Oravig

Overdose

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.

Oravig price

Contraindications

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

Undesirable effects

The following serious adverse drug reactions are discussed in detail in other sections oflabeling:

• Hypersensitivity reactions

Because clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical 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.

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 a ≥ 2% of HIV-Infected Patients in the Controlled Clinical Trial

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 alteredtaste, were reported by 35 (12.1%) patients who received miconazole buccal tablet compared to 27 (9.4%) patients who received clotrimazole troches.

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)

Overall local adverse reactions, including oral discomfort, oral pain, dry mouth, glossodynia, loss of taste, altered taste, tongue ulceration, mouth ulceration, tooth disorder, andapplication site discomfort or pain, were experienced by 14 (9.5%) patients who used ORAVIG compared to 16 (10.9%) patients who used miconazole gel.

Adverse reactions reported in the overall safety database of 480 subjects who receivedmiconazole 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

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

Therapeutic indications

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

Pharmacokinetic properties

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)

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).

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.

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

Name of the medicinal product

Fertility, pregnancy and lactation

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 motheroutweighs the potential risk to the fetus.

Miconazole nitrate administered orally at doses of 80 mg/kg/day or higher to pregnantrats 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. Teratogenicitywas not reported in any animal study with miconazole.

Qualitative and quantitative composition

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.

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

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

Manufactured By: Catalent Germany Schorndorf GmbH Steinbeisstraße 2 73614 Schorndorf Germany. Manufactured For: Vestiq Pharmaceuticals, Inc.3000 Aerial Center Parkway, 160 Morrisville, NC 27560. Distributed By: Praelia Pharmaceuticals, Inc. 100 Tower View Court Cary, NC 27513.  Revised: 08/2012

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Allergic reactions, including anaphylactic reactions and hypersensitivity, have been reported with the administration of miconazole products, including ORAVIG. DiscontinueORAVIG immediately at the first sign of hypersensitivity.

There is no information regarding cross-hypersensitivity between miconazole and otherazole antifungal agents. Monitor patients with a history of hypersensitivity to azoles.

See FDA-approved patient labeling.

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 tabletincluding:

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

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 ORAVIGand contact a healthcare provider. Patients may experience other adverse reactionsincluding diarrhea, headache, nausea, and change in taste.

Carcinogenicity studies with miconazole have not been conducted.

Miconazole nitrate was not genotoxic when tested in vitroin 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 andbone marrow cells, and morphologic abnormalities in sperm at doses similar to or belowclinical doses. However, no impairment of fertility was observed in intravenous studieswith 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 ORAVIGbuccal tablet, based on body surface area comparisons.

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 motheroutweighs the potential risk to the fetus.

Miconazole nitrate administered orally at doses of 80 mg/kg/day or higher to pregnantrats 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. Teratogenicitywas not reported in any animal study with miconazole.

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

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 applicationinstructions has not been evaluated. Use in younger children is not recommended due topotential risk of choking

Clinical studies of ORAVIG did not include sufficient numbers of subjects aged 65 andover to determine whether they respond differently from younger subjects.

Miconazole is metabolized by the liver. While miconazole systemic exposure is minimal following the application of ORAVIG, ORAVIG should be administered with caution inpatients with hepatic impairment.

Less than 1% of miconazole is excreted as unchanged drug in the urine; therefore, noadjustment to therapy is necessary in patients with renal impairment.

Dosage (Posology) and method of administration

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

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

Once applied, ORAVIG stays in position and gradually dissolves. Subsequent applications of ORAVIG should be made to alternate sides of the mouth. Before applying the next tablet, the patient should clear away anyremaining 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 gumshould 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 ofwater 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..

Interaction with other medicinal products and other forms of interaction

The following serious adverse drug reactions are discussed in detail in other sections oflabeling:

• Hypersensitivity reactions

Because clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical 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.

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 a ≥ 2% of HIV-Infected Patients in the Controlled Clinical Trial

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 alteredtaste, were reported by 35 (12.1%) patients who received miconazole buccal tablet compared to 27 (9.4%) patients who received clotrimazole troches.

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)

Overall local adverse reactions, including oral discomfort, oral pain, dry mouth, glossodynia, loss of taste, altered taste, tongue ulceration, mouth ulceration, tooth disorder, andapplication site discomfort or pain, were experienced by 14 (9.5%) patients who used ORAVIG compared to 16 (10.9%) patients who used miconazole gel.

Adverse reactions reported in the overall safety database of 480 subjects who receivedmiconazole 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

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

Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Cases of bleeding and bruising following the concomitant use ofwarfarin and topical, intravaginal, or oral miconazole were reported. Closely monitor pro-thrombin time, International Normalized Ratio (INR), or other suitable anticoagulationtests if ORAVIG is administered concomitantly with warfarin. Also monitor for evidenceof bleeding.

No formal drug interaction studies have been performed with ORAVIG. Miconazole is aknown 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 interactionwith drugs metabolized through CYP2C9 and CYP3A4 such as oral hypoglycemics,phenytoin, or ergot alkaloids cannot be ruled out.