Pharmacoeconomic Analysis of Oral Antifungal Therapies Used to Treat Dermatophyte Onychomycosis of the Toenails

Pharmacoeconomic Analysis ofOral Antifungal Therapies Used toTreat Dermatophyte Onychomycosisof the ToenailsA US Analysis

Aditya K. Gupta

Division of Dermatology, Department of Medicine, Sunnybrook Health Science Center, and theUniversity of Toronto, Toronto, Ontario, Canada

Summary Until a few years ago, griseofulvin and ketoconazole were the only 2 oralagents available for the treatment of dermatophyte onychomycosis of the toenails.With the availability of the newer antifungal agents, such as itraconazole, ter-binafine and fluconazole, the armamentarium of drugs available to treat onycho-mycosis has expanded.

The objective of this study was to determine the relative cost effectiveness ofthe most commonly used oral antifungal agents in the US for the treatment ofdermatophyte onychomycosis of the toenails from the perspective of a third-partypayer. The time horizon was 3 years.

A 5-step approach was used in this pharmacoeconomic analysis. First, thepurpose of the study, the comparator drugs and their dosage regimens weredefined. In step II, the medical practice and resource-consumption patterns asso-ciated with the treatment of onychomycosis were identified. In step III, a meta-analysis was performed on all studies meeting prespecified criteria, and themycological cure rates of the comparator drugs were determined. In step IV, thetreatment algorithm for the management of onychomycosis was constructed foreach drug. The cost-of-regimen analysis for each comparator incorporated thedrug acquisition cost, medical-management cost and cost of managing adversedrug reactions. The expected cost per patient, number of symptom-free days(SFDs), cost per SFD and the relative cost effectiveness for the comparator drugswere calculated. In step V, a sensitivity analysis was performed.

The drug comparators for this study were griseofulvin, itraconazole (conti-nuous and pulse), terbinafine and fluconazole. The mycological cure rates [mean� standard error (SE)] from the meta-analysis were griseofulvin 24.5 � 6.7%,itraconazole (continuous) 66.4 � 6.1%, itraconazole (pulse) 76 � 9.3%, terbinaf-ine 74 � 7% and fluconazole 59%. The cost per mycological cure was griseofulvin$US8089, itraconazole (continuous) $US1877, itraconazole (pulse) $US991, ter-binafine $US1125 and fluconazole $US1506. The corresponding cost per SFDwas griseofulvin $US7.05, itraconazole (continuous) $US2.18, itraconazole(pulse) $US1.26, terbinafine $US1.28 and fluconazole $US2.12. The resulting

ORIGINAL RESEARCH ARTICLE Pharmacoeconomics 1998 Feb; 13 (3): 243-2561170-7690/98/0003-0243/$07.00/0

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ratios of cost per SFD relative to itraconazole (pulse) [1.00] were terbinafine 1.02,itraconazole (continuous) 1.73, fluconazole 1.69 and griseofulvin 5.62.

In conclusion, in this analysis, itraconazole (pulse) and terbinafine were themost cost-effective therapies for dermatophyte onychomycosis of the toenails,both being substantially more cost effective than griseofulvin.

Onychomycosis is a common condition, withrecent estimates of its prevalence in North Americabeing 6.9 to 8.7%.[1,2] Furthermore, onychomyco-sis is the most common cause of nail disease, rep-resenting 18 to 40% of all onychopathies,[3,4] and30% of all mycotic infections.[5]

The availability of the newer antifungal agents,itraconazole, terbinafine and fluconazole, has re-sulted in griseofulvin being largely superseded asa treatment for dermatophyte onychomycosis ofthe toenails.[6,7] Itraconazole, in a continuous regi-men, was approved in the US in October 1995 forthe treatment of onychomycosis. However, DeDoncker et al.[8] reported that itraconazole pulsetherapy was effective in treating dermatophytepedal onychomycosis. In the US, approval for thetreatment of fingernail onychomycosis with 2pulses of itraconazole therapy was obtained in De-cember 1996, and pulse therapy for onychomyco-sis of the toenails is used widely. Terbinafine wasapproved for the treatment of onychomycosis inthe US in May 1996. Fluconazole is currently notapproved in the US for onychomycosis; however,the drug is currently under consideration by the USFood and Drug Administration for this indication.

New therapies often come at higher prices, butalso offer superior mycological cure rates. How-ever, prior pharmacoeconomic studies in this areahave been limited: none has thoroughly evaluatedeither itraconazole given as pulse therapy[9] orfluconazole. In order to evaluate both the costs andoutcomes of the new antifungal agents relative tothe older regimens in the treatment of onychomy-cosis of the toenails, a systematic pharmacoecono-mic evaluation was conducted.

