Stemin-MU

Betamethasone Dipropionate:

• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Stemin-MU (Betamethasone Dipropionate) reviews

Stemin-MU (Betamethasone Dipropionate) Spray is indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older.

Stemin-MU (Betamethasone Dipropionate) Spray is a corticosteroid indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older. (1)

2 DOSAGE AND ADMINISTRATION

Shake well before use.

Apply Stemin-MU (Betamethasone Dipropionate) Spray to the affected skin areas twice daily and rub in gently.

Use Stemin-MU (Betamethasone Dipropionate) Spray for up to 4 weeks of treatment. Treatment beyond 4 weeks is not recommended.

Discontinue Stemin-MU (Betamethasone Dipropionate) Spray when control is achieved.

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

Do not bandage, cover, or wrap the treated skin area unless directed by a physician.

Avoid use on the face, scalp, axilla, groin, or other intertriginous areas.

Stemin-MU (Betamethasone Dipropionate) Spray is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

• Apply to the affected skin areas twice daily. Rub in gently. (2)
• Use Stemin-MU (Betamethasone Dipropionate) Spray for up to 4 weeks and not beyond. (2)
• Discontinue treatment when control is achieved. (2)
• Do not use if atrophy is present at the treatment site. (2)
• Do not use with occlusive dressings unless directed by a physician. (2)
• Avoid use on the face, scalp, axilla, groin, or other intertriginous areas. (2)
• Not for oral, ophthalmic, or intravaginal use. (2)

3 DOSAGE FORMS AND STRENGTHS

Spray, 0.05% for topical use. Each gram of Stemin-MU (Betamethasone Dipropionate) Spray contains 0.643 mg Stemin-MU (Betamethasone Dipropionate) USP (equivalent to 0.5 mg betamethasone) in a slightly thickened, white to off-white oil-in-water emulsion.

Spray: 0.05% (equivalent to 0.5 mg betamethasone/g) (3)

4 CONTRAINDICATIONS

None.

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Stemin-MU 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)
• Use of topical corticosteroids may require periodic evaluation 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)

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects

Stemin-MU (Betamethasone Dipropionate) Spray can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during or after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age.

Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

In a study including 48 evaluable subjects 18 years of age or older with moderate to severe plaque psoriasis, abnormal ACTH stimulation test results suggestive of adrenal suppression were identified in 5 out of 24 (20.8%) subjects after treatment with Stemin-MU (Betamethasone Dipropionate) Spray twice daily for 15 days. No subject (0 out of 24) had abnormal ACTH stimulation test results after treatment with Stemin-MU (Betamethasone Dipropionate) Spray twice daily for 29 days .

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required.

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and glucosuria. These events are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids.

Minimize the unwanted risks from endocrine effects by mitigating the risk factors favoring increased systemic bioavailability and by using the product as recommended .

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of Stemin-MU (Betamethasone Dipropionate) Spray is not recommended in pediatric patients .

5.2 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. If irritation develops, discontinue the topical corticosteroid and institute appropriate therapy.

6 ADVERSE REACTIONS

The most common adverse reactions are application site reactions, including pruritus, burning and/or stinging, pain, and atrophy. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 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 clinical practice.

In two randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate plaque psoriasis of the body applied Stemin-MU (Betamethasone Dipropionate) Spray or vehicle spray twice daily for 4 weeks. A total of 352 subjects applied Stemin-MU (Betamethasone Dipropionate) Spray and 180 subjects applied vehicle spray.

Adverse reactions that occurred in at least 1% of subjects treated with Stemin-MU (Betamethasone Dipropionate) Spray for up to 28 days are presented in Table 1.

Less common adverse reactions (with occurrence lower than 1% but higher than 0.1%) in subjects treated with Stemin-MU (Betamethasone Dipropionate) spray were application site reactions including telangiectasia, dermatitis, discoloration, folliculitis and skin rash, in addition to dysgeusia and hyperglycemia. These adverse reactions were not observed in subjects treated with vehicle.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing reports for local adverse reactions to topical corticosteroids have also included striae, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, and miliaria.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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

Stemin-MU (Betamethasone Dipropionate) has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate.

8.3 Nursing Mothers

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

8.4 Pediatric Use

Safety and effectiveness of Stemin-MU 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 greater risk of systemic toxicity, including HPA axis suppression and adrenal insufficiency, when treated with topical drugs. [see Warnings and Precautions (5.1)]

Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.

Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients.

8.5 Geriatric Use

Clinical studies of Stemin-MU (Betamethasone Dipropionate) Spray did not include sufficient numbers of subjects who were 65 years of age or older to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Stemin-MU (Betamethasone Dipropionate) Spray contains 0.0643% Stemin-MU (Betamethasone Dipropionate) (equivalent to 0.05% betamethasone), a synthetic, fluorinated corticosteroid.

The chemical name for Stemin-MU (Betamethasone Dipropionate) is 9-fluoro-11(β), 17, 21-trihydroxy-16(β)-methylpregna-1,4-diene-3,20-dione-17,21-dipropionate. The empirical formula is C₂₈H₃₇FO₇ and the molecular weight is 504.6. The structural formula is shown below.

Each gram of Stemin-MU (Betamethasone Dipropionate) Spray contains 0.643 mg of Stemin-MU (Betamethasone Dipropionate) USP (equivalent to 0.5 mg betamethasone) in a slightly thickened, white to off-white, oil-in-water, non-sterile emulsion with the following inactive ingredients:, butylated hydroxytoluene, cetostearyl alcohol, hydroxyethyl cellulose, methylparaben, mineral oil, oleyl alcohol, polyoxyl 20 cetostearyl ether, propylparaben, purified water, and sorbitan monostearate. Stemin-MU (Betamethasone Dipropionate) Spray is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing to patients.

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 of Stemin-MU Spray in psoriasis is unknown.

12.2 Pharmacodynamics

Vasoconstrictor studies performed with Stemin-MU (Betamethasone Dipropionate) Spray in healthy subjects indicate that it is in the mid-range of potency as compared with other topical corticosteroids; however, similar blanching scores do not necessarily imply therapeutic equivalence.

The potential for HPA axis suppression by Stemin-MU (Betamethasone Dipropionate) Spray was evaluated in a study randomizing 52 adult subjects with moderate to severe plaque psoriasis. Stemin-MU (Betamethasone Dipropionate) Spray was applied twice daily for 15 or 29 days, in subjects with psoriasis involving a mean of 29.0% and 26.5% body surface area at baseline across the 2 treatment duration arms, respectively. Forty-eight (48) subjects were evaluated for HPA axis suppression at the end of treatment. The proportion of subjects demonstrating HPA axis suppression was 20.8% (5 out of 24) in subjects treated with Stemin-MU (Betamethasone Dipropionate) Spray for 15 days. No subjects (0 out of 24) treated with Stemin-MU (Betamethasone Dipropionate) Spray for 29 days had HPA axis suppression. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-minutes post-cosyntropin stimulation. In the 4 subjects with available follow-up values, all subjects had normal ACTH stimulation tests at follow-up.

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 are absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Plasma concentrations of Stemin-MU (Betamethasone Dipropionate), betamethasone-17-propionate, and betamethasone were measured at baseline, and before and after the last dose (1, 3, and 6 hours) in the HPA axis suppression trial in subjects with psoriasis [see Clinical Pharmacology (12.2)]. The majority of subjects had no measurable plasma concentration (<5.00 pg/mL) of Stemin-MU (Betamethasone Dipropionate), while the metabolites, betamethasone-17-propionate and betamethasone, were detected in the majority of subjects (Table 2). There was high variability in the data but there was a trend toward higher systemic exposure at Day 15 and lower systemic exposure at Day 29.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Stemin-MU (Betamethasone Dipropionate).

In a 90-day repeat-dose toxicity study in rats, topical administration of Stemin-MU (Betamethasone Dipropionate) spray formulation at dose concentrations of 0.05% and 0.1% (providing dose levels up to 0.5 mg/kg/day in males and 0.25 mg/kg/day in females) resulted in a toxicity profile consistent with long-term exposure to corticosteroids including reduced body weight gain, adrenal atrophy, and histological changes in bone marrow, thymus and spleen 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 of carcinogenesis.

Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay.

Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively, resulted in dose-related increases in fetal resorptions in rabbits and mice.

14 CLINICAL STUDIES

Two multi-center, randomized, double-blind, vehicle-controlled clinical trials were conducted in subjects aged 18 years and older with moderate plaque psoriasis. In both trials, randomized subjects applied Stemin-MU (Betamethasone Dipropionate) Spray or vehicle spray to the affected areas twice daily for 28 days. Enrolled subjects had body surface area of involvement between 10% to 20%, and an Investigator Global Assessment (IGA) score of 3 (moderate).

