Formulary Review ANTIFUNGAL MEDICATIONS

Formulary ReviewSM
ANTIFUNGAL MEDICATIONS
August 2012
Confidential
Executive Summary
Issues
•
Are there sufficient antifungal options on the formulary for treatment of common superficial as well as
less frequent, severe systemic fungal infections?
•
Are there specific fungal infections where generic options are insufficient, such that branded products
should be added to formulary?
•
Is there evidence that any brand name product provides additional benefit or value relative to other
available options?
Conclusion (Product Value)
•
Generic products are sufficient to address the majority of superficial fungal infections (external,
mucocutaneous, vaginal). The one exception is fungal eye infections, as natamycin (Natacyn) is
the only currently available ophthalmic.
•
Branded products, including lipid-based amphotericins, echinocandins and extended spectrum
azoles, need to be on the formulary as generics are inadequate therapy for certain systemic
infections, such as aspergillosis, histoplasmosis, fusariosis, zygomycosis (mucormycosis) and
some CNS fungal infections.
•
There is no reliable evidence demonstrating superiority of one brand antifungal product over
another. However, because of variability of disease (severity, specific organism, immune status,
infection site, antifungal susceptibility, etc.), several choices are needed for specific fungal
infections and their use supported by high quality guidelines. (See “Formulary
Recommendations”)
Background
The following classes of systemic antifungals have branded products that may provide additional value in
treating severe infections, based on antimicrobial activity, availability of generic treatment options, current
standards of practice (guidelines), comparative safety, and relative value to other treatment options:
•
Lipid-based amphotericins: liposomal (AmBisome®), lipid complex (Abelcet®), colloidal
dispersion (Amphotec®).
•
Extended-spectrum azoles: voriconazole (Vfend® IV and oral suspension), posaconazole
(Noxafil®).
•
Echinocandins: anidulafungin (Eraxis®), caspofungin (Cancidas®), micafungin (Mycamine®).
Page 1 of 10
© 2012 RegenceRx. All rights reserved.
Formulary Considerations for brand name antifungal products
Practical Considerations
Consideration
Efficacy
Description
- Based upon a large body of literature and years of clinical experience, there is high certainty
that antifungals are effective for treatment of fungal infections, including many generics.
- Liposomal amphotericin (L-AMB; AmBisome) is superior to other amphotericins for treating
CNS fungal infections and other complicated infections, however the evidence is limited to a
few randomized controlled trials, as well as pharmacokinetic data.
- Branded echinocandins and extended-spectrum azoles (posaconazole, voriconazole) are
superior to generic options for certain systemic infections, based on limited randomized
controlled trial evidence, along with antifungal activity in vitro and resistance patterns.
- Posaconazole (Noxafil) may be the only effective oral option for treatment of zygomycosis,
based on antimicrobial susceptibility.
- Many generic options are available within most of the therapeutic areas where antifungals are
Other
used, including newly-approved generic voriconazole tablets.
Treatment
- Several branded systemic products are preferred primary therapy for life-threatening infections,
Options
based on in vitro sensitivity and in vivo efficacy.
- Natamycin (Natacyn®) is the only currently available ophthalmic antifungal.
- All antifungals have an established track record of safety of more than five years.
- Hepatotoxicity, nephrotoxicity and drug interactions are significant safety concerns associated
Safety
with antifungal agents. Differences in adverse effects are significant between medication
classes. Adverse effects and drug interactions may guide treatment selection.
- Brand name antifungal products are substantially more costly than generically available
Cost
products. (Systemics: > $1000 vs. <$100; Topicals >$100 vs. <$20).
- L-AMB (AmBisome) is more costly than other lipid-based amphotericins ($5000 vs. $20,000).
- Common fungal infections, such as onychomycosis, may not require treatment.
- Though less common, systemic fungal infections can be life-threatening (i.e. aspergillosis,
Disease
fusariosis, histoplasmosis, and zygomycosis).
Characteristics
- Prophylactic antifungal therapy may prevent life-threatening infections in seriously ill,
immunocompromised patients.
- Treatment guidelines recommend use of generics, for the majority of fungal infections.[1-13]
- The Infectious Diseases Society of America (IDSA) publishes a series of high quality
guidelines that are recognized as the current standard of care for the treatment of most systemic
fungal infections. [7-13]
Standard of
- Branded lipid-based amphotericins, echinocandins, voriconazole IV (Vfend) and posaconazole
Care
(Noxafil) are IDSA-recommended as preferred therapies for severe infections.