Methods

The 5-step economic model used in this study

was patterned after Arikian et al.[10] and Van Door-slaer et al.[11]

Step I: Defining the Question

The purpose of the study, the comparator drugs,their dosage regimen, the time frame of the analysisand its perspective were identified. The compara-tors for this study were griseofulvin, itraconazole(continuous), itraconazole (pulse), terbinafine andfluconazole. Ketoconazole was not included; it isnow rarely used for the treatment of pedal onycho-mycosis because of the potential risk of hepatitis,especially with long term use of this agent. Theduration of treatment for onychomycosis of the toe-nails was griseofulvin (18 months), itraconazole(continuous treatment for 3 months), itraconazole(pulse treatment for 3 months), terbinafine (3months) and fluconazole (6 months). Evaluationfor efficacy was performed at follow-up 18 monthsafter starting treatment with griseofulvin. For thenewer antifungal agents, itraconazole (continuousor pulse), terbinafine and fluconazole, the corres-ponding time point was 12 months.

A time horizon for the study of 3 years was cho-sen, so that it would be possible to administer 1course of treatment with griseofulvin followed bya sufficient period for assessment and treatment ofrelapses. The study was performed from the per-spective of a third-party payer.

Step II: Drug and Resource Use

A treatment algorithm for the management ofonychomycosis of the toenails (fig. 1) was devel-oped, following discussion with 5 dermatologistswho have a special interest in mycology and whopractice in various parts of the US. The primarymeasures of efficacy of treatment were either my-cological cure (negative light microscopic exami-nation for fungal filaments following treatment of

244 Gupta

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the sample with potassium hydroxide and negativeculture) or failure.

In this algorithm, patients who either relapsed(recurrence of onychomycosis following mycolo-gical cure achieved at some point during therapy)after completing a course of griseofulvin therapy,or those who failed treatment with this drug, wereoffered a choice of either itraconazole (pulse) orterbinafine therapy. Information obtained duringdiscussion with the 5 dermatologists suggested thata patient would stand an equal chance of receivingeither of these 2 newer antifungal agents. In theevent that a patient did not respond to griseofulvintherapy followed by 2 subsequent courses of ther-apy with the newer antifungal agents [either itra-conazole (pulse) or terbinafine], nail avulsion wasperformed.

In the decision-analytical model, patients whorelapsed or failed after receiving either itra-conazole (pulse) or terbinafine as initial therapywere given a second course of treatment with thesame primary agent (fig. 1). It was felt that in themajority of patients, there would be sufficient cli-nical improvement after the initial course of treat-ment to justify a second course of therapy with thesame primary agent. If the patient failed a secondcourse of the initial therapy, patients who initiallyreceived terbinafine were administered itracona-zole (pulse) and vice versa. Failures or relapsesoccurring at follow-up after taking 3 courses of anycombination of itraconazole or terbinafine led tonail avulsion.

In the treatment algorithm, a second course ofitraconazole (continuous) therapy was adminis-tered to patients who relapsed or failed followingitraconazole (continuous) therapy. A subsequentfailure or relapse was managed with terbinafinetherapy. Again, nail avulsion was offered to a pa-tient who failed or relapsed following itraconazole(continuous) therapy on 2 occasions and subse-quent terbinafine (i.e. 3 courses of oral antifungaltherapy).

Patients who relapsed or failed following initialtherapy with fluconazole were offered a secondcourse of fluconazole. Subsequent failures were

treated with either itraconazole (pulse) or terbina-fine; the treatment algorithm assumed that eachdrug would be received by 50% of the patients.Failure with 3 courses of medical therapy [fluco-nazole on 2 occasions followed by either itra-conazole (pulse) or terbinafine] led to nail avul-sion.

Step III: Meta-Analysis

The efficacy rates of the comparators used in thetreatment of dermatophyte onychomycosis of toe-nails were determined using meta-analysis. AMEDLINE/EMBASE literature search datingfrom 1966 to February 1997 was performed forEnglish language publications on the use of thedrug comparators, griseofulvin, itraconazole (con-tinuous and pulse), terbinafine and fluconazole, inthe treatment of onychomycosis. The referencesection of these papers was scanned to ensure thatall relevant articles had been captured. Studies re-porting on topical therapies or the use of avulsion(chemical or surgical) for the management of ony-chomycosis were not included in the analysis.

