MICONAZOLE: 5,744 Adverse Event Reports & Safety Profile

Miconazole nitrate, zinc oxide and white petrolatum ointment contains the synthetic antifungal agent, miconazole nitrate (0.25%) USP, zinc oxide (15%) USP, and white petrolatum (81.35%) USP. The chemical name of miconazole nitrate is 1-[2, 4-dichloro-ß-{(2,4-dichlorobenzyl)oxy} phenethyl] imidazole mononitrate with empirical formula C 18 H 14 Cl 4 N 2 O•HNO 3 and molecular weight of 479.15. The structural formula of miconazole nitrate is as follows: The zinc oxide has an empirical formula of ZnO and a molecular weight of 81.39. The white petrolatum, which is obtained from petroleum and is wholly or nearly decolorized, is a purified mixture of semisolid saturated hydrocarbons having the general chemical formula C n H 2n+2 . The hydrocarbons consist mainly of branched and unbranched chains. White petrolatum contains butylated hydroxytoluene (BHT) as stabilizer. Each gram of miconazole nitrate, zinc oxide and white petrolatum ointment contains 2.5 mg of miconazole nitrate, USP, 150 mg of zinc oxide, USP and 813.5 mg of white petrolatum, USP containing butylated hydroxytoluene, trihydroxystearin, and Chemoderm 1001/B fragrance. Miconazole nitrate, zinc oxide and white petrolatum ointment is a smooth, uniform, white ointment.

Miconazole Nitrate Structural

Formula

AND USAGE

• Miconazole nitrate, zinc oxide and white petrolatum ointment is indicated for adjunctive treatment of diaper dermatitis when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast) in immunocompetent pediatric patients 4 weeks and older. ( 1.1 )
• Miconazole nitrate, zinc oxide and white petrolatum ointment should not be used as a substitute for frequent diaper changes. ( 1.1 )
• Miconazole nitrate, zinc oxide and white petrolatum ointment should not be used to prevent the occurrence of diaper dermatitis, since preventative use may result in the development of drug resistance. ( 1.2 )

1.1 Indication Miconazole nitrate, zinc oxide and white petrolatum ointment is indicated for the adjunctive treatment of diaper dermatitis only when complicated by documented candidiasis (microscopic evidence of pseudohyphae and/or budding yeast), in immunocompetent pediatric patients 4 weeks and older. A positive fungal culture for Candida albicans is not adequate evidence of candidal infection since colonization with C. albicans can result in a positive culture. The presence of candidal infection should be established by microscopic evaluation prior to initiating treatment. Miconazole nitrate, zinc oxide and white petrolatum ointment should be used as part of a treatment regimen that includes measures directed at the underlying diaper dermatitis, including gentle cleansing of the diaper area and frequent diaper changes. Miconazole nitrate, zinc oxide and white petrolatum ointment should not be used as a substitute for frequent diaper changes.

1.2 Limitations of Use The safety and efficacy of miconazole nitrate, zinc oxide and white petrolatum ointment have not been demonstrated in immunocompromised patients, or in infants less than 4 weeks of age (premature or term). The safety and efficacy of miconazole nitrate, zinc oxide and white petrolatum ointment have not been evaluated in incontinent adult patients. Miconazole nitrate, zinc oxide and white petrolatum ointment should not be used to prevent the occurrence of diaper dermatitis, such as in an adult institutional setting, since preventative use may result in the development of drug resistance.

2 DOSAGE & ADMINISTRATION Application of one ORAVIG 50 mg buccal tablet to the gum region once daily for 14 consecutive days (2.1) . Instruct patients not to crush, chew, or swallow tablets (2.2) .

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) ].

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

REACTIONS The following serious adverse drug reactions are discussed in detail in other sections of labeling: Hypersensitivity reactions [see Warnings and Precautions (5.1)] Most common adverse reactions (≥2%) are: diarrhea, headache, nausea, dysgeusia, upper abdominal pain, and vomiting (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Galt Pharmaceuticals, LLC Marietta, GA 30067 at 1-833-757-0904 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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.

Table

1 Adverse Reactions (Treatment-Emergent) Occurring in ≥ 2% of HIV-Infected Patients in the Controlled Clinical Trial Adverse Reaction (MedDRA v

9.1 System Organ Class and Preferred Term) ORAVIG N = 290 (%) Clotrimazole troches N = 287 (%) Patients with any adverse reaction during the study 158 (54.5) 146 (50.9) Gastrointestinal disorders Diarrhea Nausea Vomiting Dry mouth Abdominal pain upper 25.9 9.0 6.6 3.8 2.8 1.7 23.7 8.0 7.7 3.1 1.7

2.8 Infections and infestations Upper respiratory infection Gastroenteritis 15.9 2.1 1.4 17.1 2.4

2.8 Nervous system disorders Headache Ageusia 13.1 7.6 2.4 8.4 6.6

0.3 Blood and lymphatic disorders Anemia Lymphopenia Neutropenia 6.9 2.8 1.7 0.7 8.4 1.7 2.1

2.1 General disorders and administration site conditions Fatigue Pain 6.6 2.8 1.0 8.0 2.1

2.8 Respiratory/thoracic Cough Pharyngeal pain 5.2 2.8 0.7 7.7 1.7

2.4 Investigations Increased GGT 5.5 1.0 6.3

2.8 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.

