Flutibact

Fluticasone Propionate:

• Warning: asthma-related death
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Flutibact (Fluticasone Propionate) reviews

WARNING: ASTHMA-RELATED DEATH

Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in ADVAIR^® HFA Inhalation Aerosol, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Therefore, when treating patients with asthma, physicians should only prescribe Flutibact (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Flutibact (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Flutibact (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids .

WARNING: ASTHMA-RELATED DEATH

See full prescribing information for complete boxed warning

• Long-acting beta₂-adrenergic agonists (LABA), such as salmeterol, one of the active ingredients in Flutibact (Fluticasone Propionate) Inhalation Aerosol, increase the risk of asthma-related death. A U.S. trial showed an increase in asthma-related deaths in subjects receiving salmeterol (13 deaths out of 13,176 subjects treated for 28 weeks on salmeterol versus 3 out of 13,179 subjects on placebo). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1)
• When treating patients with asthma, only prescribe Flutibact (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Flutibact (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Flutibact (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. (1, 5.1)

1 INDICATIONS AND USAGE

Flutibact (Fluticasone Propionate) is indicated for the treatment of asthma in patients aged 12 years and older.

LABA, such as salmeterol, one of the active ingredients in Flutibact (Fluticasone Propionate), increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients . Therefore, when treating patients with asthma, physicians should only prescribe Flutibact (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Flutibact (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Flutibact (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Important Limitation of Use

Flutibact (Fluticasone Propionate) is NOT indicated for the relief of acute bronchospasm.

Flutibact (Fluticasone Propionate) is a combination product containing a corticosteroid and a LABA indicated for treatment of asthma in patients aged 12 years and older.

Important limitation:

• Not indicated for relief of acute bronchospasm. (1)

2 DOSAGE AND ADMINISTRATION

Flutibact (Fluticasone Propionate) should be administered as 2 inhalations twice daily by the orally inhaled route only. After inhalation, the patient should rinse his/her mouth with water without swallowing to help reduce the risk of oropharyngeal candidiasis.

More frequent administration or a greater number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of Flutibact (Fluticasone Propionate) is not recommended as some patients are more likely to experience adverse effects with higher doses of salmeterol. Patients using Flutibact (Fluticasone Propionate) should not use additional LABA for any reason.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta₂-agonist should be taken for immediate relief.

For patients aged 12 years and older, the dosage is 2 inhalations twice daily, approximately 12 hours apart.

The recommended starting dosages for Flutibact (Fluticasone Propionate) for patients aged 12 years and older are based upon patients’ asthma severity.

The maximum recommended dosage is 2 inhalations of Flutibact (Fluticasone Propionate) 230/21 twice daily.

Improvement in asthma control following inhaled administration of Flutibact (Fluticasone Propionate) can occur within 30 minutes of beginning treatment, although maximum benefit may not be achieved for 1 week or longer after starting treatment. Individual patients will experience a variable time to onset and degree of symptom relief.

For patients who do not respond adequately to the starting dosage after 2 weeks of therapy, replacing the current strength of Flutibact (Fluticasone Propionate) with a higher strength may provide additional improvement in asthma control.

If a previously effective dosage regimen fails to provide adequate improvement in asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of Flutibact (Fluticasone Propionate) with a higher strength, adding additional inhaled corticosteroid, initiating oral corticosteroids) should be considered.

Prime Flutibact (Fluticasone Propionate) before using for the first time by releasing 4 sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 4 weeks or when it has been dropped, prime the inhaler again by releasing 2 sprays into the air away from the face, shaking well for 5 seconds before each spray.

• For oral inhalation only. (2)
• Treatment of asthma in patients aged 12 years and older: 2 inhalations of Flutibact (Fluticasone Propionate) 45/21, 115/21, or 230/21 twice daily. Starting dosage is based on asthma severity. (2)

3 DOSAGE FORMS AND STRENGTHS

Inhalation Aerosol. Purple plastic inhaler with a light purple strapcap containing a pressurized metered-dose aerosol canister containing 60 or 120 metered inhalations and fitted with a counter. Each actuation delivers a combination of Flutibact (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) from the mouthpiece.

Inhalation Aerosol. Inhaler containing a combination of Flutibact (Fluticasone Propionate) propionate (45, 115, or 230 mcg) and salmeterol (21 mcg) as an aerosol formulation for oral inhalation. (3)

4 CONTRAINDICATIONS

The use of Flutibact (Fluticasone Propionate) is contraindicated in the following conditions:

• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required .
• Hypersensitivity to any of the ingredients .

• Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4)
• Hypersensitivity to any ingredient. (4)

5 WARNINGS AND PRECAUTIONS

• LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations.
• Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2)
• Do not use in combination with an additional medicine containing a LABA because of risk of overdose. (5.3)
• Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. (5.4)
• Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. (5.5)
• Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infection; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.6)
• Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to Flutibact (Fluticasone Propionate). (5.7)
• Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue Flutibact (Fluticasone Propionate) slowly. (5.8)
• If paradoxical bronchospasm occurs, discontinue Flutibact (Fluticasone Propionate) and institute alternative therapy. (5.10)
• Use with caution in patients with cardiovascular or central nervous system disorders because of beta-adrenergic stimulation. (5.12)
• Assess for decrease in bone mineral density initially and periodically thereafter. (5.13)
• Monitor growth of pediatric patients. (5.14)
• Close monitoring for glaucoma and cataracts is warranted. (5.15)
• Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. (5.16, 5.18)
• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.17)

5.1 Asthma-Related Death

LABA, such as salmeterol, one of the active ingredients in Flutibact (Fluticasone Propionate), increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe Flutibact (Fluticasone Propionate) for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Flutibact (Fluticasone Propionate)) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Flutibact (Fluticasone Propionate) for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

A large placebo-controlled U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol. The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized double-blind trial that enrolled LABA-naive subjects with asthma to assess the safety of salmeterol 42 mcg twice daily over 28 weeks compared with placebo when added to usual asthma therapy. A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (Table 1 and Figure 1). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%; relative risk: 4.37 [95% CI: 1.25, 15.34]).

Post hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%; relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%; relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (Table 1). Given the similar basic mechanisms of action of beta₂-agonists, the findings seen in the SMART trial are considered a class effect.

Post hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids, such as Flutibact (Fluticasone Propionate) propionate, the other active ingredient in Flutibact (Fluticasone Propionate), or other long-term asthma control therapy mitigates the risk of asthma-related death.

Table 1. Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART)

^a Life-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to trial treatment to account for early withdrawal of subjects from the trial.

^b Relative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

^c Estimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

^d The total population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the total population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 1. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment

• The counter starts at either 124 or 064, depending on which size inhaler you have. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000.
• Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the canister.
• The purple plastic actuator sprays the medicine from the canister. The actuator has a protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the canister is not in use. The strap keeps the cap attached to the actuator.
• Do not use the actuator with a canister of medicine from any other inhaler.
• Do not use an Flutibact (Fluticasone Propionate) canister with an actuator from any other inhaler.

Before using your Flutibact (Fluticasone Propionate) inhaler

• Take Flutibact (Fluticasone Propionate) out of the foil pouch just before you use it for the first time. Safely throw away the pouch and the drying packet that comes inside the pouch.
• The inhaler should be at room temperature before you use it.

Priming your Flutibact (Fluticasone Propionate) inhaler

• Before you use Flutibact (Fluticasone Propionate) for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it.
• To prime the inhaler, take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray the inhaler 1 time into the air away from your face. See Figure C. Avoid spraying in eyes.

• Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 120 or 060, depending on which size inhaler you have. See Figure D.

• You must prime your inhaler again if you have not used it in more than 4 weeks or if you drop it. Take the cap off the mouthpiece and shake the inhaler well for 5 seconds. Then spray it 1 time into the air away from your face. Shake and spray the inhaler like this 1 more time to finish priming it.

How to use your Flutibact (Fluticasone Propionate) inhaler

Follow these steps every time you use Flutibact (Fluticasone Propionate).

• Step 1. Make sure the canister fits firmly in the actuator. The counter should show through the window in the actuator.
  • Shake the inhaler well for 5 seconds before each spray.
• Take the cap off the mouthpiece of the actuator. Look inside the mouthpiece for foreign objects, and take out any you see.
• Step 2. Hold the inhaler with the mouthpiece down. See Figure E.

• Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it. See Figure F.
• Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth. See Figure F.

• Step 5. After the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.
  • Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can.
    • Wait about 30 seconds and shake the inhaler well for 5 seconds. Repeat steps 2 through 6.
• Step 7. Rinse your mouth with water after breathing in the medicine. Spit out the water. Do not swallow it. See Figure G.

• Step 8. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure it snaps firmly into place.

Cleaning your Flutibact (Fluticasone Propionate) inhaler

Clean your inhaler at least 1 time each week after your evening dose. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H.

Figure H

• Step 9. Take the cap off the mouthpiece. The strap on the cap will stay attached to the actuator. Do not take the canister out of the plastic actuator.
• Step 10. Use a dry cotton swab to clean the small circular opening where the medicine sprays out of the canister. Carefully twist the swab in a circular motion to take off any medicine. See Figure I.

Figure I

• Step 11. Wipe the inside of the mouthpiece with a clean tissue dampened with water. Let the actuator air-dry overnight.