The criteria for inclusion of prospective studiesin the meta-analysis evaluating mycological curerates were: (i) onychomycosis should be diagnosedon the basis of both clinical and mycological eval-uation; (ii) the aetiological organism should beidentified (at least with dermatophytes separatedfrom nondermatophytes); (iii) the duration of ther-apy should be longer than 6 months for griseo-fulvin, 3 months for itraconazole (continuous), 3pulses over 7 weeks for itraconazole (pulse), 3months for terbinafine and 6 months or longer forfluconazole; (iv) the dosage of the antifungal agentwas griseofulvin �500 mg/day, itraconazole (con-tinuous) 200 mg/day, itraconazole (pulse) 200mg/day twice daily for 1 week each month, ter-binafine 250 mg/day and fluconazole 300 mg/dayonce weekly; (v) the end-point terms, for example,‘cure’ and ‘response’, should be clearly stated; (vi)the site of infection (toenails or fingernails) shouldbe indicated (only onychomycosis of the toenailswas considered for this analysis); (vii) the numberof patients evaluated for efficacy measurements

Dermatophyte Onychomycosis of the Toenails 245


246 Gupta

© Adis International Limited. All rights reserved. Pharmacoeconomics 1998 Feb; 13 (2)

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must be clearly stated; (viii) there should be 10 ormore patients evaluated in the report; (ix) no oralantifungal therapy other than the primary drugshould be administered during the trial; (x) the pa-tients studied should be immunocompetent indi-viduals; and (xi) for the newer antifungal agents,itraconazole (continuous or pulse) and terbinafine,only the response rates pertaining to a minimum6-month follow-up period were used.

While double-blind and controlled studies werepreferred, because of the paucity of such studies,open and uncontrolled trials were also consideredif they met the criteria outlined above.

In the case of fluconazole, the preferred sched-ule in the US may be 300mg once weekly for 6months. The mycological cure rate from a multi-centre study conducted in the US using this regi-men was used for the pharmacoeconomic evalua-tion.

In this analysis, mycological cure (negativelight microscopy for fungal filaments and negativeculture) was chosen to be the measure of efficacyof therapy. Compared with clinical cure, the myco-logical cure rate may be a more objective methodof evaluating the efficacy of an antifungal agent.This measure was also used by Marchetti et al.[9]

in their analysis. In order to obtain accurate effi-cacy rates for the various comparator drugs, studiesthat did not follow the guidelines indicated abovefor the dosage schedule (duration of therapy anddosage) were not considered for the meta-analysis.

For each comparator drug, the data were com-bined using the method based on that of DerSimon-ian and Laird,[12] and modified by Velanovich[13]

for single-group analysis. This method produces asample-size weighted average value for each effi-cacy rate and for all drug comparators. A 95% con-fidence interval [mean � 1.96 standard error (SE)]was calculated from the value derived for the SE.

Step IV: Base-Case Analysis

For each of the comparators, the cost of the regi-men was the sum of the drug acquisition cost, medi-cal-management cost and the cost of managing ad-verse effects pertaining to the use of the particular

antifungal agent. The drug acquisition cost for eachantimycotic was determined according to the rec-ommended dosage schedule for that agent and theaverage wholesale price.[14]

Medical ManagementThe cost of medical management was divided

into charges for performing the initial consul-tation,[15] return visits, mycology (light micro-scopic examination only) and other laboratory tests[complete blood count (CBC) with platelets, andliver function tests (LFTs)].[16] The frequency withwhich the laboratory tests were conducted for eachoral antifungal agent was determined followingdiscussion with the panel of dermatologists. Forgriseofulvin and fluconazole, a return visit wasscheduled every 3 months; with itraconazole (con-tinuous) and terbinafine, return visits occurred ev-ery 6 weeks and patients on itraconazole (pulse)returned following 2 pulses of therapy. For eachpatient, mycology (light microscopic examinationonly) was performed before initiating therapy. Itwas recognised that most physicians in the US donot perform nail culture, whatever the reason.

After discussion with the panel, a conservativeapproach was taken when considering the fre-quency of monitoring. Patients receiving griseo-fulvin had a baseline CBC and LFTs, with a repeatevery 3 months while receiving therapy. Thoseplaced on fluconazole had LFTs repeated after 3months. Patients receiving itraconazole therapyhad baseline LFTs and a repeat after 6 weeks ofcontinuous administration or after 2 pulses of ther-apy. With terbinafine, CBC and LFTs were per-formed at baseline and after 4 to 6 weeks of ther-apy. For all drug comparators, the panel took theconservative approach and recommended ‘exit lab-oratory monitoring’ at the completion of therapy.