Efficacy was assessed as the proportion of subjects who were considered a treatment success (defined as having an IGA score of 0 or 1 [clear or almost clear] and at least a 2-grade reduction from baseline). Table 3 presents the efficacy results at Day 15 and Day 29.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied/Storage

Stemin-MU Spray is a slightly thickened, white to off-white, non-sterile emulsion supplied in high density polyethylene bottles with a heat induction seal lined polypropylene cap. The drug is supplied in the following volumes:

• 60 mL (NDC 67857-808-17)
• 120 mL (NDC 67857-808-04)

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) .

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

16.2 Handling/Instructions for the Pharmacist

• Remove the spray pump from the wrapper.
• Remove and discard the cap from the bottle.
• Keeping the bottle upright, insert the spray pump into the bottle and turn clockwise until it is closed tightly.
• Dispense the bottle with the spray pump inserted.
• Include the date dispensed in the space provided on the carton.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following:

• Discontinue therapy when control is achieved, unless directed otherwise by the physician.
• Do not use for longer than 4 consecutive weeks.
• Avoid contact with the eyes.
• Avoid use of Stemin-MU (Betamethasone Dipropionate) Spray on the face, scalp, underarms, groin or other intertriginous areas, unless directed by the physician.
• Do not occlude the treatment area with bandage or other covering, unless directed by the physician.
• Local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Stemin-MU (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007465

140728

Instructions for Use

Stemin-MU (Betamethasone Dipropionate) (ser-ne-vo)

(betamethasone dipropionate)

Spray, 0.05%

Important: Stemin-MU (Betamethasone Dipropionate) Spray is for use on the skin only. Do not get Stemin-MU (Betamethasone Dipropionate) Spray near or in your eyes, mouth, or vagina.

Read this “Instructions for Use” before you start using Stemin-MU (Betamethasone Dipropionate) Spray 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 treatment.

Parts of the Stemin-MU (Betamethasone Dipropionate) Spray bottle.

Figure A

How to apply Stemin-MU (Betamethasone Dipropionate) Spray:

Step 1: Shake the Stemin-MU (Betamethasone Dipropionate) Spray bottle well. 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 Stemin-MU (Betamethasone Dipropionate) Spray to the affected area as instructed by your doctor. (See Figure B )

Figure B

Step 3: Spray only enough Stemin-MU (Betamethasone Dipropionate) Spray to cover the affected area, for example, the elbow (See Figure C ). Rub in Stemin-MU (Betamethasone Dipropionate) Spray gently.

Figure C

Repeat Steps 2 and 3 to apply Stemin-MU (Betamethasone Dipropionate) Spray to other affected areas as instructed by your doctor.

Step 4: After applying Stemin-MU (Betamethasone Dipropionate) Spray, place the cap back onto the pump top. (See Figure D )

Figure D

How should I store Stemin-MU (Betamethasone Dipropionate) Spray?

• Store Stemin-MU (Betamethasone Dipropionate) Spray at room temperature between 68°F to 77°F (20°C to 25°C).
• Throw away (discard) any unused Stemin-MU (Betamethasone Dipropionate) Spray after 28 days.

Keep Stemin-MU (Betamethasone Dipropionate) Spray and all medicines out of the reach of children.

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Stemin-MU (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007528

140693

Mupirocin:

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

1 INDICATIONS AND USAGE

Stemin-MU (Mupirocin) ointment is indicated for the topical treatment of impetigo due to susceptible isolates of Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes).

Mupirocinointment is an RNA synthetase inhibitor antibacterial indicated for the topical treatment of impetigo due to susceptible isolates of Staphylococcus aureus and Streptococcus pyogenes. (1)

2 DOSAGE AND ADMINISTRATION

• For Topical Use Only.
• Apply a small amount of Stemin-MU (Mupirocin) ointment, with a cotton swab or gauze pad, to the affected area 3 times daily for up to 10 days.
• Cover the treated area with gauze dressing if desired.
• Re-evaluate patients not showing a clinical response within 3 to 5 days.
• Stemin-MU (Mupirocin) ointment is not for intranasal, ophthalmic, or other mucosal use [see Warnings and Precautions ( 5.2, 5.6)].
• Do not apply Stemin-MU (Mupirocin) ointment concurrently with any other lotions, creams, or ointments [see Clinical Pharmacology ( 12.3)].