Step 12. Put the cap back on the mouthpiece after the actuator has dried.

Replacing your Flutibact (Fluticasone Propionate) inhaler

• When the counter reads 020, you should refill your prescription or ask your healthcare provider if you need another prescription for Flutibact (Fluticasone Propionate).
• When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you may not receive the right amount of medicine.
• Do not use the inhaler after the expiration date, which is on the packaging it comes in.

For correct use of your Flutibact (Fluticasone Propionate) inhaler, remember:

• The canister should always fit firmly in the actuator.
• Breathe in deeply and slowly to make sure you get all the medicine.
• Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully.
• After each dose, rinse your mouth with water and spit it out. Do not swallow the water.
• Do not take the inhaler apart.
• Always keep the protective cap on the mouthpiece when your inhaler is not in use.
• Always store your inhaler with the mouthpiece pointing down.
• Clean your inhaler at least 1 time each week.

If you have questions about Flutibact (Fluticasone Propionate) or how to use your inhaler, call GlaxoSmithKline (GSK) at 1-888-825-5249 or visit www.advair.com.

ADVAIR is a registered trademark of the GSK group of companies.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2017 the GSK group of companies. All rights reserved.

ADH:1IFU

• This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: February 2017

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
• Flutibact (Mupirocin) reviews

1 INDICATIONS AND USAGE

Flutibact (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 Flutibact (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.
• Flutibact (Mupirocin) ointment is not for intranasal, ophthalmic, or other mucosal use [see Warnings and Precautions ( 5.2, 5.6)].
• Do not apply Flutibact (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 Flutibact (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 Flutibact (Mupirocin) Ointment USP contains 20 mg Flutibact (Mupirocin), USP in a water-miscible ointment base supplied in 22-gram tubes.

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

4 CONTRAINDICATIONS

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

• Known hypersensitivity to Flutibact (Mupirocin) or any of the excipients of Flutibact (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 Flutibact, including Flutibact (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: Flutibact (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: Flutibact (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: Flutibact (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 Flutibact (Mupirocin), including Flutibact (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 Flutibact 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 Flutibact ointment may result in overgrowth of nonsusceptible microorganisms, including fungi .

5.6 Risk Associated with Mucosal Use

Flutibact (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, Flutibact 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

Flutibact (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 Flutibact (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 Flutibact (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 Flutibact (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 Flutibact ointment in pregnant women. Systemic absorption of Flutibact (Mupirocin) through intact human skin is minimal following topical administration of Flutibact (Mupirocin) ointment [see Clinical Pharmacology ( 12.3)]. No developmental toxicity was observed in rats or rabbits treated with Flutibact (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 Flutibact (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 Flutibact (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.

Flutibact (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 Flutibact (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 Flutibact (Mupirocin) in humans following topical administration of Flutibact (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 Flutibact (Mupirocin) ointment and any potential adverse effects on the breastfed child from Flutibact (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 Flutibact (Mupirocin) ointment should be thoroughly washed prior to breastfeeding.

8.4 Pediatric Use

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

11 DESCRIPTION

Flutibact (Mupirocin) Ointment USP, 2% contains the RNA synthetase inhibitor antibacterial, Flutibact (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 Flutibact (Mupirocin), USP is C₂₆H₄₄O₉, and the molecular weight is 500.6. The structural formula of Flutibact (Mupirocin), USP is:

Figure 1. Structure of Flutibact (Mupirocin), USP

Each gram of Flutibact (Mupirocin) Ointment USP, 2% contains 20 mg Flutibact (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

Flutibact is an RNA synthetase inhibitor antibacterial .

12.3 Pharmacokinetics

Absorption

Application of ¹⁴C-labeled Flutibact (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 Flutibact (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 Flutibact (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 Flutibact (Mupirocin) was 20 to 40 minutes for Flutibact (Mupirocin) and 30 to 80 minutes for monic acid.

Metabolism: Following intravenous or oral administration, Flutibact (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

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

Mechanism of Action

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

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

Resistance

When Flutibact (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. Flutibact (Mupirocin) resistance occurs with greater frequency in methicillin-resistant than methicillin-susceptible staphylococci.

Cross Resistance

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

Antimicrobial Activity

Flutibact (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. Flutibact (Mupirocin) is active against most isolates of Staphylococcus epidermidis.

Susceptibility Test Methods

High-level Flutibact (Mupirocin) resistance (≥512 mcg/mL) may be determined using standard disk diffusion or broth microdilution tests.^1,2 Because of the occurrence of Flutibact (Mupirocin) resistance in methicillin-resistant S. aureus (MRSA), it is appropriate to test MRSA populations for Flutibact (Mupirocin) susceptibility prior to the use of Flutibact (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 Flutibact (Mupirocin) have not been conducted.

