Denomix

Desoximetasone:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Denomix (Desoximetasone) reviews

1 INDICATIONS AND USAGE

Denomix (Desoximetasone)^® Topical Spray is a corticosteroid indicated for the treatment of plaque psoriasis in patients 18 years of age or older.

Denomix (Desoximetasone)^® Topical Spray is a corticosteroid indicated for the treatment of plaque psoriasis in patients 18 years of age or older (1).

2 DOSAGE AND ADMINISTRATION

Apply Denomix (Desoximetasone)^® Topical Spray as a thin film to the affected skin areas twice daily. Rub in gently.

The treated skin area should not be bandaged or otherwise covered or wrapped unless directed by the physician.

Denomix (Desoximetasone)^® Topical Spray should be discontinued when control is achieved.

Treatment beyond 4 weeks is not recommended.

Do not use if atrophy is present at the treatment site.

Avoid use on the face, axilla or groin.

Denomix (Desoximetasone)^® Topical Spray is for external use only. It is not for oral, ophthalmic, or intravaginal use.

• Apply a thin film to the affected skin areas twice daily. Rub in gently. (2)
• Denomix (Desoximetasone)^® Topical Spray should be discontinued when control is achieved. (2)
• Treatment beyond 4 weeks is not recommended. (2)
• Do not use if atrophy is present at the treatment site. (2)
• Do not use with occlusive dressings, unless directed by the physician (2)
• Avoid use on the face, axilla or groin. (2)
• Denomix (Desoximetasone)^® Topical Spray is not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS AND STRENGTHS

Topical Spray, 0.25%. Each gram of Denomix (Desoximetasone)^® Topical Spray contains 2.5 mg of Denomix (Desoximetasone) in a clear, colorless liquid.

Spray, 0.25% w/w (3)

4 CONTRAINDICATIONS

None

None (4)

5 WARNINGS AND PRECAUTIONS

• Denomix ^® Topical Spray can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during or after treatment. (5.1)
• Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can result from systemic absorption of topical corticosteroids. (5.1)
• Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. (5.1)
• Modify use if HPA axis suppression develops. (5.1)
• High potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age may predispose patients to HPA axis suppression. (5.1)
• Pediatric patients may be more susceptible to systemic toxicity when treated with topical corticosteroids. (5.1, 8.4)
• Denomix (Desoximetasone)^® Topical Spray is flammable; keep away from heat or flame. (5.5)

5.1 Effect on Endocrine System

Denomix (Desoximetasone)^® Topical Spray is a topical corticosteroid that has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

Systemic absorption of topical corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid.

In a study including 21 evaluable subjects 18 years of age or older with moderate to severe plaque psoriasis, adrenal suppression was identified in 1 out of 12 subjects having involvement of 10-15% of body surface area (BSA) and 2 out of 9 subjects having involvement of >15% of BSA after treatment with Denomix (Desoximetasone)^® Topical Spray twice a day for 28 days. [see Clinical Pharmacology (12.2) ]

Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be periodically evaluated for HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of high potency steroids, larger treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age.

An ACTH stimulation test may be helpful in evaluating patients for HPA axis suppression.

If HPA axis suppression is documented, an attempt should be made to gradually withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids.

Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids.

Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure.

Pediatric patients may be more susceptible to systemic toxicity from use of topical corticosteroids. [see Use in Specific Populations (8.4) ]

5.2 Local Adverse Reactions with Topical Corticosteroids

Local adverse reactions may be more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids. Reactions may include atrophy, striae, telangiectasias, burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria. Some local adverse reactions may be irreversible.

5.3 Allergic Contact Dermatitis with Topical Corticosteroids

Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by a failure to heal rather than a clinical exacerbation. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.

5.4 Concomitant Skin Infections

Concomitant skin infections should be treated with an appropriate antimicrobial agent.

If the infection persists, Denomix ^® Topical Spray should be discontinued until the infection has been adequately treated.