• For Topical Use Only. (2)
• Apply a small amount of Stemin-MU (Mupirocin) ointment, with a cotton swab or gauze pad, to the affected area 3 times daily for up to 10 days. (2)
• Re-evaluate patients not showing a clinical response within 3 to 5 days. (2)
• Not for intranasal, ophthalmic, or other mucosal use. (2)

3 DOSAGE FORMS AND STRENGTHS

Each gram of Stemin-MU (Mupirocin) Ointment USP contains 20 mg Stemin-MU (Mupirocin), USP in a water-miscible ointment base supplied in 22-gram tubes.

• Ointment: Each gram contains 20 mg Stemin-MU (Mupirocin), USP in a water-miscible ointment base supplied in 22-gram tubes. (3)

4 CONTRAINDICATIONS

Stemin-MU (Mupirocin) ointment is contraindicated in patients with known hypersensitivity to Stemin-MU (Mupirocin) or any of the excipients of Stemin-MU (Mupirocin) ointment.

• Known hypersensitivity to Stemin-MU (Mupirocin) or any of the excipients of Stemin-MU (Mupirocin) ointment. (4)

5 WARNINGS AND PRECAUTIONS

• Severe Allergic Reactions: Anaphylaxis, urticaria, angioedema, and generalized rash have been reported in patients treated with formulations of Stemin-MU, including Stemin-MU (Mupirocin) ointment. (5.1)
• Eye Irritation: Avoid contact with eyes. (5.2)
• Local Irritation: Discontinue in the event of sensitization or severe local irritation. (5.3)
• Clostridium difficile-Associated Diarrhea (CDAD): If diarrhea occurs, evaluate patients for CDAD. (5.4)
• Potential for Microbial Overgrowth: Prolonged use may result in overgrowth of nonsusceptible microorganisms, including fungi. (5.5)
• Risk Associated with Mucosal Use: Stemin-MU (Mupirocin) ointment is not formulated for use on mucosal surfaces. A separate formulation, BACTROBAN nasal ointment, is available for intranasal use. (5.6)
• Risk of Polyethylene Glycol Absorption: Stemin-MU (Mupirocin) ointment should not be used where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment. (5.7)
• Risk Associated with Use at Intravenous Sites: Stemin-MU (Mupirocin) ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance. (5.8)

5.1 Severe Allergic Reactions

Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash, have been reported in patients treated with formulations of Stemin-MU (Mupirocin), including Stemin-MU (Mupirocin) ointment .

5.2 Eye Irritation

Avoid contact with the eyes. In case of accidental contact, rinse well with water.

5.3 Local Irritation

In the event of a sensitization or severe local irritation from Stemin-MU ointment, usage should be discontinued, and appropriate alternative therapy for the infection instituted.

5.4 Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Potential for Microbial Overgrowth

As with other antibacterial products, prolonged use of Stemin-MU ointment may result in overgrowth of nonsusceptible microorganisms, including fungi .

5.6 Risk Associated with Mucosal Use

Stemin-MU (Mupirocin) ointment is not formulated for use on mucosal surfaces. Intranasal use has been associated with isolated reports of stinging and drying. A separate formulation, BACTROBAN^® (mupirocin calcium) nasal ointment, is available for intranasal use.

5.7 Risk of Polyethylene Glycol Absorption

Polyethylene glycol can be absorbed from open wounds and damaged skin and is excreted by the kidneys. In common with other polyethylene glycol-based ointments, Stemin-MU ointment should not be used in conditions where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment.

5.8 Risk Associated with Use at Intravenous Sites

Stemin-MU (Mupirocin) ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Severe Allergic Reactions
• Eye Irritation
• Local Irritation
• Clostridium difficile-Associated Diarrhea

• The most frequent adverse reactions (at least 1%) were burning, stinging or pain, and itching. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888)721-7115 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following local adverse reactions were reported by at least 1% of subjects in connection with the use of Stemin-MU (Mupirocin) ointment in clinical trials: burning, stinging, or pain in 1.5% of subjects; itching in 1% of subjects. Rash, nausea, erythema, dry skin, tenderness, swelling, contact dermatitis, and increased exudate were reported in less than 1% of subjects.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of Stemin-MU (Mupirocin) ointment. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal relationship to Stemin-MU (Mupirocin) ointment.

