Oravig

CLINICAL PHARMACOLOGY

Mechanism of Action

Miconazole is an antifungal drug.

Pharmacokinetics

Absorption and Distribution

Salivary

Single dose application of ORAVIG containing 50 mg of miconazole to the buccalmucosa of 18 healthy volunteers provided mean maximum salivary concentrations of15 mcg/mL at 7 hours after application of the tablet. This provided an average salivaexposure to miconazole estimated from the AUC (0-24h) of 55.23 mcg·h/mL. The pharmacokinetic parameters of miconazole in the saliva of healthy volunteers are provided in Table 4.

Table 4: Pharmacokinetic (PK) Parameters of Miconazole in Saliva FollowingApplication of a Single ORAVIG 50 mg Tablet in Healthy Volunteers (N = 18)

Salivary PK Parameters (N = 18) Mean ±SD (Min - Max)
AUC0-24h (mcg.h/mL) 55.2 ±35.1 (0.5 – 128.3)
Cmax (mcg/mL) 15.1 ±16.2 (0.5 – 64.8)
Tmax (hour) 7* (2.0 – 24.1)

In healthy volunteers, the duration of buccal adhesion was on average 15 hours following a single dose application of ORAVIG 50 mg.

Plasma

Plasma concentrations of miconazole were below the lower limit of quantification (0.4 mcg/mL) in 157/162 (97%) samples from healthy volunteers following single-doseapplication of ORAVIG 50 mg. Measurable plasma concentrations ranged from 0.5 to 0.83 mcg/mL.

Plasma concentrations of miconazole evaluated after 7 days of treatment in 40 HIV-positive patients were all below the limit of quantification (0.1 mcg/mL).

Metabolism and Excretion

Most of the absorbed miconazole is metabolized by the liver with less than 1% of theadministered dose found unchanged in urine. In healthy volunteers, the terminal half-life is 24 hours following systemic administration. There are no active metabolites of miconazole.

Food Effect

There was no formal food effect study conducted with ORAVIG; however, in clinical stud­ies patients were allowed to eat and drink while taking ORAVIG.

Microbiology

Mechanism of Action

Miconazole inhibits the enzyme cytochrome P450 14α-demethylase which leads to inhi­bition of ergosterol synthesis, an essential component of the fungal cell membrane. Miconazole also affects the synthesis of triglycerides and fatty acids and inhibits oxida­tive and peroxidative enzymes, increasing the amount of reactive oxygen species within the cell.

Activity in vitroand in vivo

Miconazole is active against Candida albicans, C. parapsilosis and C. tropicalis. Correlation between minimum inhibitory concentration (MIC) results in vitroand clinical outcome has yet to be established.

Drug Resistance

In vitro studies have shown that some Candida strains that demonstrate reduced susceptibility to one antifungal azole may also exhibit reduced susceptibility to other azoles suggesting cross-resistance.

Clinically relevant resistance to systemically utilized triazoles may occur in Candida species. Resistance may occur by multiple mechanisms such as changes in amino acidsand/or in the regulation of the target enzyme and of a variety of efflux pump proteins.Multiple mechanisms may coexist in the same isolate. Resistance breakpoints, correlating in vitroactivity with clinical efficacy, have not been established for miconazole.

Animal Toxicology and/or Pharmacology

Local tolerance studies (LLNA sensitization test and tolerance study on the jugal mucosaof hamster) did not reveal any toxicity.

Clinical Studies

Study in HIV Infected Patients

The efficacy and safety of ORAVIG in the treatment of OPC was evaluated in a randomized, double-blind, double-dummy, multicenter trial comparing ORAVIG 50 mg once dailyfor 14 consecutive days (n = 290) with clotrimazole troches 10 mg 5 times per day for14 days (n = 287) in HIV-positive patients with OPC. Seventy-five percent ofpatients were not receiving highly active antiretroviral treatment, 5% had CD4+ cellcount < 50 cells/mm³ , and 17% had a history of previous OPC. The mean viral load was 117,000 copies/mL. Patients were required to have symptoms and microbiological documentation of OPC for study entry. Most of the infections were caused by C. albicans (85%), followed by C. tropicalis (9%), and C. parapsilosis (3%). About 2% of the subjects were infected with more than one Candidaspecies.