5.5 Flammable Contents

Denomix (Desoximetasone)^® Topical Spray is flammable; keep away from heat or flame.

6 ADVERSE REACTIONS

The most common adverse reactions are application site dryness, application site irritation and application site pruritus. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Taro at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 practice.

In randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate to severe plaque psoriasis of the body applied Denomix (Desoximetasone)^® Topical Spray or vehicle spray twice daily for 4 weeks. A total of 149 subjects applied Denomix (Desoximetasone)^® Topical Spray.

Adverse reactions that occurred in ≥ 1% of subjects treated with Denomix (Desoximetasone)^® Topical Spray were application site dryness (2.7%), application site irritation (2.7%) and application site pruritus (2.0%).

Another less common adverse reaction (<1% but >0.1%) was folliculitis.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Denomix ^® Topical Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels.

Denomix (Desoximetasone) has been shown to be teratogenic and embryotoxic in mice, rats, and rabbits when given by subcutaneous or dermal routes of administration at doses 3 to 30 times the human dose of Denomix (Desoximetasone)^® Topical Spray based on a body surface area comparison.

8.3 Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Because many drugs are excreted in human milk, caution should be exercised when Denomix (Desoximetasone)^® Topical Spray is administered to a nursing woman.

If used during lactation, Denomix (Desoximetasone)^® Topical Spray should not be applied on the chest to avoid accidental ingestion by the infant.

8.4 Pediatric Use

Safety and effectiveness of Denomix ^® Topical Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are therefore at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children. [see Warnings and Precautions (5.1) ]

HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema. [see Warnings and Precautions (5.1) ]

8.5 Geriatric Use

Clinical studies of Denomix (Desoximetasone)^® Topical Spray did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Denomix (Desoximetasone)^® Topical Spray can be absorbed in sufficient amounts to produce systemic effects. [see Warnings and Precautions (5.1) ]

11 DESCRIPTION

Denomix (Desoximetasone)^® (desoximetasone) Topical Spray, 0.25% contains Denomix (Desoximetasone) as the active ingredient.

Denomix (Desoximetasone) is a corticosteroid with the chemical name of pregna-1, 4-diene-3, 20-dione, 9-fluoro-11, 21-dihydroxy-16-methyl-, (11β,16α)-.

Denomix (Desoximetasone) has the molecular formula of C₂₂H₂₉FO₄ and a molecular weight of 376.47. The CAS Registry Number is 382-67-2.

The structural formula is:

Each gram of Denomix (Desoximetasone)^® Topical Spray contains 2.5 mg of Denomix (Desoximetasone) in a clear, colorless liquid with the following inactive ingredients: glyceryl oleate, isopropyl alcohol (23.4%), isopropyl myristate, L-menthol, and mineral oil. Denomix (Desoximetasone)^® Topical Spray is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing to patients.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation and protein regulation; however, the precise mechanism of action in psoriasis is unknown.

12.2 Pharmacodynamics

Vasoconstrictor studies performed with Denomix ^® Topical Spray in healthy subjects indicate that it is in the high to super-high range of potency as compared with other topical corticosteroids.

The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression was evaluated in a study of 24 adult subjects with moderate to severe plaque psoriasis. Denomix (Desoximetasone)^® Topical Spray was applied twice a day for 28 days. Twenty-one subjects had evaluable serum cortisol levels. The proportion of subjects demonstrating HPA axis suppression was 8.3% (1 out of 12) in subjects having psoriasis involvement of 10-15% of body surface area (BSA), and 22.2% (2 out of 9) in subjects having psoriasis involvement of > 15% of their BSA. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-min post cosyntropin stimulation. In the 2 subjects with available follow-up values, suppression reversed 28 days after the end of treatment.