Adverse EffectsThe cost of managing adverse effects was deter-

mined with the help of the panel. For each compa-rator, a representative profile was used: in the caseof itraconazole (continuous) and terbinafine, theappropriate section from the US product mono-graphs on adverse effects requiring either tempo-rary or permanent discontinuation from the study



was consulted.[17,18] For griseofulvin, a represen-tative study was identified[19] and in the case ofitraconazole (pulse) therapy, the adverse effects re-sulting in permanent discontinuation from US con-trolled trials on pedal onychomycosis was used(data on file, Janssen). In the case of fluconazole,there are no published adverse-effect data pertain-ing to the dosage of 300mg once weekly. There-fore, the adverse-effect profile from a represen-tative study using the dosage of 150mg onceweekly was considered instead.[20]

All adverse effects requiring temporary or per-manent discontinuation of therapy were managedwith an additional visit to the dermatologist. Pa-tients paid for over-the-counter medications. Ele-vated LFTs during therapy were managed with anadditional set of liver enzyme levels; abnormalhaematological parameters required an additionalCBC and a visit to a haematologist in 50% of cases.Visual disturbances resulting in discontinuation oftherapy were referred to a specialist.

Relapse RatesThe relapse rate for an antifungal agent is a func-

tion of the duration of time elapsed since startingtherapy. Relapse rates in the literature for the dif-ferent comparators have been reported at varioustime-points, often in patient samples from which asubstantial portion of the original population hasbeen lost to follow-up.

For griseofulvin, it was decided to use the re-lapse rate reported by Villars and Jones[21] as beingrepresentative. For itraconazole (continuous) andterbinafine therapies, the relapse rates given in theUS product monographs were used.[17,18] Foritraconazole (pulse) therapy, the relapse rate is10.4%, based on worldwide data.[22] However, wedecided to be conservative and use the same relapserate as used for itraconazole (continuous) therapy,which was 21%. The cost effectiveness of pulsetherapy with a relapse rate of 10.4% was exploredin the sensitivity analysis. For fluconazole, the re-lapse rate of 4.8% from the study using 300mgonce weekly to treat toenail onychomycosis wasincorporated into the analysis.[23]

Cost EffectivenessThe expected cost of therapy was calculated

based on the decision-analytical model and theprobabilities of mycological cure, failure and re-lapse. For all comparators, the cumulative prob-ability of each branch of the decision-analyticalmodel tree was calculated. This information, aswell as the cost pertaining to that branch, enabledthe expected cost of therapy to be calculated foreach comparator.

A cost-effectiveness analysis was then per-formed. Expected costs and cure rates were deter-mined for each comparator. Furthermore, as an ag-gregated measure of cures, failures, relapses andtime on therapy, the number of symptom-free days(SFDs) was determined. Following successfulcompletion of therapy, it was assumed that the pa-tient would not experience any symptoms unless arelapse occurred. The expected number of SFDswas determined for each drug comparator. This en-abled the cost per SFD to be calculated. The rela-tive cost-effectiveness ratios for the comparatordrugs were computed, with the therapy having thelowest cost per SFD being assigned a value of 1.

Step V: Sensitivity Analysis

A sensitivity analysis was performed, in whichthe values of key parameters were varied throughrelevant ranges. The parameters that were exam-ined included efficacy (mycological cure, clinicalresponse and relapse rates), drug acquisition costand duration of therapy. For each parameter, therange of values over which the analysis was stablewas determined. Threshold values corresponded topoints at which there was a change in the rank ofcost effectiveness with the nearest comparator.[24]

Results

Meta-Analysis

Of the studies evaluated for possible inclusionin the meta-analysis, only those meeting the criteriaset for inclusion are listed in table I. For each ac-cepted study, the type of study, regimen used andduration of therapy are indicated.

248 Gupta


Table I. Relevant studies used in the meta-analysis to determine cure and relapse rates

Study Type of study Dosage (mg/day) Duration Mycological cure rate(%)

Griseofulvina

Davies et al.[25] Open 1000 24 months 9/31 (29)

Russell et al.[26] Open 1500 12 months 3/11 (27.2)

Svejgaard[27] Open-controlled 500-1000 30 months 0/7 (0)

Korting et al.[28] Open-controlled 660 (ultra microsize) 18 months 2/36 (5.6)

990 (ultra microsize) 18 months 2/36 (5.6)

Walsøe et al.[29] Double-blind comparative 500 6 months 0/10 (0)

Arenas et al.[30] Open, comparative randomised 500 6 months 5/15 (33.3)

Faergemann et al.[19] Double-blind parallel-group 500 12 months 19/41 (46.3)

Hofmann et al.[31] Randomised double-blind 1000 12 months 59/72 (81.9)

Itraconazole (continuous)b

Williemsen et al.[45] Open 200 3 months 15/19 (78.9)

Haneke et al.[46] Open 200 3 months 147/188 (78.2)

