazole buccal 50 mg tablets daily were compared to clotrimazole 10 mg troches five times daily for 14 days in 577 HIV-positive patients with oropharyngeal candidiasis. 153,154 Patients were required to have symptoms and microbiological documentation of candidiasis for study entry. Clinical cure was defined as a complete resolution of signs and symptoms of oropharyngeal candidiasis at the test-of-cure visit (days 17-22). Clinical cure was achieved in 61 percent of miconazole patients compared to 65 percent of clotrimazole patients (p=NS) in the intent to treat population. Clinical relapse occurred in 27.3 and 27.8 percent of patients, respectively. Mycological cure (eradication of Candida on days 17-22) occurred in 27.2 and 24.7 percent of patients, respectively. Adverse events were similar between treatments. terbinafine (Lamisil) versus itraconazole (Sporanox) - onychomycosis In a prospective, randomized, double-blind, multicenter study, researchers compared the efficacy and tolerability of continuous terbinafine with intermittent itraconazole for treatment of toenail onychomycosis. 155 The study included 496 patients diagnosed with toenail onychomycosis caused by a dermatophyte. Patients were randomly assigned to four parallel groups: terbinafine 250 mg per day for 12 or 16 weeks or itraconazole 400 mg per day for one week in every four weeks for 12 or 16 weeks. The primary outcome measure was mycological cure, defined as negative microscopy and negative culture of samples from the target toenail. At week 72, mycological cure rates were 75.5 percent in the 12-week terbinafine group and 80.8 percent in the 16-week terbinafine group, compared with 38.3 percent in the itraconazole 12-week study group and 49.1 percent in the itraconazole 16-week group. All treatments were well tolerated, with no significant differences in the number or type of adverse events reported. Researchers concluded continuous terbinafine is more effective than intermittent itraconazole for the treatment of toenail onychomycosis. In a five-year, blinded, prospective follow-up study to the aforementioned study, the long-term effectiveness of terbinafine was compared to itraconazole in 151 patients. 156 At the end of five years, mycologic cure achieved with one treatment course was found in 46 percent and 13 percent of the terbinafine-treated and itraconazole-treated patients, respectively (p<0.001). Mycologic and clinical relapse rates were significantly higher in the itraconazole-treated group, 53 percent and 48 percent, respectively, compared to the terbinafine-treated group, 23 percent and 21 percent, respectively. A prospective, investigator-blinded, long-term follow-up (1.25 to seven years) study comparing four treatment regimens with itraconazole and terbinafine was conducted.157 The four regimens were either terbinafine continuous, intermittent, or in combination with itraconazole, and pulsed itraconazole. Recurrence rate of onychomycosis was the outcome used to determine which of the four regimens was the most effective at decreasing the rate of re-infection. Although no statistical significance was found between the dosing regimens, it was determined that itraconazole therapy was associated with higher rates of recurrence (59 percent) than was terbinafine regimens (32 percent Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 23 of 30 August 2013 Antifungals, Oral Review recurrence rate for continuous and 36 percent for intermittent). Combining the two drugs did not reduce the rate of recurrence of the infection as compared to monotherapy (57 percent rate of recurrence of infection for combination therapy). itraconazole (Onmel) versus itraconazole (Sporanox) - onychomycosis The efficacy of itraconazole (Onmel) for the treatment of onychomycosis of the toenail was evaluated in a 12-week, randomized, placebo-controlled, third-party blinded, multicenter trial comparing one 200 mg Onmel tablet to two 100 mg itraconazole capsules and placebo once daily tablets, in 791 patients.158 The primary endpoint of Complete Cure at Week 52, nine months after completion of study medication, was 22.3 and one percent, for Onmel and placebo, respectively. The Mycologic Cure rate was 44 percent and the Clinical Cure rate was 26 percent for subjects treated with Onmel. The Mycological