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

Plasma concentrations of Denomix (Desoximetasone) were measured at two single random time points in the HPA axis suppression trial in 24 subjects with psoriasis [see Clinical Pharmacology (12.2) ]. The mean (% Coefficient of Variation) concentration of Denomix (Desoximetasone) was 449 pg/mL (86%) at Day 14 and 678 pg/mL (135%) at Day 28. The concentration time profile following application of Denomix (Desoximetasone)^® Topical Spray is not known.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Denomix (Desoximetasone)^® Topical Spray.

In a 13-week repeat-dose toxicity study in rats, topical administration of Denomix (Desoximetasone) spray at concentrations of 0.001, 0.005 and 0.02% BID (which corresponds to dose levels of 0.01, 0.05, or 0.2 mg/kg/dose BID, respectively) resulted in a toxicity profile consistent with long-term exposure to corticosteroids, including adrenal atrophy and histopathological changes in several organ systems indicative of severe immune suppression. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk for carcinogenesis.

Denomix (Desoximetasone) revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster ovary cell chromosome aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus assay).

No evidence of impairment of male or female fertility was observed at subcutaneous Denomix (Desoximetasone) doses up to 0.1 mg/kg/day (0.6 mg/m²/day) in Sprague-Dawley rats.

14 CLINICAL STUDIES

Two multi-center, randomized, double-blind, vehicle- controlled clinical trials were conducted in 239 subjects aged 18 years and older with moderate to severe plaque psoriasis of the body. In both trials, randomized subjects applied Denomix (Desoximetasone) ^® Topical Spray or vehicle spray to the affected areas twice daily for 4 weeks. Enrolled subjects had a minimum body surface area of involvement of 10%, and a Physician's Global Assessment score (PGA) of 3 (moderate) or 4 (severe).

Efficacy was assessed at Week 4 as the proportion of subjects who were considered a Clinical Success ("clear" (0) or "almost clear" (1) according to the PGA scale). Table 2 presents the efficacy results.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied/Storage

Denomix ^® (desoximetasone) Topical Spray, 0.25% is a clear colorless liquid supplied in white, opaque bottles with white, opaque screw caps in the following sizes:

• 30 mL (NDC 51672-5281-3)
• 50 mL (NDC 51672-5281-4)
• 100 mL (2-50 mL bottles) (NDC 51672-5281-6)
• 100 mL (NDC 51672-5281-7)

Store at controlled room temperature between 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Spray is flammable; avoid heat, flame or smoking when using this product.

Each unit is co-packaged with a manual spray pump for installation by the pharmacist.

16.2 Instructions for the Pharmacist

• Remove the spray pump from the wrapper
• Remove and discard the cap from the bottle
• Keeping the bottle vertical, insert the spray pump into the bottle and turn clockwise until well-fastened
• Dispense the bottle with the spray pump inserted
• Label the bottle with "discard the product 30 days after dispensing"

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Inform patients of the following:

• Use this medication as directed by the physician.
• Denomix (Desoximetasone)^® Topical Spray is for external use only. Avoid use on the face, axilla or groin.
• Do not to use this medication for any disorder other than that for which it was prescribed.
• Do not bandage or otherwise cover or wrap the treated skin so as to be occlusive.
• Report any signs of local or systemic adverse reactions to the physician.
• Do not use other corticosteroid-containing products with Denomix (Desoximetasone)^® Topical Spray without first consulting with the physician.
• Discontinue therapy when control is achieved. If no improvement is seen within 4 weeks, contact the physician.
• This medication is flammable; avoid heat, flame, or smoking when applying this product.
• Discard this product 30 days after dispensed by pharmacist.

Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1

Dist. by: TaroPharma^® a division of Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532

PK-6681-3 111

Instructions for Use

Denomix (Desoximetasone)^® (Top-i-cort)

(desoximetasone) Topical Spray

Important information: Denomix (Desoximetasone)^® Topical Spray is for use on skin only. Do not get Denomix (Desoximetasone)^® Topical Spray near or in your mouth, eyes or vagina.