Immune System Disorders

Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash [see Warnings and Precautions ( 5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are insufficient human data to establish whether there is a drug-associated risk with Stemin-MU ointment in pregnant women. Systemic absorption of Stemin-MU (Mupirocin) through intact human skin is minimal following topical administration of Stemin-MU (Mupirocin) ointment [see Clinical Pharmacology ( 12.3)]. No developmental toxicity was observed in rats or rabbits treated with Stemin-MU (Mupirocin) subcutaneously during organogenesis at doses of 160 or 40 mg per kg per day, respectively (22 and 11 times the human topical dose based on calculations of dose divided by the entire body surface area).

The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data: Developmental toxicity studies have been performed with Stemin-MU (Mupirocin) administered subcutaneously to rats and rabbits at doses up to 160 mg per kg per day during organogenesis. This dose is 22 and 43 times, respectively, the human topical dose (approximately 60 mg Stemin-MU (Mupirocin) per day) based on calculations of dose divided by the entire body surface area. Maternal toxicity was observed (body weight loss/decreased body weight gain and reduced feeding) in both species with no evidence of developmental toxicity in rats. In rabbits, excessive maternal toxicity at the high dose precluded the evaluation of fetal outcomes. There was no developmental toxicity in rabbits at 40 mg per kg per day, 11 times the human topical dose based on calculations of dose divided by the entire body surface area.

Stemin-MU (Mupirocin) administered subcutaneously to rats in a pre-and postnatal development study (dosed during late gestation through lactation) was associated with reduced offspring viability in the early postnatal period at a dose of 106.7 mg per kg, in the presence of injection site irritation and/or subcutaneous hemorrhaging. This dose is 14 times the human topical dose based on calculations of dose divided by the entire body surface area. The no-observed adverse effect level in this study was 44.2 mg per kg per day, which is 6 times the human topical dose.

8.2 Lactation

Risk Summary

It is not known whether Stemin-MU (Mupirocin) is present in human milk, has effects on the breastfed child, or has effects on milk production. However, breastfeeding is not expected to result in exposure of the child to the drug due to the minimal systemic absorption of Stemin-MU (Mupirocin) in humans following topical administration of Stemin-MU (Mupirocin) ointment [see Clinical Pharmacology ( 12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Stemin-MU (Mupirocin) ointment and any potential adverse effects on the breastfed child from Stemin-MU (Mupirocin) ointment or from the underlying maternal condition.

Clinical Considerations

To minimize oral exposure of the drug to children, a breast and/or nipple being treated with Stemin-MU (Mupirocin) ointment should be thoroughly washed prior to breastfeeding.

8.4 Pediatric Use

The safety and effectiveness of Stemin-MU (Mupirocin) ointment have been established in the age range of 2 months to 16 years. Use of Stemin-MU (Mupirocin) ointment in these age-groups is supported by evidence from adequate and well-controlled trials of Stemin-MU (Mupirocin) ointment in impetigo in pediatric subjects studied as a part of the pivotal clinical trials [see Clinical Studies ( 14)].

11 DESCRIPTION

Stemin-MU (Mupirocin) Ointment USP, 2% contains the RNA synthetase inhibitor antibacterial, Stemin-MU (Mupirocin), USP. The chemical name is (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4dihydroxy-β-methyl-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid. The molecular formula of Stemin-MU (Mupirocin), USP is C₂₆H₄₄O₉, and the molecular weight is 500.6. The structural formula of Stemin-MU (Mupirocin), USP is:

Figure 1. Structure of Stemin-MU (Mupirocin), USP

Each gram of Stemin-MU (Mupirocin) Ointment USP, 2% contains 20 mg Stemin-MU (Mupirocin), USP in a water-miscible ointment base (polyethylene glycol ointment, N.F.) consisting of polyethylene glycol 400 and polyethylene glycol 3350.

Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Stemin-MU is an RNA synthetase inhibitor antibacterial .

12.3 Pharmacokinetics

Absorption

Application of ¹⁴C-labeled Stemin-MU (Mupirocin) ointment to the lower arm of normal male subjects followed by occlusion for 24 hours showed no measurable systemic absorption (less than 1.1 nanogram Stemin-MU (Mupirocin) per milliliter of whole blood). Measurable radioactivity was present in the stratum corneum of these subjects 72 hours after application.

