Ciinical trial

Itraconazole in onychomycosis: intermittent dose schedule

Alexandro Bonifaz, MB, Eugenio Carrasco-Gerard, MD, MSC, and Amado Saul, MD

From the Dermatology Service,Department of Mycology, GeneralHospital of Mexico, iVIexico

CorrespondenceA. Bonifaz, MDZempoaia 60-101NarvarteMexico D.F. C.P. 03020

Drug namesfamotidine: Pepcidfluconazole: Diflucanifraconazoie: Sporanox

Fifty (13 men and 37 women) consecutive patients, attending the Dermatology

Department of the Generai Hospitai of Mexico, with mycoiogicaiiy proven onychomycosis

of the finger and toenails were included in an open clinical trial. These patients received a

pulse regimen of itraconazoie (200 mg twice daiiy) given after meais during the first week

of each month, for 3 consecutive months. After the last dose, the drug was discontinued,

and patients were foliowed-up for 9 months.

Initially, the patients underwent a clinical and fungal evaluation. The study included

those with positive potassium hydroxide (KOH) preparation and mycologic cultures, who

had not been treated either with a systemic antifungal agent for a period of 3 months prior

to the study or with a topical agent for a 1-month period prior to the study. Complete

blood count and liver test functions that included transaminase, total bilirubin, alkaline

phosphatase, and lactic dehydrogenase were carried out at the beginning of the study,

after the first half of the study (second pulse), and 2 weeks after completion of treatment.

Exclusion criteria were pregnant or lactating women, patients receiving antimycotic

treatment during the 3 previous months or patients under treatment for gastric : .

hyperacidity.

Three mycologic examinations were carried out: before starting treatment in order to

identify the fungal species; after the third pulse; and 3, 6, and 9 months after the last drug

administration. The effectiveness of the drug was evaluated based on Zaias' method^ to

estimate the reduction of the affected area.

A 400 mg/day dose of oral itraconazole was administered in two takes; 200 mg after

breakfast and 200 mg after dinner for 1 week (first pulse). The drug was discontinued for

a 3-week period and this regimen was applied twice. This meant that only three treatment

periods or pulses were carried out. Follow-up visits were scheduled at 6 months after

completion of treatment for handnaiis and 9 months for toenails.

At the end of the study, a correlation between clinical-mycologic outcome and liver

function tests were carried out to assess the effectiveness and safety of the proposed

treatment regimen.

70

Results

Of the 50 patients treated, 37 were women and 13 men.The youngest was 19 years old and the oldest was 67,with an average age of 32.1 years. Forty-two cases hadonychomycosis of toenails, seven of fingernails, and onewith both. The average number of involved nails was 4.3The shortest disease period was 6 months and the longestwas 26 years, with an average of 11.6 years. Tinea pediswas observed in most cases (42 patients).

The cases studied were classified according to the follow-ing clinical varieties: 37 distal subungual onychomycosis(DSO), four proximal subungual onychomycosis (PSO),and three paronychia, which corresponded to Candida spp.

The etiology before the study was as follows: 44 cases(88%) had Trichophyton rubrum, two cases (4%) hadTrichophyton mentagrophytes, three (6%) had Candidaalbicans, and one (2%) had Candida parapsilosis. Of thecases due to Candida spp., three occurred in fingernails.

According to the mycologic evaluation at the end of thestudy, 41 cases (82%) were negative, three (6%) hadpositive KOH examination, and six (12%) had both posit-ive KOH examination and positive culture (Table i andFig. i). - . ,

Of the cultures that were positive at the end of the study,five were T. rubrum and one T. mentagrophytes.

© 1997 Blackwell Science Ltd

Bonifaz, Carrasco-Gerard, and Saul Itraconazole in onychomycosis Clinical trial 71

60

50

4 0 • "•• ' ••""•• . ; , ,

30

20

10

Initial After 3rcl pulse 6th month 9th

KOHCulture

5050

3826

— K

2514

OH 1- Culture

• - — - -

month

128

12th month

:

Figure 1 Course of the mycologic results: KOH and cultures

Table 1 Results of the study

Evaluation Group Group Groupfailures improvement success

Number of patients (n) 5 4 41Average of residual ungual 16.5 mm 5.1mm 0 mmafection grade, Zaias' metiiod'Rates 10% 8% 82%

Adverse events were reported by five patients (TO%);

four of tbem had gastric discomfort, but none discontinuedtbe treatment. One patient showed alteration of totalbilirubin values: the initial value was 0.22 units (u); afterthe second pulse it was 0.51 u and after the last dose0.20 u. All complete blood counts were witbin tbe normalranges before, during atid after treatment.

