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Oravig (Miconazole) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ORAVIG (miconazole) buccal tablets are applied topically to the gum once daily and release miconazole as the buccal tablet gradually dissolves [ see Clinical Pharmacology (12.3)].

Miconazole is an imidazole antifungal agent and is described chemically as 1-[(2RS)-2-[(2,4-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole with an empirical formula of C 18H14Cl4N2O and a molecular weight of 416.13. The structural formula is shown in Figure 1.

Figure 1: Structural Formula of Miconazole

Figure 1: Structural Formula of Miconazole

Miconazole drug substance is a white to almost white powder.

ORAVIG contains 50 mg of miconazole base, USP and the following inactive ingredients: hypromellose, USP; milk protein concentrate; corn starch, NF; lactose monohydrate, NF; sodium lauryl sulfate, NF; magnesium stearate, NF; and talc, USP.

CLINICAL PHARMACOLOGY

Mechanism of Action

Miconazole is an antifungal drug [ see Clinical Pharmacology (12.4)].

Pharmacokinetics

Absorption and Distribution

Salivary

Single dose application of ORAVIG containing 50 mg of miconazole to the buccal mucosa of 18 healthy volunteers provided mean maximum salivary concentrations of 15 mcg/mL at 7 hours after application of the tablet. This provided an average saliva exposure 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 Following Application 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 1  
(2.0 – 24.1)

1 Median

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-dose application 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 the administered 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 vitro and in vivo

Miconazole is active against Candida albicans, C. parapsilosis, and C. tropicalis. Correlation between minimum inhibitory concentration (MIC) results in vitro and 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 acids and/or in the regulation of the target enzyme and of a variety of efflux pump proteins. Multiple mechanisms may co-exist in the same isolate. Resistance breakpoints, correlating in vitro activity with clinical efficacy, have not been established for miconazole.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with miconazole have not been conducted.

Miconazole nitrate was not genotoxic when tested in vitro in a bacterial reverse mutation (Ames) assay or in an in vivo mouse bone marrow micronucleus test. Intraperitoneal injections of miconazole to mice induced chromosomal aberrations in spermatocytes and bone marrow cells, and morphologic abnormalities in sperm at doses similar to or below clinical doses. However, no impairment of fertility was observed in intravenous studies with miconazole at 40 mg/kg/day in rats or 20 mg/kg/day in rabbits, which are approximately 8 times higher than the dose a patient would receive if she swallowed an ORAVIG buccal tablet, based on body surface area comparisons.

Animal Toxicology and/or Pharmacology

Local tolerance studies (LLNA sensitization test and tolerance study on the jugal mucosa of 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 daily for 14 consecutive days (n = 290) with clotrimazole troches 10 mg 5 times per day for 14 days (n = 287) in HIV-positive patients with OPC. Seventy-five percent of patients were not receiving highly active antiretroviral treatment, 5% had CD4+ cell count < 50 cells/mm 3, 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 Candida species.

Clinical cure [defined as a complete resolution of both signs and symptoms of OPC at the test of cure (TOC) visit (days 17-22)], and clinical relapse by days 35-38 (21-24 days after end of therapy) are presented in Table 5. Mycological cure [defined as eradication (i.e., no yeast isolates) of Candida species] 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=290 1  (%)
Clotrimazole troches
N=287 (%)
Clinical cure 2   176 (60.7%) 187 (65.2%)
     Clinical relapse 3      
         Yes 4   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%)

1 Analysis population includes all randomized patients who took at least 1 dose of study medication.  One  randomized subject excluded from the ORAVIG arm.
2

Difference in clinical cure rates (ORAVIG-Clotrimazole troche) was -4.5%,  with a 95% CI: (–12.4%, 3.4%).


3 Percentage based on those who had clinical cure.
4

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.


Study in Head 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 gel 125 mg four times daily for 14 days in head and neck cancer patients who had received radiation 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 of the score for extent of oral lesion compared with the score at day 1) based on a blind assessment] 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 Head and Neck Cancer who had Received Radiation Therapy
  ORAVIG
50 mg
N=148 1  (%)
Miconazole oral gel
N=146 (%)
 Success rate (CR+PR) 2   79 (53.4%) 69 (46.6%)
 CR 3   74 (50.0%) 64 (43.8%)
     Clinical relapse 4  
         Yes 5   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%)

1

Analysis 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.


2 CR: complete response;  PR: partial response
3

Difference in clinical complete response rates (ORAVIG-Miconazole oral gel) was 6.2%, with a 95% CI: (-5.2%, 17.6%).


4 Percentage based on those who had complete response.
5

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.


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