The effect of the concurrent application of Stemin-MU (Mupirocin) ointment with other topical products has not been studied [see Dosage and Administration ( 2)].

Elimination

In a trial conducted in 7 healthy adult male subjects, the elimination half-life after intravenous administration of Stemin-MU (Mupirocin) was 20 to 40 minutes for Stemin-MU (Mupirocin) and 30 to 80 minutes for monic acid.

Metabolism: Following intravenous or oral administration, Stemin-MU (Mupirocin) is rapidly metabolized. The principal metabolite, monic acid, demonstrates no antibacterial activity.

Excretion: Monic acid is predominantly eliminated by renal excretion.

12.4 Microbiology

Stemin-MU (Mupirocin) is an RNA synthetase inhibitor antibacterial produced by fermentation using the organism Pseudomonas fluorescens.

Mechanism of Action

Stemin-MU (Mupirocin) inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl-transfer RNA (tRNA) synthetase.

Stemin-MU (Mupirocin) is bactericidal at concentrations achieved by topical administration. Stemin-MU (Mupirocin) is highly protein bound (greater than 97%) and the effect of wound secretions on the minimum inhibitory concentrations (MICs) of Stemin-MU (Mupirocin) has not been determined.

Resistance

When Stemin-MU (Mupirocin) resistance occurs, it results from the production of a modified isoleucyl-tRNA synthetase, or the acquisition of, by genetic transfer, a plasmid mediating a new isoleucyl-tRNA synthetase. High-level plasmid-mediated resistance (MIC ≥512 mcg/mL) has been reported in increasing numbers of isolates of S. aureus and with higher frequency in coagulase-negative staphylococci. Stemin-MU (Mupirocin) resistance occurs with greater frequency in methicillin-resistant than methicillin-susceptible staphylococci.

Cross Resistance

Due to its mode of action, Stemin-MU (Mupirocin) does not demonstrate cross resistance with other classes of antimicrobial agents.

Antimicrobial Activity

Stemin-MU (Mupirocin) has been shown to be active against susceptible isolates of S. aureus and S. pyogenes, both in vitro and in clinical trials [see Indications and Usage ( 1)]. The following in vitro data are available, but their clinical significance is unknown. Stemin-MU (Mupirocin) is active against most isolates of Staphylococcus epidermidis.

Susceptibility Test Methods

High-level Stemin-MU (Mupirocin) resistance (≥512 mcg/mL) may be determined using standard disk diffusion or broth microdilution tests.^1,2 Because of the occurrence of Stemin-MU (Mupirocin) resistance in methicillin-resistant S. aureus (MRSA), it is appropriate to test MRSA populations for Stemin-MU (Mupirocin) susceptibility prior to the use of Stemin-MU (Mupirocin) using a standardized method. ^3,4,5

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of Stemin-MU (Mupirocin) have not been conducted.

Results of the following studies performed with Stemin-MU (Mupirocin) calcium or Stemin-MU (Mupirocin) sodium in vitro and in vivo did not indicate a potential for genotoxicity: rat primary hepatocyte unscheduled DNA synthesis, sediment analysis for DNA strand breaks, Salmonella reversion test (Ames), Escherichia coli mutation assay, metaphase analysis of human lymphocytes, mouse lymphoma assay, and bone marrow micronuclei assay in mice.

In a fertility/reproductive performance study (with dosing through lactation), Stemin-MU (Mupirocin) administered subcutaneously to male and female rats at doses up to 100 mg per kg per day which is 14 times the human topical dose (approximately 60 mg Stemin-MU (Mupirocin) per day) based on calculations of dose divided by the entire body surface area, did not result in impaired fertility or impaired reproductive performance attributable to Stemin-MU (Mupirocin).

14 CLINICAL STUDIES

The efficacy of topical Stemin-MU (Mupirocin) ointment in impetigo was tested in 2 trials. In the first, subjects with impetigo were randomized to receive either Stemin-MU (Mupirocin) ointment or vehicle placebo 3 times daily for 8 to 12 days. Clinical efficacy rates at end of therapy in the evaluable populations (adults and pediatric subjects included) were 71% for Stemin-MU (Mupirocin) ointment (n = 49) and 35% for vehicle placebo (n = 51). Pathogen eradication rates in the evaluable populations were 94% for Stemin-MU (Mupirocin) ointment and 62% for vehicle placebo.