De Backer et al.[47] Randomised double-blind 200 3 months 77/168 (45.8)

Brautigam et al.[48] Randomised double-blind 200 3 months 53/84 (63.1)

Arenas et al.[49] Open comparative 200 3 months 22/23 (95.7)

Odom et al.[50] Placebo-controlled 200 3 months 18/38 (47.4)

Jones et al.[51] Double-blind placebo-controlled 200 3 months 24/35 (68.6)

Havu et al.[52] Double-blind parallel-group 200 3 months 41/62 (66.1)

US Product monograph[17] Double-blind placebo-controlled 200 3 months 59/110 (53.6)

Itraconazole (pulse)c

De Doncker et al.[62] Open 400 � 1 week 3 pulses 5/5 (100)

De Doncker et al.[8] Open 400 � 1 week 3 pulses 16/25 (64)

Havu et al.[52] Double-blind parallel-group 400 � 1 week 3 pulses 41/59 (69.5)

Gupta et al.[63] Placebo-controlled 400 � 1 week 3 pulses 48/78 (61.5)

Bonifaz et al.[64] Open 400 � 1 week 3 pulses 41/50 (82)

Terbinafined

Goodfield et al.[67] Double-blind placebo-controlled 250 3 months 37/45 (82.2)

VanDer Schroef et al.[68] Open 250 3 months 24/34 (70.6)

Galimberti et al.[69] Open 250 3 months 19/22 (86.4)

Arenas et al.[49] Open comparative 250 3 months 17/17 (100)

Bräutigam et al.[48] Double-blind comparative 250 3 months 70/86 (81.4)

De Backer et al.[47] Double-blind comparative 250 3 months 119/163 (73)

Watson et al.[70] Double-blind placebo-controlled 250 3 months 33/56 (58.9)

US Product monograph[18] Double-blind placebo-controlled 250 3 months 99/141 (70.2)

Svejgaard et al.[71] Double-blind placebo-controlled 250 3 months 19/48 (39.6)

a 13 reports[32-44] were partly or entirely excluded for 1 or more of the following reasons: (i) unable to extract mycological cure rate;(ii) less than 6 months of therapy (inadequate length of treatment); (iii) fewer than 10 patients; or (iv) evaluation of fingernails only.

b 10 reports[30,53-61] were partly or entirely excluded for 1 or more of the following reasons: (i) dosage was less than 200 mg/day for part ofor the complete duration of therapy; (ii) treatment continued for longer than 3 months; (iii) studies had fewer than 10 patients; (iv) datainvolved fingernails only; or (v) Candida species or other nondermatophytes were evaluated.

c Two reports[60,66] were partly or entirely excluded for 1 or more of the following reasons: (i) nondermatophytes evaluated; or (ii) durationof therapy not 3 pulses.

d 19 reports[18,44,66,72-87] were partly or entirely excluded because of 1 or more of the following reasons: (i) duration of treatment is longerthan 3 months; (ii) dosage not equal to 250 mg/day; (iii) fewer than 10 patients; (iv) fingernails evaluated; (v) evaluation of non-dermatophytes; or (vi) possibly immunocompromised population.

Abbreviations: CI = confidence interval; SE = standard error.



The pharmacoeconomic analysis in this paperused the mycological cure rates of the comparatordrugs. Itraconazole (pulse) and terbinafine thera-pies had similar mycological cure rates. Griseo-fulvin had the lowest mycological cure rate (tableII). In dermatophyte onychomycosis of the toe-nails, fluconazole (300mg given once weekly untilcure, assumed to be on average 6 months) achieveda mycological cure rate of 59%.[23]

Pharmacoeconomic Analysis

Cost-of-Regimen AnalysisThe cost-of-regimen analysis incorporated drug

acquisition costs (table III), the cost of managingadverse effects (table IV) and the cost of medicalmanagement (table V).

Itraconazole (pulse) therapy had a cost of regi-men that was similar to terbinafine, and these 2regimens were less expensive than the other com-parators (table VI).

Cost-Effectiveness AnalysisThe 2 drugs with the lowest expected cost per

patient were itraconazole (pulse) at $US1182 andterbinafine at $US1211 (table VII). The cost permycological cure for itraconazole (pulse) and ter-binafine therapies was $US991 and $US1125, re-spectively, lower than the values for the other com-parators.

The cost per SFD was essentially similar forboth itraconazole (pulse): $US1.26 and terbinafine$US1.28 (table VII). The cost effectiveness of ter-binafine relative to itraconazole (pulse) [1.00] was1.02. Griseofulvin was the most expensive of thecomparators, with a relative cost effectiveness toitraconazole (pulse) of 5.62.