Read the Instructions for Use that comes with Denomix (Desoximetasone)^® Topical Spray before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

Parts of Denomix (Desoximetasone)^® Topical Spray bottle

Figure A

How to apply Denomix (Desoximetasone)^® Topical Spray:

Step 1: Remove the cap from the pump top.

Step 2: Hold the bottle in an upright position while pointing the opening of the pump top in the direction of the affected area. To spray, push down on the pump top. Apply Denomix (Desoximetasone)^® Topical Spray to the affected area as instructed by your doctor. (See Figure B )

Figure B

Step 3: Spray only enough Denomix (Desoximetasone)^® Topical Spray to cover the affected area, for example, the elbow

(See Figure C ). Rub in Denomix (Desoximetasone)^® Topical Spray gently.

Figure C

Repeat Steps 2 and 3 to apply Denomix (Desoximetasone)^® Topical Spray to other affected areas as instructed by your doctor.

Step 4: After applying Denomix (Desoximetasone)^® Topical Spray, place the cap back onto the pump top. (See Figure D )

Figure D

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1

Dist. by: TaroPharma a division of Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532

Denomix (Desoximetasone)^® and TaroPharma^® are registered trademarks of Taro Pharmaceuticals U.S.A., Inc. and/or its affiliates.

Issued: 04/2013

PK-7265-0 110

Figure A Figure B Figure C Figure D

PATIENT INFORMATION

Denomix (Desoximetasone)^® (Top-i-cort)

(desoximetasone) Topical Spray

Important information: Denomix (Desoximetasone)^® Topical Spray is for use on skin only. Do not get Denomix (Desoximetasone)^® Topical Spray near or in your eyes, mouth or vagina.

What is Denomix (Desoximetasone)^® Topical Spray?

• Denomix (Desoximetasone)^® Topical Spray is a prescription corticosteroid medicine used to treat plaque psoriasis of the body in people 18 years of age and older.
• You should not use Denomix (Desoximetasone)^® Topical Spray on your face, underarms (armpits), or groin areas.
• It is not known if Denomix (Desoximetasone)^® Topical Spray is safe and effective in children under 18 years of age. Denomix (Desoximetasone)^® Topical Spray should not be used in children under 18 years of age.

Before you use Denomix (Desoximetasone)^® Topical Spray, tell your doctor if you:

• are allergic to any of the ingredients in Denomix (Desoximetasone)^® Topical Spray. See the end of this leaflet for a list of the ingredients in Denomix (Desoximetasone)^® Topical Spray.
• have a skin infection. You may need medicine to treat the skin infection before you use Denomix (Desoximetasone)^® Topical Spray.
• have thinning of the skin (atrophy) at the treatment site
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Denomix (Desoximetasone)^® Topical Spray will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Denomix (Desoximetasone)^® Topical Spray passes into your breast milk. Do not apply Denomix (Desoximetasone)^® Topical Spray to your chest area if you are breastfeeding. This will help to prevent your baby from accidentally getting Denomix (Desoximetasone)^® Topical Spray into the mouth.

Tell your doctor about all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. Especially tell your doctor if you take other corticosteroid medicines by mouth or use other products on your skin that contain corticosteroids.

What should I avoid while using Denomix (Desoximetasone)^® Topical Spray?

Denomix (Desoximetasone)^® Topical Spray is flammable. Avoid heat, flames or smoking while applying Denomix (Desoximetasone)^® Topical Spray to your skin.

How should I use Denomix (Desoximetasone)^® Topical Spray?

• Use Denomix (Desoximetasone)^® Topical Spray exactly as your doctor tells you to use it.
• Apply Denomix (Desoximetasone)^® Topical Spray 2 times a day.
• Do not bandage, cover, or wrap the treated skin area.
• Denomix (Desoximetasone)^® Topical Spray should be used for the shortest amount of time needed to treat your plaque psoriasis. Tell your doctor if your skin condition is not getting better after 4 weeks of using Denomix (Desoximetasone)^® Topical Spray. You should not use Denomix (Desoximetasone)^® Topical Spray for longer than 4 weeks.
• Wash your hands after applying Denomix (Desoximetasone)^® Topical Spray.
• Safely throw away (discard) any unused Denomix (Desoximetasone)^® Topical Spray after 30 days.