Discussion

Tbe results of tbe effectiveness of our trial with three pulsesof itraconazole were good, with an 8z% cure rate. These

data are similar to the cure rates reported by otber studies,particularly wben itraconazole is given at 200 mg/day for3 montbs. Cure rates reported by different autbors rangefrom 75% to 89%.^'' Tbis intermittent or pulse treatmentregimen results from tbe properties of itraconazole, wbichinclude easy access to the ungual bed and matrix, its"reservoir" effect, the long periods during which the MICsare maintained as a result of high doses, and finally, itslow side-effect profile"*'' (Fig. 2).

Tbe quickest response to treatment was observed inonycbomycosis caused by C. alhicans and C. parapsilopsis,not only because of tbeir susceptibility to itraconazole, butalso because most of them occurred in handnails.^ Of thenine failures (18%), eight were DSO and one PSO; however,only five had positive cultures; T. rubrum was identified infour of them and T. mentagrophytes in one. The finalevaluation included a group considered as having had"improvement," even though at the end of the study theyhad a positive KOH and only one of tbem also bad apositive culture. We should note that in all of these patientsa reduction of the involved area was observed (usitig theZaias' method') with an average of 5.1 mm (see Table i).

Despite the fact that the objective of tbis paper was nottbe evaluation of itraconazole in the treatment of tineapedis, 42 patients had this condition. Thirty-nine patientsdid not have either positive KOH or positive culture whenthey started the second pulse, indicating that most of themneeded otily 1 week of treatment at 400 mg/day; this hadalready been reported in tbe literature.'' Tbe remainingtbree patients had hyperkeratotic tinea pedis and werecured after the second pulse of itraconazole. It is importantto eAipliasize the association witb tinea pedis, because it

•easily results in nail reinfection.Tbe pulse administration system may be considered as

safe, because only 10% of patients reported side-effects.Most of tbem bad gastric discomfort, wbicb was reducedby giving the drug with milk. Because itraconazole is alipophilic derivative, it should always be adtninistered aftermeals for better absorption and less side-effects.̂ Onepatient bad an alteration of total bilirubin figures tbat was

Figure 2 (a) Before treatment; (b) after third pulse; (c) after 9 months

International Journal of Dermatology 1997, 36, 70-72

72 Clinical triai Itraconazole in onychomycosis Bonifaz, Carrasco-Gerard, and Saui

not considered as permanent liver damage because theremaining parameters, such as transaminase, alkaline phos-phatase, and lactic dehydrogenase, were within the normalranges. Bilirubin increased temporarily and after comple-tion of treatment it went back to baseline levels. Thistreatment regimen is not recommended for patients withgastric problems, particularly gastritis, and cannot beadministered together with H-2 blockers such as famotid-ine, because triazoles, such as fluconazole and itraconazole,result in decreased intestinal absorption.^

References

1 Zaias N, Drachman D. A method for the determinationof drug effectiveness in onychomycosis. / Am AcadDermatol 1983; 9: 912-919.

2 Hay RJ, Clayton YM, Moore MK, et al. An evaluationof itraconazole in the management of onychomycosis. BrJ Dermatol 1988; 119: 359-366.

3 Gupta AK, Sauder D, Shear NH. Antifungal agents: an

overview. Part II. / Am Acad Dermatol 1994; 30: 911-933-

4 Willemsen M, De Doncker P, Willems J, et al.Posttreatment itraconazole levels in the nail. / Am AcadDermatol 199Z; 2,6: 731-735.

5 Roseeuw D, De Doncker P. New approaches to thetreatment of onychomycosis. / Am Acad Dermatol1993; 29: ii5-"7-

6 Hay RJ, Baran R, Moore MK, et al. Candidaonychomycosis. An evaluation of the role of Candidaspecies in nail disease. Br J Dermatol 1988; 118: 47-58.

7 Dhondt A, Cauwenbergh G, De Doncker P. Short oraltherapy in difficult-to-treat tinea infections. ] Eur AcadDermatol Venereol 1992; i (SuppL): S11-14.

8 Van Peer A, Woestenborghs R, Heykants J, et al. Theeffects of the food and dose on the oral systemicavailability of itraconazole in healthy subjects. Eur JCtin Phannacot 1989; 36: 423-426.

9 Lim SG. The absorption of fluconazole and itraconazoleunder low acid conditions. XII Congress ISHAM,Adelaide, March 13-18 1994, abstract S11-4: 13.

Tattoo art by Greg Hardy of the China Sea Tattoo Studio,Honolulu, Hawaii, from the collection of Norman Goldstein, MD(dubbed the "tattoo guru" by Charles Grupper, MD, University ofParis) - The World of Tattoos, Honolulu, Hawaii.

internalionai Journai of Dermatoiogy 1997, 36, 70-72