Sensitivity AnalysisThe sensitivity analysis (table VIII) indicates

that the rank order for itraconazole (pulse) and ter-binafine therapies changes with minor variations inmycological cure, clinical response and relapserates; in other words, the 2 agents appear to beequivalent. In the case of fluconazole, the pharma-coeconomic evaluation is of a preliminary naturebecause the drug has not been formally approvedby the FDA, with no official recommendations re-garding dosage regimen, duration of therapy anddrug acquisition cost. The sensitivity analysis con-firms that griseofulvin has been superseded by thenewer antifungal agents as more cost effectivetreatments for onychomycosis of the toenailscaused by dermatophytes.

The worldwide data indicate that the relapse rateof itraconazole (pulse) therapy 1 year after the startof therapy is 10.4%.[22] When this relapse rate was

Table II. Mycological cure and relapse rates of oral antifungalagents used to treat dermatophyte onychomycosis of the toenails

Agent Mycological cure rate (%) Relapserate (%)mean � SE 95% CI

Griseofulvin 24.5 � 6.7 11.3-37.7 40[21]

Itraconazole:

continuous 66.4 � 6.1 54.4-78.4 21[17]

pulse 76.0 � 9.3 57.8-94.2 21a

Terbinafine 74.0 � 7.0 60.2-87.7 15[18]

Fluconazole 59 NA 4.8[23]

a Conservatively assumed rate.

Abbreviations: CI = confidence interval; NA = not applicable;SE = standard error.

Table III. Drug acquisition costs ($US; 1997 values)

Drug Regimen Average wholesaleprice/unit ($US)

Number of tablets Drug acquisitioncost ($US)

Griseofulvin 500mg twice daily � 18 months 1.20/500mg tablet 1095 1314.00

Itraconazole

continuous 200 mg/day � 3 months 5.82/100mg tablet 168 977.76

pulse 400 mg/day � 1 week � 3 pulses 5.82/100mg tablet 84 488.90

Terbinafine 250 mg/day � 3 months 6.22/250mg tablet 84 522.50

Fluconazolea 300 mg/week � 6 months 10.63/150mg tablet 52 (150mg size) 552.76

a It is possible that the recommended dosage in the US will be different from 300mg once weekly. Also, in the US, the cost of the 300mgtablet may not be twice the current price of the 150mg tablet.

250 Gupta


used in place of the value of 21% [relapse rate ofitraconazole (continuous) therapy], the expectedcost per patient and number of SFDs foritraconazole (pulse) therapy were $US1091 and953, respectively. The corresponding values forterbinafine therapy were $US1210 and 945. Thecost per SFD for itraconazole (pulse) and terbina-fine thus became $US1.15 and $US1.28, respec-tively, making itraconazole (pulse) therapy themost cost-effective treatment; in this situation, the

relative cost effectiveness for terbinafine was 1.12.The corresponding values for griseofulvin,itraconazole (continuous) and fluconazole were6.06, 1.90 and 1.85, respectively.

Discussion

This pharmacoeconomic analysis indicates thatthe most cost-effective therapies for the treatmentof dermatophyte onychomycosis of the toenails areitraconazole (pulse) and terbinafine. It is clear that

Table IV. Number (expressed as a % of total) of patients who withdrew from the study (either temporarily or permanently) because of adverseeffects

Adverse effect Griseofulvin[19]

(n = 45)Itraconazole Terbinafine[9,18]

(n = 465)Fluconazole[20]b

(n = 73)continuous(n = 112)[17]

pulse(n = 171)[22]a

General disorder 1.2

Gastrointestinal 3.3 4 1.7 1.4

Nausea 0.6 0.2

Elevated liver function tests 4 0.6 0.2

Rash and other dermatological symptoms 3 2.9 1.1

Urticaria 2.2

Vasculitis 1

Headache 1.1 1 0.6 0.2

Malaise 1

Vertigo 1

Myalgia 1

Hypertension 2

Moderate neutropenia 1.7

Orthostatic hypotension 1

Dependent oedema 0.6

Dyspnoea 0.6

Taste disturbance 0.2

Visual disturbance 0.9

a Also data on file with Janssen Pharmaceutica.

b No adverse events were reported in the study.