See the "Instructions for Use" at the end of the Patient Information for detailed information about the right way to apply Denomix (Desoximetasone)^® Topical Spray.

What are the possible side effects of Denomix (Desoximetasone)^® Topical Spray?

Denomix (Desoximetasone)^® Topical Spray may cause serious side effects, including:

• Topicort® Topical Spray can pass through your skin. Too much Denomix (Desoximetasone)^® Topical Spray passing through your skin can cause your adrenal glands to stop working. Your doctor may do blood tests to check for adrenal gland problems.

The most common side effects of Denomix (Desoximetasone)^® Topical Spray include dryness, irritation and itching of skin at the treated site.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Denomix (Desoximetasone)^® Topical Spray. For more information, ask your doctor.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov.

How should I store Denomix (Desoximetasone)^® Topical Spray?

• Store Denomix (Desoximetasone)^® Topical Spray at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Denomix (Desoximetasone)^® Topical Spray and all medicines out of the reach of children.

General information about the safe and effective use of Denomix (Desoximetasone)^® Topical Spray.

• Do not use Denomix (Desoximetasone)^® Topical Spray for a condition for which it was not prescribed. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Denomix (Desoximetasone)^® Topical Spray that is written for health professionals.

What are the ingredients in Denomix (Desoximetasone)^® Topical Spray?

Active ingredient: Denomix (Desoximetasone)

Inactive ingredients: glyceryl oleate, isopropyl alcohol, isopropyl myristate, L-menthol, and mineral oil

Mfd. by: Taro Pharmaceuticals Inc., Brampton, Ontario, Canada L6T 1C1

Dist. by: TaroPharma a division of Taro Pharmaceuticals U.S.A., Inc., Hawthorne, NY 10532

Issued: 04/2013

PK-7265-0 110

PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton

NDC 51672-5281-7

100 mL

Rx only

Denomix (Desoximetasone) ^®

(desoximetasone)

Topical Spray, 0.25%

0.25%

SPRAY

For Topical Use Only

Not For Oral, Ophthalmic, or Intravaginal Use

TaroPharma ^®

PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton

Neomycin Sulfate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Denomix (Neomycin Sulfate) reviews

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Denomix (Neomycin Sulfate) tablets and other antibacterial drugs, Denomix (Neomycin Sulfate) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Suppression of Intestinal Bacteria

Denomix (Neomycin Sulfate) tablets are indicated as adjunctive therapy as part of a regimen for the suppression of the normal bacterial flora of the bowel, e.g., preoperative preparation of the bowel. It is given concomitantly with erythromycin enteric-coated base (see DOSAGE AND ADMINISTRATION ).

Hepatic Coma (Portal-Systemic Encephalopathy)

Denomix (Neomycin Sulfate) has been shown to be effective adjunctive therapy in hepatic coma by reduction of the ammonia-forming bacteria in the intestinal tract. The subsequent reduction in blood ammonia has resulted in neurologic improvement.

CONTRAINDICATIONS

Denomix (Neomycin Sulfate) oral preparations are contraindicated in the presence of intestinal obstruction and in individuals with a history of hypersensitivity to the drug.

Patients with a history of hypersensitivity or serious toxic reaction to other aminoglycosides may have a cross-sensitivity to neomycin. Denomix (Neomycin Sulfate) oral preparations are contraindicated in patients with inflammatory or ulcerative gastrointestinal disease because of the potential for enhanced gastrointestinal absorption of neomycin.

WARNINGS

Additional manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.

The risk of hearing loss continues after drug withdrawal. Aminoglycosides can cause fetal harm when administered to a pregnant woman.