- Though guidelines recommend specific echinocandins based on their different antifungal
activity, experts queried for this review consider echinocandins clinically interchangeable for
most situations.
Impact on
No branded antifungal reduces or eliminates significant barriers to care. Intravenous products
Clinical
are used primarily in the inpatient setting, then changed to oral azoles when possible, for
Burden
outpatient therapy.
Commercial Formulary Decision
Azoles (systemic)
Add posaconazole oral suspension (Noxafil) as
preferred/formulary
Ophthalmics
Add natamycin (Natacyn) as preferred/formulary
Rationale (See Appendix D, “Rule 6”)
Fills unmet need. IDSA-preferred oral therapy for
zygomycosis, based on antifungal activity.
Rationale (See Appendix D, “Rule 8”)
Fills unmet need. Only ophthalmic antifungal available.
Medicare Part D Formulary Decision
No changes to the Medicare Part D formulary are recommended at this time.
Page 2 of 10
© 2012 RegenceRx. All rights reserved.
I.
Product Information and Cost
A. Current antifungals – Systemic and Topical therapies
Systemic therapies
Drug Products
FDA
approvala
Patent
Expiration(s)b
FDA approved indications
Forms and
Usual
Dose/Duration
Cost
3 to 5 mg/kg/day
IV 240-400mg
$8,10013,400d
3 to 4 mg/kg/day
IV
$5,4007,200d
3 to 6 mg/kg/day
IV
$13,20021,980d
Potential Off-label Uses e
Amphotericins
Generic Products: amphotericin B deoxycholate injection (AMB-D) [Cost: $564]d
Branded Products:
amphotericin B lipid
complex injection
(ABLC; Abelcet®)[14]
[sigma-tau
Pharmaceuticals]
amphotericin B
cholesteryl sulfate
complex injection
(ABCD;
Amphotec®)[15]
11/1995
6/2019
Invasive infections in patients who
are resistant to or intolerant of
amphotericin B deoxycholate
including aspergillosis, candidiasis,
zygomycosis, cryptococcosis, and
fusariosis
Aspergillosis (with renal impairment
or amphotericin B deoxycholateresistant)
11/1996
Expired
8/1997
10/2016 - Febrile neutropenia
- Cryptococcal meningitis
- Aspergillus, Candida infections
resistant to ampho B deoxycholate
- Pulmonary aspergillosis
- Visceral leishmaniasis
Blastomycosis,
coccidioidomycosis,
histoplasmosis, sporotrichosis,
leishmaniasis, systemic
mycosis
Candidiasis; leishmaniasis;
mycosis
(a.k.a. amphotericin B colloidal
dispersion, ABCD)
[Three Rivers]
amphotericin B
liposome injection
(L-AMB,
AmBisome®)[16]
[Astellas]
Variety of candidal infections;
cryptococcosis; blastomycosis;
coccidioidomycosis;
histoplasmosis; mycosis;
sporotrichosis
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
Page 3 of 10
© 2012 RegenceRx. All rights reserved.
(Systemic therapies continued)
Patent
Drug
FDA
Expira
Products
approval
ation(s)b
FDA approved indications
Forms and Usual
Dose/Duration
Cost
Potential Off-label Uses e
Azoles
Generic Products: fluconazole injection, oral tablets/suspension, itraconazole oral capsules/suspension, ketoconazole oral [Cost: $676 IV; $5-351oral d]
Branded Products:
posaconazole
oral
suspension
(Noxafil®)[17]
[Merck]
voriconazole
oral tablet
(generic)
9/15/06
5/24/02
7/2019 - Prophylaxis of aspergillus and
candida infections
- Oropharyngeal candidiasis (OPC)
- Fluconazole-refractory OPC (rOPC)
Prophylaxis: 200 mg PO TID
Expired - Invasive aspergillosis
- Mycosis, serious infections.
- Candidemia and disseminated
candidiasis
- Serious infections caused by
Scedosporium and Fusarium spp
- Esophageal candidiasis
6 mg/kg IV every 12 hr for 2
doses, followed by 3-4 mg/kg IV
every 12 hr may switch to oral
dosing as tolerated
(anticipated
date of IV
generic
unknown)
oral
suspension,
injection
(Vfend®)[18]
[Pfizer]
$2,445c
OPC: 100 mg PO BID x 3 days,
then 100 mg PO once daily for
up to 28 days
Aspergillus infections,
esophageal candidiasis,
Fusarium infection;
mycosis
r-OPC: 400 mg PO BID
Esophageal candidiasis: 200 mg
PO q12 hrs
$2,500
(generic
tablet)c
$2,9005,800
(Vfend
tabs)d
Allergic
bronchopulmonary
aspergillosis; aspergillosis
prophylaxis;
blastomycosis; variety of
candida infections; febrile
neutropenia; mycosis.