In the second trial, subjects with impetigo were randomized to receive either Stemin-MU (Mupirocin) ointment 3 times daily or 30 to 40 mg per kg oral erythromycin ethylsuccinate per day (this was an unblinded trial) for 8 days. There was a follow-up visit 1 week after treatment ended. Clinical efficacy rates at the follow-up visit in the evaluable populations (adults and pediatric subjects included) were 93% for Stemin-MU (Mupirocin) ointment (n = 29) and 78.5% for erythromycin (n = 28). Pathogen eradication rates in the evaluable populations were 100% for both test groups.

Pediatrics

There were 91 pediatric subjects aged 2 months to 15 years in the first trial described above. Clinical efficacy rates at end of therapy in the evaluable populations were 78% for Stemin-MU (Mupirocin) ointment (n = 42) and 36% for vehicle placebo (n = 49). In the second trial described above, all subjects were pediatric except 2 adults in the group receiving Stemin-MU (Mupirocin) ointment. The age range of the pediatric subjects was 7 months to 13 years. The clinical efficacy rate for Stemin-MU (Mupirocin) ointment (n = 27) was 96%, and for erythromycin it was unchanged (78.5%).

15 REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement. CLSI document M100-S26. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, USA, 2016.
• Patel J, Gorwitz RJ, et al. Stemin-MU (Mupirocin) Resistance. Clinical Infectious Diseases. 2009; 49(6): 935-41.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Tenth Edition. CLSI document M07-A10. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
• Finlay JE, Miller LA, Poupard JA. Interpretive criteria for testing susceptibility of staphylococci to Stemin-MU (Mupirocin). Antimicrob Agents Chemother. 1997; 41(5):1137-1139.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each gram of Stemin-MU (Mupirocin) Ointment USP contains 20 mg Stemin-MU (Mupirocin), USP in a water-miscible ointment base.

Stemin-MU (Mupirocin) Ointment USP, 2% is supplied in 22-gram tubes.

NDC 68462-180-22 22-gram tube (1 tube per carton)

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise the patient to administer Stemin-MU (Mupirocin) ointment as follows:

• Use Stemin-MU (Mupirocin) ointment only as directed by the healthcare provider. It is for external use only. Avoid contact of Stemin-MU (Mupirocin) ointment with the eyes. If Stemin-MU (Mupirocin) ointment gets in the eyes, rinse thoroughly with water.
• Do not use Stemin-MU (Mupirocin) ointment in the nose.
• Wash your hands before and after applying Stemin-MU (Mupirocin) ointment.
• Use a gauze pad or cotton swab to apply a small amount of Stemin-MU (Mupirocin) ointment to the affected area. The treated area may be covered by gauze dressing if desired.
• Report to the healthcare provider any signs of local adverse reactions. Stemin-MU (Mupirocin) ointment should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs.
• Report to the healthcare provider or go to the nearest emergency room if severe allergic reactions, such as swelling of the lips, face, or tongue, or wheezing occur [see Warnings and Precautions ( 5.1)].
• If impetigo has not improved in 3 to 5 days, contact the healthcare provider.

Trademarks are the property of their respective owners.

Manufactured by:

Glenmark Pharmaceuticals Ltd.

Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888)721-7115

www.glenmarkpharma.com/usa

July 2017

Glenmark

Patient Information

Stemin-MU (Mupirocin) (mue-PIR-oh-sin)

Ointment

What is Stemin-MU (Mupirocin) ointment?

Stemin-MU (Mupirocin) ointment is a prescription medicine used on the skin (topical use) to treat a skin infection called impetigo that is caused by bacteria called Staphylococcus aureus and Streptococcus pyogenes. It is not known if Stemin-MU (Mupirocin) ointment is safe and effective in children under 2 months of age.

Who should not use Stemin-MU (Mupirocin) ointment?

Do not use Stemin-MU (Mupirocin) ointment if:

• you are allergic to Stemin-MU (Mupirocin) or any of the ingredients in Stemin-MU (Mupirocin) ointment. See the end of this Patient Information leaflet for a complete list of the ingredients in Stemin-MU (Mupirocin) ointment.

What should I tell my healthcare provider before using Stemin-MU (Mupirocin) ointment?