Aminoglycoside antibiotics cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to fetus or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Animal reproduction studies of neomycin have not been conducted. If neomycin is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

PRECAUTIONS

General

Prescribing Denomix tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antibiotics, use of oral neomycin may result in overgrowth of nonsusceptible organisms, particularly fungi. If this occurs, appropriate therapy should be instituted.

Neomycin is quickly and almost totally absorbed from body surfaces (except the urinary bladder) after local irrigation and when applied topically in association with surgical procedures. Delayed-onset irreversible deafness, renal failure and death due to neuromuscular blockade (regardless of the status of renal function) have been reported following irrigation of both small and large surgical fields with minute quantities of neomycin.

Cross-allergenicity among aminoglycosides has been demonstrated.

Aminoglycosides should be used with caution in patients with muscular disorders such as myasthenia gravis or parkinsonism since these drugs may aggravate muscle weakness because of their potential curare-like effect on the neuromuscular junction.

Small amounts of orally administered neomycin are absorbed through intact intestinal mucosa.

There have been many reports in the literature of nephrotoxicity and/or ototoxicity with oral use of neomycin. If renal insufficiency develops during oral therapy, consideration should be given to reducing the drug dosage or discontinuing therapy.

An oral neomycin dose of 12 grams per day produces a malabsorption syndrome for a variety of substances, including fat, nitrogen, cholesterol, carotene, glucose, xylose, lactose, sodium, calcium, cyanocobalamin and iron.

Orally administered neomycin increases fecal bile acid excretion and reduces intestinal lactase activity.

Information for The Patient

Patients should be counseled that antibacterial drugs including Denomix (Neomycin Sulfate) tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Denomix (Neomycin Sulfate) tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Denomix (Neomycin Sulfate) tablets or other antibacterial drugs in the future.

Before administering the drug, patients or members of their families should be informed of possible toxic effects on the eighth nerve. The possibility of acute toxicity increases in premature infants and neonates.

Laboratory Tests

Patients with renal insufficiency may develop toxic neomycin blood levels unless doses are properly regulated. If renal insufficiency develops during treatment, the dosage should be reduced or the antibiotic discontinued. To avoid nephrotoxicity and eighth nerve damage associated with high doses and prolonged treatment, the following should be performed prior to and periodically during therapy: urinalysis for increased excretion of protein, decreased specific gravity, casts and cells; renal function tests such as serum creatinine, BUN or creatinine clearance; tests of the vestibulocochlearis nerve function.

Serial, vestibular and audiometric tests should be performed (especially in high-risk patients). Since elderly patients may have reduced renal function which may not be evident in the results of routine screening tests such as BUN or serum creatinine, a creatinine clearance determination may be more useful.

Drug Interactions

Caution should be taken in concurrent or serial use of other neurotoxic and/or nephrotoxic drugs because of possible enhancement of the nephrotoxicity and/or ototoxicity of neomycin (see boxed WARNINGS ).

Caution should also be taken in concurrent or serial use of other aminoglycosides and polymyxins because they may enhance neomycin’s nephrotoxicity and/or ototoxicity and potentiate neomycin sulfate’s neuromuscular blocking effects.

Oral neomycin inhibits the gastrointestinal absorption of penicillin V, oral vitamin B-12, methotrexate and 5-fluorouracil. The gastrointestinal absorption of digoxin also appears to be inhibited. Therefore, digoxin serum levels should be monitored.

Oral Denomix (Neomycin Sulfate) may enhance the effect of coumarin in anticoagulants by decreasing vitamin K availability.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed with Denomix to evaluate carcinogenic or mutagenic potential or impairment of fertility.

Pregnancy Category D

See WARNINGS section.

Nursing Mothers

It is not known whether neomycin is excreted in human milk, but it has been shown to be excreted in cow milk following a single intramuscular injection. Other aminoglycosides have been shown to be excreted in human milk. Because of the potential for serious adverse reactions from the aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of oral Denomix (Neomycin Sulfate) in patients less than 18 years of age have not been established. If treatment of a patient less than 18 years of age is necessary, neomycin should be used with caution and the period of treatment should not exceed two weeks because of absorption from the gastrointestinal tract.