Cure rate was six percent and the Clinical Cure rate was three percent for subjects treated with placebo. Efficacy results comparing a single 200 mg Onmel tablet to 200 mg of itraconazole capsules (two 100 mg capsules) were similar. posaconazole (Noxafil), fluconazole (Diflucan) and/or itraconazole (Sporanox) Due to the lack of other comparative data with posaconazole, this study is included in the review. In a randomized, multicenter study, safety and efficacy of posaconazole (n=304), fluconazole (n=240), and itraconazole (n=58) were compared for invasive fungal infection prophylaxis in patients with prolonged neutropenia.159 Patients were undergoing treatment for acute myelogenous leukemia or myelodysplastic syndrome. In this investigator-blinded study, patients received prophylaxis with the assigned treatment with each cycle of chemotherapy until recovery from neutropenia and complete remission occurred or until the occurrence of an invasive fungal infection or for up to 12 weeks. Proven or probable invasive fungal infections were reported in two percent of the posaconazole group and eight percent in the fluconazole or itraconazole group (absolute reduction, 6 percent; 95% CI, -9.7 to 2.5; p<0.001). Invasive aspergillosis was significantly lower in the posaconazole group (one percent versus seven percent, p<0.001). Survival was significantly higher in the posaconazole group (16 percent mortality) than in the fluconazole/itraconazole group (22 percent mortality, p=0.04). Serious adverse effects were significantly more common in the posaconazole group (six percent versus two percent; p=0.01). The most common adverse effects related to the gastrointestinal tract. In a multicenter, randomized, double-blind trial, oral posaconazole and fluconazole were compared for prophylaxis against invasive fungal infections in patients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy. 160 Six hundred allogenic hematopoietic stem-cell transplant patients were enrolled. At the end of the 112-day treatment period, posaconazole and fluconazole were similarly effective in preventing all invasive fungal infections (5.3 and 9 percent, respectively; odds ratio=0.56; 95% CI, 0.30 to 1.07, p=0.07). Posaconazole was superior to fluconazole in preventing proven or probable invasive aspergillosis (2.3 and 7 percent, odds ratio=0.31, 95% CI, 0.13 to 0.75, p=0.006). Overall mortality was similar in the two groups; however, the number of deaths from invasive fungal infections was lower in the posaconazole group (1 and 4 percent, p=0.046). Treatment-related adverse effects were similar in both groups (36 percent for posaconazole and 38 percent for fluconazole). Due to the lack of other comparative data with posaconazole, this study is included in the review. Posaconazole was compared to fluconazole in a multicenter, randomized, single-blinded trial evaluating efficacy and safety in the treatment of oropharyngeal candidiasis in patients with Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 24 of 30 August 2013 Antifungals, Oral Review HIV/AIDS. 161 Patients (n=350) were randomized to posaconazole or fluconazole 200 mg on day one then 100 mg daily for 13 days. Clinical success, defined as cure or improvement on day 14, was observed in 91.7 and 92.5 percent for posaconazole and fluconazole groups, respectively (95% CI, -6.61 to 5.04). Mycological success was 68 percent in both arms on day 14, but mycological success on day 42 was 40.6 and 26.4 percent for posaconazole and fluconazole, respectively (p=0.038). Clinical relapse rates were 31.5 percent for posaconazole and 38.2 percent for fluconazole. Adverse effects were similar. META-ANALYSIS A meta-analysis determined mycological cure rate in randomized clinical trials is consistently 76 percent for terbinafine (Lamisil) and 63 percent for pulse dose itraconazole (Sporanox). 162 Thirty-six randomized, controlled trials evaluated the efficacy of terbinafine, itraconazole, fluconazole (Diflucan), and griseofulvin (Grifulvin V, Gris-PEG) in the treatment of dermatophyte toenail onychomycosis. 