Table

2: Adverse Reactions (Treatment-Emergent) Occurring in ≥ 2% of Patients with Head and Neck Cancer who had Received Radiation Therapy (Controlled Clinical Trial)

Adverse

Reaction (MedDRA v

9.1 System Organ Class and Preferred Term) ORAVIG N = 147 (%) Miconazole gel N = 147 (%) Patients with at least one adverse reaction 30 (20.4) 32 (21.8) Gastrointestinal disorders Abdominal pain, upper Oral discomfort Nausea Vomiting Glossodynia 8.8 1.4 2.7 0.7 0.7 0 13.6 2.0 2.7 2.7 2.0

2.0 Nervous system disorders Dysgeusia 5.4 4.1 1.4 0 Skin and subcutaneous Pruritus 3.4 2.0 0.7

0.7 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.

Table

3 Adverse Reactions Reported in ≥ 2% of Patients and Healthy Subjects who Received ORAVIG in Clinical Trials Adverse reaction (MedDRA v

9.1 System Organ Class and Preferred Term) ORAVIG N = 480 (%) Patients with at least one AE 209 (43.5) Gastrointestinal disorders Diarrhea Nausea Abdominal pain upper Vomiting 20.6 6.0 4.6 2.5

2.5 Infections and infestations

11.9 Nervous system disorders Headache Dysgeusia 10.6 5.0

2.9 Discontinuation of ORAVIG due to adverse drug reactions occurred in 0.6% overall.

Warnings For vaginal use only Do not use if you have never had a vaginal yeast infection diagnosed by a doctor. Ask a doctor before use if you have

• vaginal itching and discomfort for the first time
• lower abdominal, back or shoulder pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge. You may have a more serious condition.
• vaginal yeast infections often (such as once a month or 3 in 6 months). You could be pregnant or have a serious underlying medical cause for your symptoms, including diabetes or a weakened immune system.
• been exposed to the human immunodeficiency virus (HIV) that causes AIDS Ask a doctor or pharmacist before use if you are taking the prescription blood thinning medicine warfarin, because bleeding or bruising may occur. When using this product
• do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs).
• do not have vaginal intercourse
• mild increase in vaginal burning, itching or irritation may occur
• if you do not get complete relief ask a doctor before using another product Stop use and ask a doctor if:
• symptoms do not get better in 3 days
• symptoms last more than 7 days
• you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away (1-800-222-1222).

PRECAUTIONS General Discontinue drug if sensitization or irritation is reported during use. The base contained in the suppository formulation may interact with certain latex products, such as that used in vaginal contraceptive diaphragms. Concurrent use is not recommended.

Miconazole Nitrate Vaginal

Cream USP, 2% may be considered for use under these conditions.

Laboratory

Tests If there is a lack of response to Miconazole Nitrate Vaginal Suppositories, appropriate microbiological studies (standard KOH smear and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to determine carcinogenic potential have not been performed. Fertility (Reproduction): Oral administration of miconazole nitrate in rats has been reported to produce prolonged gestation. However, this effect was not observed in oral rabbit studies. In addition, signs of fetal and embryo toxicity were reported in rat and rabbit studies, and dystocia was reported in rat studies after oral doses at and above 80 mg per kg. Intravaginal administration did not produce these effects in rats.

Pregnancy

Since imidazoles are absorbed in small amounts from the human vagina, they should not be used in the first trimester of pregnancy unless the physician considers it essential to the welfare of the patient. Clinical studies, during which miconazole nitrate vaginal cream and suppositories were used for up to 14 days, were reported to include 541 pregnant patients. Follow-up reports available in 471 of these patients reveal no adverse effects or complications attributable to miconazole nitrate therapy in infants born to these women.

Nursing

Mothers It is not known whether miconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when miconazole nitrate is administered to a nursing woman.

INTERACTIONS Warfarin: Miconazole may enhance anticoagulant effect. Monitor prothrombin time, INR, and watch for bleeding (7.1).

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.

Uses For the treatment of most athlete's foot (tinea pedis), jock itch (tinea cruris), ringworm (tinea corporis) Relieves itching, scaling, burning, discomfort and chafing associated with jock itch or itching, burning feet

Inactive Ingredients Acrylates/C10-30 Alkyl Acrylate Crosspolymer, Arginine HCl, Ascorbyl Palmitate, Butyrospermum Parkii (Shea) Butter, Caprylyl Glycol, Cetearyl Alcohol, Cinnamomum Zeylanicum Leaf Oil, Citrus Aurantium Dulcis (Orange)

Peel

Oil, Cocos Nucifera (Coconut) Oil, Cymbopogon Flexuosus Oil, Dimethyl Isosorbide, Disodium EDTA, Dodecane, Ethylhexylglycerin, Eucalyptus Globulus Leaf Oil, Eugenia Caryophyllus (Clove)

Bud

Oil, Fusanus Spicatus Wood (Sandalwood) Oil, Glycerin, Hexylene Glycol, Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer, Lavandula Angustifolia (Lavender) Oil, Leptospermum Scoparium Branch/Leaf Oil, Melaleuca Alternifolia (Tea Tree)

Leaf

Oil, Mentha Piperita (Peppermint) Oil, Origanum Vulgare (Oregano)

Leaf

Oil, Panthenol, PEG-12 Dimethicone, PEG-4 Dilaurate, PEG-40 Hydrogenated Castor Oil, Persea Gratissima (Avocado) Oil, Phenoxyethanol, Phospholipids, Polysorbate 20, Polysorbate 60, PPG-26-Buteth-26, Retinyl Palmitate, Salicylic Acid, Simmondsia Chinensis (Jojoba)

Seed

Oil, Sodium Benzoate, Sodium Bicarbonate, Squalane, Tocopheryl Acetate, Triethanolamine, Undecylenic Acid, Urea, Water, Xanthan Gum