Miconazole (buccal)

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# Overview
Miconazole (buccal) is an antifungal that is FDA approved for the treatment of oropharyngeal candidiasis in adults.   Common adverse reactions include diarrhea, headache, nausea, dysgeusia, upper abdominal pain, and vomiting.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- ORAVIG is indicated for the local treatment of oropharyngeal candidiasis (OPC) in adults.

# Dosing
- The recommended dosing schedule for ORAVIG is the application of one 50 mg buccal tablet to the upper gum region (canine fossa) once daily for 14 consecutive days.

# DOSAGE FORMS AND STRENGTHS
- ORAVIG is a buccal tablet containing 50 mg of miconazole. ORAVIG tablets are round, off-white tablets, with a rounded side and a flat side. The tablets are marked with an L on the flat side.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miconazole (buccal) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Miconazole (buccal) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Miconazole (buccal) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Miconazole (buccal) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Miconazole (buccal) in pediatric patients.

# Contraindications
- ORAVIG is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to miconazole, milk protein concentrate, or any other component of the product.

# Warnings
Hypersensitivity
- Allergic reactions, including anaphylactic reactions and hypersensitivity, have been reported with the administration of miconazole products, including ORAVIG. Discontinue ORAVIG immediately at the first sign of hypersensitivity.
- There is no information regarding cross-hypersensitivity between miconazole and other azole antifungal agents. Monitor patients with a history of hypersensitivity to azoles.

# Adverse Reactions

## Clinical Trials Experience
- The following serious adverse drug reactions are discussed in detail in other sections of labeling:
- Hypersensitivity reactions

# Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The overall safety of ORAVIG was assessed in 480 adult subjects: 315 HIV-infected subjects, 147 subjects with head and neck cancer, and 18 healthy subjects.
HIV Infected Patients
- Two trials were conducted in immunocompromised HIV infected patients: one randomized, double-blind, double-dummy, active-controlled design (N = 290 ORAVIG, 287 control) and one non-comparative trial (N = 25).
- In the randomized, double blind trial (Study 1), 290 HIV infected subjects used ORAVIG once daily for 14 days, and 287 subjects used 10 mg clotrimazole troches five times daily for 14 days. Adverse reactions occurring in  2% of patients in either treatment are presented in Table 1.
Overall local adverse reactions, including oral discomfort, oral burning, oral pain, gingival pain, gingival swelling, gingival pruritis, tongue ulceration, mouth ulceration, glossodynia, dry mouth, application site pain or discomfort, toothache, loss of taste, and altered taste, were reported by 35 (12.1%) patients who received miconazole buccal tablet compared to 27 (9.4%) patients who received clotrimazole troches.
Head and Neck Cancer Patients
- In the randomized, open-label comparative trial of oropharyngeal candidiasis in patients with head and neck cancer who had received radiation therapy (Study 2), 147 patients used ORAVIG once daily for 14 days and 147 patients used 125 mg of miconazole oral gel four times daily for 14 days. Adverse reactions occurring in 2% of patients in either arm are listed in Table 2.
- Overall local adverse reactions, including oral discomfort, oral pain, dry mouth, glossodynia, loss of taste, altered taste, tongue ulceration, mouth ulceration, tooth disorder, and application site discomfort or pain, were experienced by 14 (9.5%) patients who used ORAVIG compared to 16 (10.9%) patients who used miconazole gel.
Overall ORAVIG Safety Experience In Patients and Healthy Subjects
- Adverse reactions reported in the overall safety database of 480 subjects who received miconazole buccal tablet is listed in Table 3.
- Discontinuation of ORAVIG due to adverse drug reactions occurred in 0.6% overall.

## Postmarketing Experience
There is limited information regarding Miconazole (buccal) Postmarketing Experience in the drug label.

# Drug Interactions
Warfarin
- Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Cases of bleeding and bruising following the concomitant use of warfarin and topical, intravaginal, or oral miconazole were reported. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if ORAVIG is administered concomitantly with warfarin. Also monitor for evidence of bleeding.
Drugs Metabolized Through CYP2C9 and 3A4
- No formal drug interaction studies have been performed with ORAVIG. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. Although the systemic absorption of miconazole following ORAVIG administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 and CYP3A4 such as oral hypoglycemics, phenytoin, or ergot alkaloids cannot be ruled out.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category C
- There are no adequate and well-controlled clinical trials of ORAVIG in pregnant women. ORAVIG should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.
- Miconazole nitrate administered orally at doses of 80 mg/kg/day or higher to pregnant rats or rabbits crossed the placenta and resulted in embryo- and fetotoxicity, including increased fetal resorptions. These doses also resulted in prolonged gestation and dystocia in rats, but not in rabbits. Embryofetotoxicity was not observed in intravenous studies with miconazole at lower doses of 40 mg/kg/day in rats and 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. Teratogenicity was not reported in any animal study with miconazole.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Miconazole (buccal) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Miconazole (buccal) during labor and delivery.

### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ORAVIG is administered to a nursing woman.

### Pediatric Use
- Safety and effectiveness of ORAVIG in pediatric patients below the age of 16 years have not been established. The ability of pediatric patients to comply with the application instructions has not been evaluated. Use in younger children is not recommended due to potential risk of choking.

### Geriatic Use
- Clinical studies of ORAVIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

### Gender
There is no FDA guidance on the use of Miconazole (buccal) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Miconazole (buccal) with respect to specific racial populations.

### Renal Impairment
- Less than 1% of miconazole is excreted as unchanged drug in the urine; therefore, no adjustment to therapy is necessary in patients with renal impairment

### Hepatic Impairment
- Miconazole is metabolized by the liver. While miconazole systemic exposure is minimal following the application of ORAVIG, ORAVIG should be administered with caution in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Miconazole (buccal) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Miconazole (buccal) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Miconazole (buccal) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Miconazole (buccal) and IV administrations.

# Overdosage
- Overdose with miconazole in humans has not been reported in the literature.
- Miconazole absorption and systemic exposure following application of ORAVIG are minimal.
- Symptomatic and supportive care is the basis for management.

# Pharmacology

## Mechanism of Action
- Miconazole inhibits the enzyme cytochrome P450 14-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.

## Structure
- ORAVIG (miconazole) buccal tablets are applied topically to the gum once daily and release miconazole as the buccal tablet gradually dissolves.
- Miconazole is an imidazole antifungal agent and is described chemically as 1--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
- 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.

## Pharmacodynamics
There is limited information regarding Miconazole (buccal) Pharmacodynamics in the drug label.

## 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 mcgh/mL. The pharmacokinetic parameters of miconazole in the saliva of healthy volunteers are provided in Table 4.
- 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.

## 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 , and clinical relapse by days 35-38 (21-24 days after end of therapy) are presented in Table 5. Mycological cure  at the TOC visit (days 17-22) is also reported in the table.
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  are shown in Table 6. Also reported in Table 6 are relapse rate at day 30, and mycologic cure assessed at day 14.

# How Supplied
- ORAVIG 50 mg buccal tablets are supplied as off-white tablets containing 50 mg of miconazole. ORAVIG tablets have a rounded side and a flat side. ORAVIG tablets are packaged in bottles of 14 tablets (NDC 43288-250-14).

## Storage
- ORAVIG should be stored at 20 to 25C (68 to 77 F) ; excursions between 15 and 30C permitted at room temperature. Protect from moisture, and keep out of reach of children.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

# Precautions with Alcohol
Alcohol-Miconazole (buccal) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ORAVIG

# Look-Alike Drug Names
There is limited information regarding Miconazole (buccal) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price