Results of the following studies performed with Flutibact (Mupirocin) calcium or Flutibact (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), Flutibact (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 Flutibact (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 Flutibact (Mupirocin).

14 CLINICAL STUDIES

The efficacy of topical Flutibact (Mupirocin) ointment in impetigo was tested in 2 trials. In the first, subjects with impetigo were randomized to receive either Flutibact (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 Flutibact (Mupirocin) ointment (n = 49) and 35% for vehicle placebo (n = 51). Pathogen eradication rates in the evaluable populations were 94% for Flutibact (Mupirocin) ointment and 62% for vehicle placebo.

In the second trial, subjects with impetigo were randomized to receive either Flutibact (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 Flutibact (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 Flutibact (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 Flutibact (Mupirocin) ointment. The age range of the pediatric subjects was 7 months to 13 years. The clinical efficacy rate for Flutibact (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. Flutibact (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 Flutibact (Mupirocin). Antimicrob Agents Chemother. 1997; 41(5):1137-1139.

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Flutibact (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 Flutibact (Mupirocin) ointment as follows:

• Use Flutibact (Mupirocin) ointment only as directed by the healthcare provider. It is for external use only. Avoid contact of Flutibact (Mupirocin) ointment with the eyes. If Flutibact (Mupirocin) ointment gets in the eyes, rinse thoroughly with water.
• Do not use Flutibact (Mupirocin) ointment in the nose.
• Wash your hands before and after applying Flutibact (Mupirocin) ointment.
• Use a gauze pad or cotton swab to apply a small amount of Flutibact (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. Flutibact (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

Flutibact (Mupirocin) (mue-PIR-oh-sin)

Ointment

What is Flutibact (Mupirocin) ointment?

Flutibact (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 Flutibact (Mupirocin) ointment is safe and effective in children under 2 months of age.

Who should not use Flutibact (Mupirocin) ointment?

Do not use Flutibact (Mupirocin) ointment if:

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

What should I tell my healthcare provider before using Flutibact (Mupirocin) ointment?

Before using Flutibact (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 Flutibact (Mupirocin) ointment will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Flutibact (Mupirocin) ointment passes into your breast milk. You and your healthcare provider should decide if you can use Flutibact (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 Flutibact (Mupirocin) ointment with other lotions, creams, or ointments.

How should I use Flutibact (Mupirocin) ointment?

• Flutibact (Mupirocin) ointment is for use on the skin (topical). Do not get Flutibact (Mupirocin) ointment in your eyes, nose, mouth, or vagina (mucosal surfaces).
• Use Flutibact (Mupirocin) ointment exactly as your healthcare provider tells you to use it.
• Apply a small amount of Flutibact (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 Flutibact (Mupirocin) ointment. Do not stop early because your symptoms may disappear before the infection is fully cleared.
• Wash your hands before and after applying Flutibact (Mupirocin) ointment.
• After applying Flutibact (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 Flutibact (Mupirocin) ointment.
• If you are breastfeeding and use Flutibact (Mupirocin) ointment on your breast or nipple, wash the area well before breastfeeding your child.

What are the possible side effects of Flutibact (Mupirocin) ointment?

Flutibact (Mupirocin) ointment may cause serious side effects, including:

• severe allergic reactions. Stop using Flutibact (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 Flutibact (Mupirocin) ointment in your eyes. If Flutibact (Mupirocin) ointment gets in your eyes, rinse your eyes well with water.
  • irritation in the area Flutibact (Mupirocin) ointment is used. Stop using Flutibact (Mupirocin) ointment and call your healthcare provider if you develop an irritation, severe itching, or a rash while using Flutibact (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 Flutibact (Mupirocin) ointment.
  • risk of absorption of polyethylene glycol through the skin. Flutibact (Mupirocin) ointment contains polyethylene glycol, which in large amounts can cause kidney damage. You should not apply Flutibact (Mupirocin) ointment to open skin wounds or damaged skin, especially if you have kidney problems.
  • increased risk of infection at IV (intravenous) sites. Flutibact (Mupirocin) ointment should not be used on skin that is near an IV (intravenous) site.

The most common side effects of Flutibact (Mupirocin) ointment include:

• • burning
  • stinging or pain
  • itching

These are not all the possible side effects of Flutibact (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 Flutibact (Mupirocin) ointment?

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

General information about the safe and effective use of Flutibact (Mupirocin) ointment

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Flutibact (Mupirocin) ointment for a condition for which it was not prescribed. Do not give Flutibact (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 Flutibact (Mupirocin) ointment that is written for health professionals.

What are the ingredients in Flutibact (Mupirocin) ointment?

Active Ingredient: Flutibact (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

Flutibact (Mupirocin) Ointment USP, 2% - 22 g