163 Studies were required to use a standard dosage regimen (pulse or continuous), treatment duration, and follow-up period. Mycological and clinical response rates were compared for the randomized controlled trials and open trials for each of the agents. Studies were pooled from earliest (1966) to most recent to determine the cumulative meta-analytical average. The overall cumulative metaaverage for mycological cure rates were terbinafine 76 ± 3 percent (18 studies), itraconazole pulse 63 ± 7 percent (six studies), itraconazole continuous 59 ± 5 percent (seven studies), fluconazole 48 ± 5 percent (three studies), and griseofulvin 60 ± 6 percent (three studies). When comparing randomized controlled trials and open-label trials, the cumulative meta-analytical average for mycological cure rates were significantly higher in the open-label trials for terbinafine, itraconazole pulse dose, and fluconazole. Randomized controlled trials (21 studies) that evaluated systemic antifungal therapy for tinea capitis in immunocompetent children (n=1,812) were identified. 164 All studies required a tinea capitis diagnosis to be confirmed by microscopy or growth of dermatophytes in culture or both. For infections caused by Trichophyton species, terbinafine for four weeks and griseofulvin for eight weeks showed similar efficacy (RR 1.09; 95% CI, 0.95 to 1.26). Two studies found cure rates to be similar following treatment with itraconazole and griseofulvin for six weeks. There was no difference between itraconazole and terbinafine for treatment periods lasting two to three weeks in two studies involving 160 children (RR 0.93; 95% CI, 0.72 to 1.19). Two studies that included 140 children found similar cure rates between two to four weeks of fluconazole with six weeks of griseofulvin (RR 0.92; 95% CI, 0.8 to 1.05). For Microsporum infections, no significant difference in cure rates were observed between terbinafine and griseofulvin, based on one small study of 29 children (RR 0.64; 95% CI, 0.19 to 2.20). Shorter treatment durations may improve treatment adherence. A meta-analysis compared griseofulvin (Grifulvin V, Gris-PEG) and terbinafine in the treatment of tinea capitis in children. 165 Randomized, clinical studies with treatment for at least six weeks were included. Identification of the dermatophyte was required for inclusion. A total of six trials were evaluated. Outcome parameters were compared at 12 to 16 weeks after enrollment. The common odds ratio was 0.86, which tells us that the studies included had similar outcomes. When Trichophyton species were isolated in studies looking at outcomes at 12 weeks, the results trended toward terbinafine. Outcomes after eight weeks for both treatments were similar. Authors concluded terbinafine for two to four weeks is at least as effective as griseofulvin for at least six weeks for Trichophyton infections of the scalp. With other pathogens, griseofulvin may be a superior agent. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 25 of 30 August 2013 Antifungals, Oral Review Another meta-analysis evaluated seven trials with griseofulvin for the treatment of tinea capitis. Overall cure rate after four to six weeks post-treatment was 73.4 percent (seven studies; n=438 patients). 166 Higher efficacy rates were reported with the use of higher dosages of griseofulvin (>18 mg/kg/day). When broken down by species, the mean efficacy for Trichophyton and Microsporum were 67.6 percent (five studies, n=396) and 88.1 percent (two studies, n=42 patients), respectively. A Cochrane review found very few comparative trials on which to evaluate efficacy of prophylaxis of oropharyngeal candidiasis in HIV-positive patients.167 It appeared that ketoconazole, fluconazole, itraconazole, and clotrimazole improved treatment outcomes in the treatment of oropharyngeal candidiasis. An update was performed evaluating clinical trials performed between 2005 and 2009.168 Five additional studies were identified. Only one study was performed in children; therefore, little evidence exists. For adults, very few comparative trials for each comparison exist. Due to insufficient evidence, no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole, or ketoconazole with regard to oropharyngeal candidiasis prophylaxis. A meta-analysis completed in 2011 reviewed itraconazole recurrence rates as compared to terbinafine recurrence rates. This analysis concluded that itraconazole had a higher rate of onychomycosis recurrence than did terbinafine. 