$6,800 (IV)d
Echinocandins
Generic Products: no generics expected prior to 2017.
Branded Products:
anidulafungin
injection
(Eraxis®)[19]
[Pfizer]
2/17/06
4/2021 - Candidemia
- Disseminated candidiasis – intraabdominal/peritonitis
- Esophageal candidiasis
Candidemia: 200 mg IV load,
then 100 mg IV daily
Esophageal candidiasis: 100 mg
IV load, then 50 mg IV daily
$1,6203,240d
Treatment and prophylaxis
of a variety of candidal
infections.
Empirical antifungal
therapy.
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
Page 4 of 10
© 2012 RegenceRx. All rights reserved.
(Systemic therapies continued)
Drug Products
FDA
approvala
Patent
Expiration(s)b
FDA approved
indications
1/26/01
9/2017
-
3/16/05
1/2021
- Candidemia
- Esophageal candidiasis
- Candida prophylaxis in
stem cell transplant
patients
Forms and Usual
Dose/Duration
Cost
Potential Off-label
Uses e
Echinocandins
caspofungin
injection
(Cancidas®)[20]
[Merck]
micafungin injection
(Mycamine®)[21]
[Astellas]
Invasive aspergillosis
Febrile neutropenia
Esophageal candidiasis
Candidemia and other
Candida infections.
Initial dose: 70 mg IV on day 1;
subsequent dosing: 50 mg/day
IV; if clinical response
inadequate, may increase up to
70 mg/day if tolerated
Candidemia: 100 mg IV daily
$5,670d Treatment and
prophylaxis of a variety
of candidal, aspergillus
and other invasive
fungal infection.
$3,136d
Esophageal: 150 mg IV daily
Prophylaxis: 50 mg IV daily
Miscellaneous Orals (systemic)
Generic Products: flucytosine [$3,800-11,400/14 days d], griseofulvin microsize suspension [$77 c], terbinafine [$8c]
Branded Products:
griseofulvin ultramicrosize tablet
(Gris-PEG®)[22]
[Pedinol]
griseofulvin
microsize tablet
(Grifulvin V®)[23]
4/16/75
Expired
- Onychomycosis
- Tinea barbae, capitis,
corporis, cruris, pedis
375 to 750 mg orally per day
(single or divided dose)
8/22/62
Expired
- Onychomycosis
- Tinea barbae, capitis,
corporis, cruris, pedis
500 to 1000 mg orally per day
(single or divided dose)
$141c
Lichen planus;
pityriasis versicolor;
systemic sclerosis
$156c
[Valeant]
Topical therapies
Oro-mucosal Topicals: buccal tablet, oral lozenge, oral suspension, oral troche
Generic Products: clotrimazole troche/lozenge [$46 c], nystatin oral powder/suspension/tablet[$36-51c]
Branded Products: none
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
Page 5 of 10
© 2012 RegenceRx. All rights reserved.
(Topical therapies continued)
FDA
Patent
approvala Expiration(s)b
Drug Products
FDA approved
indications
Forms and Usual
Dose/Duration
Cost
Potential Off-label
Uses e
Ophthalmic Topicals
Generic Products: none
Branded Products:
natamycin ophthalmic suspension
(Natacyn®)[24]
1/1/82
Expired
[Alcon]
Fungal blepharitis,
conjunctivitis and
keratitis
1 drop in affected
eye(s) 4 to 8
times/day
$228d none
External Topicals
Generic Products: Cream: clotrimazole, econazole, ketoconazole, miconazole, nystatin [$21-36 c]; OTC: terbinafine, tolnaftate [~ $10 d]
Foam: ketoconazole [$162-300d]
Gel: ciclopirox [$92 c]; OTC: terbinafine [~ $10d]
Nail lacquer solution: ciclopirox [$13c]
Ointment: miconazole, nystatin ointment [$10-24c]
Powder: miconazole spray/powder, nystatin powder [$10-33c]; OTC: tolnaftate powder/spray [~ $10 d]
Shampoo: ciclopirox [$123c], ketoconazole 2% [$17 c]
Solution: clotrimazole, miconazole [$10-13 c]; OTC: terbinafine, tolnaftate [~ $10 d]
Branded Products:
butenafine 1% topical cream
(Mentax®, OTC Lotrimin Ultra)[25]
[Bertek Pharmaceuticals]
10/1996
Expired
Topical treatment of
tinea – pedis, cruris,
corporis, and
versicolor
Apply once or
twice daily to
affected area
$125c
Onychomycosis;
seborrheic
dermatitis
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
Page 6 of 10
© 2012 RegenceRx. All rights reserved.