Clinical cure [defined as a complete resolution of both signs and symptoms of OPC at thetest of cure (TOC) visit (days 17-22)], and clinical relapse by days 35-38 (21-24 daysafter end of therapy) are presented in Table 5. Mycological cure [defined as eradication (i.e., no yeast isolates) of Candidaspecies] at the TOC visit (days 17-22) is also reported in the table.

Table 5: Clinical Cure and Mycological Cure at the TOC Visit and Relapse at Days 35-38 in HIV Infected Patients

  ORAVIG 50 mg
N=287a (%)
Clotrimazole troches
N=290a (%)
Clinical cure† 176 (60.7%) 187 (65.2%)
  Clinical relapse‡    
    Yesb 48 (27.3%) 52 (27.8%)
     No 124 (70.5%) 133 (71.1%)
     Missing 4 (2.3%) 2 (1.1%)
Mycological cure 79 (27.2%) 71 (24.7%)
a Analysis population includes all randomized patients who took at least 1 dose of studymedication. One randomized subject excluded from the ORAVIG arm.
b In those subjects who relapsed, the mean time to relapse was 15.3 days (SD 4.6) and 15.7 days (SD 6.6), in the ORAVIG and Clotrimazole treatment arms, respectively.
† Difference in clinical cure rates (ORAVIG-Clotrimazole troche) was -4.5%, with a95% CI: (–12.4%, 3.4%).
‡ Percentage based on those who had clinical cure.

Study inHead and Neck Cancer Patients

The efficacy and safety of ORAVIG 50 mg was evaluated in an open-label, randomized,multicenter trial comparing ORAVIG 50 mg once daily for 14 days to miconazole oral gel125 mg four times daily for 14 days in head and neck cancer patients who had receivedradiation therapy. Most of the infections were caused by C. albicans (71%), and C. tropicalis (8%). About 7% of the subjects were infected with more than one Candida species. Success rates of treatment at day 14 [defined as a complete (complete disappearance of candidiasis lesions) or partial response (improvement by at least 2 points ofthe score for extent of oral lesion compared with the score at day 1) based on a blindassessment] are shown in Table 6. Also reported in Table 6 are relapse rate at day 30,and mycologic cure assessed at day 14.

Table 6: Clinical Success and Mycological Cure at Day 14, in Patients with Headand Neck Cancer who had Received Radiation Therapy

  ORAVIG 50 mg
N=146a (%)
Miconazole oral gel
N=148a (%)
Success rate (CR+PR)b 79 (53.4%) 69 (46.6%)
CR † 74 (50.0%) 64 (43.8%)
  Clinical relapse‡    
    Yesc 14 (18.9%) 8 (12.5%)
    No 59 (79.7%) 56 (87.5%)
    Missing 1(1.4%) 0
Mycological cure 66 (44.6%) 78 (53.4%)
aAnalysis population includes all subjects who received at least one dose of study medication. Reasons for not receiving treatment included negative mycological culture, informed consent withdrawn, or lost during screening. Six patients excluded per arm.
bCR: complete response; PR: partial response
c In those subjects who relapsed, the mean time to relapse was 18.8 days (SD 16.3) and 20.6 days (SD 13.5), in the ORAVIG and Miconazole oral gel group, respectively.
† Difference in clinical complete response rates (ORAVIG-Miconazole oral gel) was 6.2%,with a 95% CI: (-5.2%, 17.6%).
‡ Percentage based on those who had complete response.

Last reviewed on RxList: 3/25/2013
This monograph has been modified to include the generic and brand name in many instances.

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