169 SUMMARY Oral antifungal agents are useful in the treatment of a variety of infections in both the immunocompetent and immunocompromised patient. Oral antifungals used in the outpatient setting generally treat fungal infections such as oropharyngeal candidiasis, urinary tract infections, superficial skin infections, and onychomycosis. Due to its excellent penetration into many tissues, fluconazole (Diflucan) is effective Candida treatment for a variety of infections, lacking concerns about pHdependent absorption such as that seen with ketoconazole (Nizoral). Effective therapy for oropharyngeal candidiasis includes fluconazole, itraconazole, ketoconazole, nystatin, and clotrimazole troches (Mycelex). Voriconazole (Vfend) has been shown to have similar efficacy to fluconazole in the treatment of esophageal candidiasis; however, more adverse effects are reported with voriconazole. Posaconazole (Noxafil) oral suspension has an indication for treatment of oropharyngeal candidiasis when refractory to itraconazole and/or fluconazole. Nystatin is also used to treat intestinal candidiasis and may be used in infants and children. In comparative trials, terbinafine (Lamisil) demonstrated higher treatment success rates of toenail onychomycosis in immunocompetent patients compared to itraconazole (Sporanox). Terbinafine also demonstrated higher clinical success rates in the treatment of tinea capitis than griseofulvin (Grifulvin V, Gris-PEG); however, griseofulvin had higher success rates in those infections caused by Microsporum. Utility of griseofulvin for treatment of onychomycosis has decreased since the introduction of the azole antifungals and terbinafine. Duration of therapy is often longer than with other agents, which may result in increased adverse effects and require monitoring of liver, renal, and hematopoietic function. However, griseofulvin is still a useful agent in the treatment of many fungal skin infections that do not respond to topical therapies. For serious fungal infections, posaconazole, flucytosine (Ancobon), voriconazole, itraconazole, and fluconazole have indications for the treatment and/or prophylaxis of various serious fungal infections. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2013, Provider Synergies, LLC, an affiliate of Magellan Medicaid Administration, Inc. All Rights Reserved. Page 26 of 30 August 2013 Antifungals, Oral Review REFERENCES 1 Mycelex troche [package insert]. West Haven, CT; Bayer Pharmaceuticals; September 2004. 2 Diflucan [package insert]. New York, NY; Pfizer; March 2013. 3 Ancobon [package insert]. Alisa Viejo, CA; Valeant; February 2011. 4 Available at: http://www.clinicalpharmacology.com. Accessed July 30, 2013. 5 Griseofulvin microsized [package insert]. Lincolnton, NC; Actavis Mid Atlantic; July 2007. 6 Gris-PEG [package insert]. Farmingdale, NY; Pedinol Pharmacal; October 2010. 7 Onmel [package insert]. Greensboro, NC; Merz; November 2012. 8 Sporanox [package insert]. Titusville, NJ; Janssen; June 2012. 9 Nizoral [package insert]. Titusville, NJ; Janssen; July 2013. 10 Oravig [package insert]. Woodcliff Lake, NJ: Strativa Pharmaceuticals; August 2012. 10 Nystatin [package insert]. Baltimore, MD; Actavis Mid Atlantic; September 2006. 12 Noxafil [package insert]. Whitehouse Station, NJ; Merck; November 2013. 13 Lamisil [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; June 2013. 14 Lamisil Granules [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; June 2013. 15 Terbinex [package insert]. Charleston, SC; JSJ Pharmaceuticals; October 2011. 16 Vfend [package insert]. New York, NY; Pfizer; November 2011. 17 FDA drug safety communication: FDA limits use of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. Available at http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm. Accessed July 31 2013. 18 Pappas PG, Kauffman CA, Andes D, et al. Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 48:503–35. Available at: http://dukespace.lib.duke.edu/dspace/bitstream/handle/10161/4137/273500300001.pdf?sequence=1. Accessed September 11, 2012. 19 Mofenson LM, Brady MT, Danner SP, et al. Centers for Disease Control and Prevention, National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America, Pediatric Infectious Diseases Society, American Academy of Pediatrics. 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