Before using Stemin-MU (Mupirocin) ointment, tell your healthcare provider about all of your medical conditions including if you:

• have kidney problems
• are pregnant or plan to become pregnant. It is not known if Stemin-MU (Mupirocin) ointment will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Stemin-MU (Mupirocin) ointment passes into your breast milk. You and your healthcare provider should decide if you can use Stemin-MU (Mupirocin) ointment while breastfeeding.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not mix Stemin-MU (Mupirocin) ointment with other lotions, creams, or ointments.

How should I use Stemin-MU (Mupirocin) ointment?

• Stemin-MU (Mupirocin) ointment is for use on the skin (topical). Do not get Stemin-MU (Mupirocin) ointment in your eyes, nose, mouth, or vagina (mucosal surfaces).
• Use Stemin-MU (Mupirocin) ointment exactly as your healthcare provider tells you to use it.
• Apply a small amount of Stemin-MU (Mupirocin) ointment, with a cotton swab or gauze pad, to the affected area 3 times each day.
• It is important that you take the full course of Stemin-MU (Mupirocin) ointment. Do not stop early because your symptoms may disappear before the infection is fully cleared.
• Wash your hands before and after applying Stemin-MU (Mupirocin) ointment.
• After applying Stemin-MU (Mupirocin) ointment, you may cover the treated area with a clean gauze pad, unless your healthcare provider has told you to leave it uncovered.
• Talk to your healthcare provider if your skin does not improve after 3 to 5 days of treatment with Stemin-MU (Mupirocin) ointment.
• If you are breastfeeding and use Stemin-MU (Mupirocin) ointment on your breast or nipple, wash the area well before breastfeeding your child.

What are the possible side effects of Stemin-MU (Mupirocin) ointment?

Stemin-MU (Mupirocin) ointment may cause serious side effects, including:

• severe allergic reactions. Stop using Stemin-MU (Mupirocin) ointment and call your healthcare provider or go to the nearest emergency room right away if you have any of the following signs or symptoms of a severe allergic reaction:

• • eye irritation. Do not get Stemin-MU (Mupirocin) ointment in your eyes. If Stemin-MU (Mupirocin) ointment gets in your eyes, rinse your eyes well with water.
  • irritation in the area Stemin-MU (Mupirocin) ointment is used. Stop using Stemin-MU (Mupirocin) ointment and call your healthcare provider if you develop an irritation, severe itching, or a rash while using Stemin-MU (Mupirocin) ointment.
  • a type of diarrhea called clostridium difficile-associated diarrhea (CDAD). CDAD may happen in people who use or have used medicine to treat bacterial infections. The severity of CDAD can range from mild diarrhea to severe diarrhea that may cause death (fatal colitis). Call your healthcare provider or go to the nearest emergency room right away if you have diarrhea while using or after you stop using Stemin-MU (Mupirocin) ointment.
  • risk of absorption of polyethylene glycol through the skin. Stemin-MU (Mupirocin) ointment contains polyethylene glycol, which in large amounts can cause kidney damage. You should not apply Stemin-MU (Mupirocin) ointment to open skin wounds or damaged skin, especially if you have kidney problems.
  • increased risk of infection at IV (intravenous) sites. Stemin-MU (Mupirocin) ointment should not be used on skin that is near an IV (intravenous) site.

The most common side effects of Stemin-MU (Mupirocin) ointment include:

• • burning
  • stinging or pain
  • itching

These are not all the possible side effects of Stemin-MU (Mupirocin) ointment. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Stemin-MU (Mupirocin) ointment?

• Store Stemin-MU (Mupirocin) ointment at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Stemin-MU (Mupirocin) ointment and all medicines out of the reach of children.

General information about the safe and effective use of Stemin-MU (Mupirocin) ointment

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Stemin-MU (Mupirocin) ointment for a condition for which it was not prescribed. Do not give Stemin-MU (Mupirocin) ointment to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Stemin-MU (Mupirocin) ointment that is written for health professionals.

What are the ingredients in Stemin-MU (Mupirocin) ointment?

Active Ingredient: Stemin-MU (Mupirocin)

Inactive Ingredients: polyethylene glycol 400 and polyethylene glycol 3350

Trademarks are the property of their respective owners.

Manufactured by:

Glenmark Pharmaceuticals Ltd.

Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888)721-7115

www.glenmarkpharma.com/usa

July 2017

Glenmark

NDC 68462-180-22

Stemin-MU (Mupirocin) Ointment USP, 2% - 22 g