ADVERSE REACTIONS

The most common adverse reactions to oral Denomix (Neomycin Sulfate) are nausea, vomiting and diarrhea. The "Malabsorption Syndrome" characterized by increased fecal fat, decreased serum carotene and fall in xylose absorption has been reported with prolonged therapy. Nephrotoxicity, ototoxicity and neuromuscular blockage have been reported (see boxed WARNINGS and PRECAUTIONS sections).

OVERDOSAGE

Because of low absorption, it is unlikely that acute overdosage would occur with oral Denomix (Neomycin Sulfate). However, prolonged administration could result in sufficient systemic drug levels to produce neurotoxicity, ototoxicity and/or nephrotoxicity.

Hemodialysis will remove Denomix (Neomycin Sulfate) from the blood.

DOSAGE AND ADMINISTRATION

To minimize the risk of toxicity, use the lowest possible dose and the shortest possible treatment period to control the condition. Treatment for periods longer than two weeks is not recommended.

Hepatic Coma

For use as an adjunct in the management of hepatic coma, the recommended dose is 4 to 12 grams per day given in the following regimen:

• Withdraw protein from diet. Avoid use of diuretic agents.
• Give supportive therapy, including blood products, as indicated.
• Give Denomix (Neomycin Sulfate) tablets in doses of 4 to 12 grams of Denomix (Neomycin Sulfate) per day (eight to 24 tablets) in divided doses. Treatment should be continued over a period of five to six days, during which time protein should be returned incrementally to the diet.
• If less potentially toxic drugs cannot be used for chronic hepatic insufficiency, neomycin in doses of up to four grams daily (eight tablets per day) may be necessary. The risk for the development of neomycin-induced toxicity progressively increases when treatment must be extended to preserve the life of a patient with hepatic encephalopathy who has failed to fully respond. Frequent periodic monitoring of these patients to ascertain the presence of drug toxicity is mandatory (see PRECAUTIONS ). Also, neomycin serum concentrations should be monitored to avoid potentially toxic levels. The benefits to the patient should be weighed against the risks of nephrotoxicity, permanent ototoxicity and neuromuscular blockade following the accumulation of neomycin in the tissues.

Preoperative Prophylaxis for Elective Colorectal Surgery

Listed below is an example of a recommended bowel preparation regimen. A proposed surgery time of 8:00 a.m. has been used.

Pre-op Day 3: Minimum residue or clear liquid diet. Bisacodyl, 1 tablet orally at 6:00 p.m.

Pre-op Day 2: Minimum residue or clear liquid diet. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., 2:00 p.m., and 6:00 p.m. Enema at 7:00 p.m. and 8:00 p.m.

Pre-op Day 1: Clear liquid diet. Supplemental (IV) fluids as needed. Magnesium sulfate, 30 mL, 50% solution (15 g) orally at 10:00 a.m., and 2:00 p.m. Denomix (Neomycin Sulfate) (1 g) and erythromycin base (1 g) orally at 1:00 p.m., 2:00 p.m. and 11:00 p.m. No enema.

Day of Operation: Patient evacuates rectum at 6:30 a.m. for scheduled operation at 8:00 a.m.

HOW SUPPLIED

Denomix (Neomycin Sulfate) tablets USP, 500 mg (equivalent to 350 mg of neomycin base per tablet) are available as white to off-white, round, standard convex tablets debossed "LCI" on one side and "1210", on the other side and are supplied in:

Bottles of 100 (NDC 0527-1210-01)

Store at 20° to 25°C (68° to 77°F).

Dispense in tight containers as defined in the USP/NF.

Distributed By:

Lannett Company, Inc.

Philadelphia, PA 19154

Made in the USA

Rev. 01/17

CIB71710A