2.1 Basic Dosing Information

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.

2.2 Administration Instructions

ORAVIG should be applied in the morning, after brushing the teeth. The tablet should be applied with dry hands. The rounded side surface of the tablet should be placed against the upper gum just above the incisor tooth (canine fossa) and held in place with slight pressure over the upper lip for 30 seconds to ensure adhesion. The tablet is round on one side for comfort, but either side of the tablet can be applied to the gum.

Once applied, ORAVIG stays in position and gradually dissolves. [See Clinical Pharmacology (12.3)] Subsequent applications of ORAVIG should be made to alternate sides of the mouth. Before applying the next tablet, the patient should clear away any remaining tablet material. In addition,

• ORAVIG should not be crushed, chewed or swallowed.
• Food and drink can be taken normally when ORAVIG is in place but chewing gum should be avoided.
• If ORAVIG does not adhere or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet still does not adhere, a new tablet should be placed.
• If ORAVIG is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied only once.
• If ORAVIG falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose. [see Patient Counseling Information (17)].

5.1 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.

6.1 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.

7.1 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.

7.2 Drugs Metabolized Through CYP 2C9 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.

8.1 Pregnancy

8.2 Lactation

8.4 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.

8.5 Geriatric 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.

8.6 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.

8.7 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.

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

12.4 Microbiology

13.1 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.

13.2 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.

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/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 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.

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.

ORAVIG should be stored at 20 to 25°C (68 to 77 °F) [see USP controlled room temperature]; excursions between 15 and 30°C permitted at room temperature. Protect from moisture, and keep out of reach of children.

Important Administration Instructions

The tablet should be used immediately after removal from the bottle.

• Instruct patients not to crush, chew, or swallow the tablet.
• The rounded side of the tablet should be applied to the upper gum above the incisor tooth in the morning, after brushing the teeth.
• The tablet should be held in place for 30 seconds with a slight pressure of the finger over the upper lip to make the tablet stick to the gum.
• The tablet may be used if it sticks to the cheek, inside of the lip or the gum.
• If the tablet does not adhere, it should be repositioned.
• As the ORAVIG tablet absorbs moisture from the mouth, it will slowly dissolve over time and should be left in place – there is no need to remove the tablet.
• Subsequent applications of ORAVIG should be made to alternate sides of the gum.
• If ORAVIG does not stick or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet does not adhere, a new tablet should be placed.
• If ORAVIG is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied only once.
• If ORAVIG falls off or is swallowed after it was in place for 6 hours or more, a new tablet should not be applied until the next regularly scheduled dose.

Patients should avoid situations that could interfere with the sticking of the tablet including:

• touching or pressing the tablet after placement
• wearing upper denture
• chewing gum
• hitting tablet when brushing teeth
• rinsing mouth too vigorously

Hypersensitivity and Other Adverse Reactions

Patients who develop hives, skin rash, or other symptoms of an allergic reaction, and patients who develop swelling or pain, at the tablet application site should stop ORAVIG and contact a healthcare provider. Patients may experience other adverse reactions including diarrhea, headache, nausea, and change in taste.

Potential Embryo-fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].