Table V. Cost ($US; 1997 values) of medical management using oral antifungal agents for the treatment of dermatophyte onychomycosis ofthe toenails

Item Cost ($US) Number of uses

griseofulvin itraconazole terbinafine fluconazole

continuous pulse

Initial consultation 54 1 1 1 1 1

Return visit 29 6 2 2 2 3

Mycology 11 1 1 1 1 1

Liver function tests 46 7 3 3 3 4

Complete blood count + platelets 15 7 0 0 3 0

Total cost ($US) 666 261 261 306 336



griseofulvin is relatively ineffective in treating toe-nail onychomycosis, requires of a long duration oftherapy and has the highest total drug acquisitioncost. This results in the drug being less cost effec-tive than the newer antifungal agents. The poor costeffectiveness of griseofulvin has been reported byother investigators.[9,10,88,89]

In the US, many physicians still treat onycho-mycosis of the toes with griseofulvin for a varietyof reasons, including lack of familiarity with thenewer antifungal agents, or because healthcare pro-viders mistakenly feel that griseofulvin is morecost effective than the newer antifungal agents. Thedata suggest that there is need for more educationon the appropriate choice of antifungal agent.

Pharmacoeconomic analyses merely provideguidelines that may aid healthcare providers andpatients in deciding which agent to use for the man-agement of medical conditions, such as onychomy-cosis. In the majority of cases in the US, the diag-

nosis of onychomycosis is not confirmed prior toinitiating therapy. Although dermatophytes mayaccount for approximately 90% of the organismsimplicated in pedal onychomycosis,[90] it may beprudent to choose an antifungal agent that has awide spectrum of action in vivo, thereby maximi-sing the probability of a successful outcome, what-ever the aetiological organism.

The results of our analysis are similar to thoseof Van Doorslaer et al.[11] The pharmacoeconomicanalyses by Arikian et al.[10] and Marchetti et al.[9]

were performed when there were very few publish-ed studies on itraconazole (pulse) therapy for ony-chomycosis. The relative lack of data on itraco-nazole (pulse) therapy was recognised by theseinvestigators,[9,10] and it placed them at a disadvan-tage when trying to calculate rates of success andfailure with itraconazole (pulse) therapy usingmeta-analysis of available studies. Einarson etal.[88] did not use itraconazole as a comparator and

Table VI. Cost-of-regimen analysis ($US; 1997 values)

Cost item Griseofulvin Itraconazole Terbinafine Fluconazole

continuous pulse

Drug acquisition 1314.00 977.80 488.90 522.50 552.76

Medical management 666.00 261.00 261.00 306.00 336.00

Adverse effect management 1.90 7.30 3.00 3.70 0

Total cost of regimen 1981.90 1246.10 752.90 832.20 888.76

Table VII. Summary of pharmacoeconomic analysis (all costs are in $US; 1997 values)

Cost factor Griseofulvin Itraconazole Terbinafine Fluconazole

continuous pulse

Total cost of regimen ($US) 1981.90 1246.10 752.90 832.20 888.80

Mycological cure rate 0.245 0.664 0.76 0.740 0.59

Cost ($US)/mycological cure rate 8089 1877 991 1125 1506

Expected cost per patient ($US) 2880 2022 1182 1211 1443

Expected number of SFDs 408 929 942 945 680

Cost effectiveness (CE):a

cost per SFD 7.05 2.18 1.26 1.28 2.12

relative CEb 5.62 1.73 1.00 1.02 1.69

incremental (marginal) CE ratio ($US/SFD)c

Dominated byitraconazole (pulse)and terbinafine

Dominated byitraconazole (pulse)and terbinafine

9.67 Dominated byitraconazole (pulse)and terbinafine

a Calculated using expected cost per patient.

b Compared with itraconazole (pulse) therapy.

c Dominated indicates a higher expected cost, lower cure rate and fewer SFDs.

Abbreviation: SFD = symptom-free day.

252 Gupta


Arikian et al.[10] combined data for itraconazole(continuous) and (pulse) therapies. Marchetti etal.[9] did not perform a meta-analysis on efficacydata pertaining to itraconazole (pulse) therapy;these authors discussed pulse therapy as part oftheir sensitivity analysis only.[9] As further pla-cebo-controlled and comparative studies are pub-lished, meta-analysis will be able to provide uswith more precise rates of success and failure.

In the present analysis, several factors pre-vented accurate comparison of the various studieson the treatment of onychomycosis with antifungalagents. Sometimes, the criteria for inclusion of pa-tients into the study were not explicitly stated. Arange of criteria were used to measure efficacy oftherapy, including: area of nail plate clinically in-volved; length of outgrowth of unaffected nail;number of infected nails; degree of hyperkeratosis,onycholysis and leukonychia; thickness of the nail;and degree of pruritus. Unpublished observationsby Gupta and Shear indicate inconsistencies in thereporting criteria associated with the various stud-

ies. An adoption of uniform criteria for reportingthe efficacy of treatment with the various antifun-gal agents will enable a more rational and accurateassessment of the different treatment protocols.Similarly, the assessment of relapse rates is diffi-cult based on the published data. It is recognisedthat there will be an increasing number of patientsfrom the original group evaluated at the end of thestudy who will become lost to follow-up. This re-duces the accuracy of relapse rates reported for thatcohort of patients.