(Topical therapies continued)
7/2006
Patent
Expiration(s) b
12/2018
[Aqua]
naftifine 1-2% topical
cream, gel (Naftin®)[27]
2/1988
Expired
Tinea superficial corporis, cruris, pedis
Apply topically to affected area
once or twice daily
$308c
none
[Merz]
oxiconazole 1% topical
cream, lotion (Oxistat®)[28]
12/1988
Expired
Pityriasis versicolor; tinea
– superficial, corporis,
cruris, pedis
Apply topically to affected area
and surrounding areas 1-2 times
daily for 2-4 weeks
$153c
none
[Pharma Derm]
sertaconazole 2% topical
cream (Ertaczo®)[29]
12/2003
5/2014
Tinea pedis, interdigital
Apply cream topically twice daily
for 4 weeks
$169c
Tinea
2/1989
Expired
Topical treatment of tinea
– cruris, corporis, and
versicolor
Apply once or twice daily to
affected area
$106c
Candidiasis of skin
Drug Products
ketoconazole 2% topical
gel (Xolegel®)[26]
[Bertek]
sulconazole 1% topical
cream, solution
(Exelderm®)[30]
FDA
approvala
FDA approved
indications
Potential Off-label
Uses e
Forms and Usual Dose/Duration
Cost
Seborrheic dermatitis
Apply topically to affected area
once daily for 2 weeks
$376d Candidiasis of the
skin; pityriasis
versicolor; tinea
[Ranbaxy]
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
Page 7 of 10
© 2012 RegenceRx. All rights reserved.
(Topical therapies continued)
Drug
Products
FDA
approvala
Patent
Expiration(s) b
FDA approved
indications
Forms and Usual
Dose/Duration
Cost
Potential Off-label Uses
e
Vaginals
Generic Products: Rx: miconazole vaginal suppository 200 mg [Cost: $10c], nystatin vaginal tablets [Cost: $74d], terconazole cream/suppository [Cost:
$40d]
OTC: clotrimazole vaginal cream/tablet, miconazole vaginal cream/suppository 100 mg, tioconazole vaginal ointment [Cost: ~$8-14d]
Branded Products: none
a
Date applies to approval date for the original brand name medication where there are now generics available.
Based on patents listed in Orange Book as of April 12, 2012.
c
Cost listed in RegenceRx PriceGuide of April 12, 2012 for one course of therapy. Typical course of therapy is 14 days.
d
Based on AWP as listed in MediSpan as of April 12, 2012 for one course of therapy, assuming an 80 kg patient and a 14-day course of therapy or an approximate one prescription fill (for topicals, ophthalmics).
e
As listed in © 1974 - 2012 Thomson MICROMEDEX database or as referenced.
b
B. Classification of topical products (by mechanism of action)[1,23]
Imidazoles: clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, tioconazole
Allylamines: naftifine, terbinafine
Benzylamine: butenafine
Ciclopirox
Polyene antibiotics: amphotericin, natamycin, nystatin
Miscellaneous: benzoic acid preparations, tolnaftate
C. Pipeline products
Pipeline
Medication
isavuconazole
(oral)
Manufacturer
Anticipated Potential Indication
Launch
Basilea
2014
Invasive fungal
Pharmaceutica,
infections and
Ltd and
esophageal candidiasis
Astellas
Pharma, Inc
Comments
Fast track designation
April 2008; first trial results
expected in 2013.
Page 8 of 10
© 2012 RegenceRx. All rights reserved.
IX.
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Disclaimer: The information contained within this document best reflects the current state of medication information at the date of
publication. Conclusions may be subject to change over time because of many factors, including but not limited to: emerging
scientific evidence for safety and efficacy, evolving best-practices for critical appraisal of scientific evidence, market availability of
medications, medication cost information, and evolving medical practice standards.
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