In this study, the 2 most cost-effective agents fortreating dermatophyte onychomycosis of the toe-nails were itraconazole (pulse) and terbinafine.Since they have a similar cost effectiveness fordermatophytoses, we must look at other differ-ences between the agents that may influence thedecision to prescribe one drug over the other.

The rational use of the pharmacokinetic andpharmacodynamic properties of itraconazole hasenabled its widespread use as pulse therapy. Afterdiscontinuation of itraconazole (1-week pulse)

Table VIII. Sensitivity analysis. The rank order of the drugs, in terms of their cost effectiveness in the base-case analysis, is shown in eachcategory. The lower and upper limits indicate the range of values outside which a change in the rank order of the drugs would occur. Lowerlimit: for A and B, a value lower than this would result in a decrease of one place in the relative rank order of this treatment (i.e. less costeffective); for C, D and E, a value lower than this would result in an increase of one place in the rank order of this treatment (i.e. more costeffective). Upper limit: for A and B, a value higher than this would result in an increase of one place in the rank order of this treatment (i.e.more cost effective); for C, D and E, a value higher than this would result in a decrease of one place in the rank order of that treatment (i.e.less cost effective). Data for fluconazole, itraconazole (continuous) and griseofluvin not shown

Category and drug Lower limit Actual value Upper limit 95% CI

A. Mycological cure rate (%)1. Itraconazole (pulse) 74.0 76.0 57.8-94.2

2. Terbinafine 17.5 74.0 76.5 60.2-87.7

B. Clinical response (%)1. Itraconazole (pulse) 75.5 80.6 75.3-85.9

2. Terbinafine 50.5 75.7 82.0 70.8-80.7

C. Relapse rate (%)1. Itraconazole (pulse) 21 23.0

2. Terbinafine 12.0 15 >100.0

D. Drug acquisition cost for course of therapy ($US) [price per tablet in parentheses]1. Itraconazole (pulse) 488.90 (5.82) 504.00 (6.00)

2. Terbinafine 504 (6) 522.50 (6.22) 1100.40 (13.10)

E. Number of tablets (duration of treatment)1. Itraconazole (pulse) 84 (21 days) 87.0 (21.75 days)

2. Terbinafine 81 (81 days) 84 (84 days) 177.0 (177 days)

Abbreviation: CI = confidence interval.



therapy, plasma drug levels fall to almost undetect-able levels within 7 days.[91] However, in the toe-nail, itraconazole levels continue to increase be-tween successive pulses, with therapeutic levelsbeing achieved by the completion of 3 pulses oftherapy.[8] In contrast to other comparator drugs,patients receiving itraconazole (pulse) therapy mayexperience reduced systemic exposure to the drug.It is therefore important to carefully evaluate thetolerability profiles of the available antifungalagents. In general, however, the newer antifungalsare very well tolerated.

The potential for drug interactions can also in-fluence the choice of therapy. An advantage of ter-binafine may be fewer reported drug interactions.However, with itraconazole, in some instances, itmay be possible to replace the potentially interact-ing drug with a suitable alternative; for example,the antihistamines cetirizine, fexofenadine orhydroxyzine could be used in place of astemizoleor terfenadine.

Compliance with therapy is an issue that was notfactored into the pharmacoeconomic analysis,given the lack of data on the compliance with thedifferent drug comparators. It is recognised that asthe duration of therapy increases, there is likely tobe a reduction in compliance, resulting in lowersuccess rates. In this study, 100% compliance wasassumed for all the drug comparators; this is leastlikely to be true for griseofulvin. Patient prefer-ences for pulse or continuous therapy may influ-ence the choice of therapy.

Conclusion

The availability of the newer antifungal agentshas resulted in griseofulvin being superseded in thetreatment of dermatophyte onychomycosis of thetoenails. In the present analysis, itraconazole(pulse) and terbinafine had similar cost effective-ness and were the 2 most cost-effective therapiesfor the management of dermatophyte onychomy-cosis of the toenails.

Acknowledgements

The study was supported in part by an educational grantprovided by Janssen Pharmaceutica, Inc.

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Correspondence and reprints: Dr Aditya Gupta, 490 Won-derland Road South, Suite 6, London, Ontario N6K 1L6,Canada.E-mail: [email protected]

256 Gupta


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Pharmacoeconomic Analysis of Oral Antifungal Therapies Used to Treat Dermatophyte Onychomycosis of the Toenails