Pirnuo

1 INDICATIONS AND USAGE PIRNUO cream is indicated for the treatment of secondarily infected traumatic skin lesions (up to 10 cm in length or 100 cm 2 in area) due to susceptible isolates of Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes). PIRNUO cream is an RNA synthetase inhibitor antibacterial indicated for the treatment of secondarily infected traumatic skin lesions (up to 10 cm in length or 100 cm 2 in area) due to susceptible isolates of Staphylococcus aureus and Streptococcus pyogenes. ( 1 )

2 DOSAGE AND ADMINISTRATION • For Topical Use Only. • Apply a small amount of PIRNUO cream, with a cotton swab or gauze pad, to the affected area 3 times daily for 10 days. • Cover the treated area with gauze dressing if desired. • Re-evaluate patients not showing a clinical response within 3 to 5 days. • PIRNUO cream is not for intranasal, ophthalmic, or other mucosal use [see Warnings and Precautions ( 5.2 , 5.6 )] . • Do not apply PIRNUO cream concurrently with any other lotions, creams, or ointments [see Clinical Pharmacology ( 12.3 )]. • For Topical Use Only. ( 2 ) • Apply a small amount of PIRNUO cream, with a cotton swab or gauze pad, to the affected area 3 times daily for 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 )

4 CONTRAINDICATIONS PIRNUO cream is contraindicated in patients with known hypersensitivity to mupirocin or any of the excipients of PIRNUO cream. • Known hypersensitivity to mupirocin or any of the excipients of PIRNUO cream. ( 4 )

5 WARNINGS AND PRECAUTIONS • Severe Allergic Reactions: Anaphylaxis, urticaria, angioedema, and generalized rash have been reported in patients treated with formulations of mupirocin, including mupirocin cream. ( 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: PIRNUO cream is not formulated for use on mucosal surfaces. A separate formulation, BACTROBAN nasal ointment, is available for intranasal use. ( 5.6 ) 5.1 Severe Allergic Reactions Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash, have been reported in patients treated with formulations of mupirocin, including mupirocin cream [see Adverse Reactions ( 6.2 )]. 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 PIRNUO cream, 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 PIRNUO cream may result in overgrowth of nonsusceptible microorganisms, including fungi [see Dosage and Administration ( 2 )] . 5.6 Risk Associated with Mucosal Use PIRNUO cream is not formulated for use on mucosal surfaces. A separate formulation, BACTROBAN(mupirocin) nasal ointment, is available for intranasal use.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Severe Allergic Reactions [see Warnings and Precautions ( 5.1 )] • Eye Irritation [see Warnings and Precautions ( 5.2 )] • Local Irritation [see Warnings and Precautions ( 5.3 )] • Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] • The most frequent adverse reactions (at least 1%) were headache, rash, and nausea. ( 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. In 2 randomized, double-blind, double-dummy trials, 339 subjects were treated with topical mupirocin cream plus oral placebo. Adverse reactions occurred in 28 (8.3%) subjects. The following adverse reactions were reported by at least 1% of subjects in connection with the use of mupirocin cream in clinical trials: headache (1.7%), rash (1.1%), and nausea (1.1%). Other adverse reactions which occurred in less than 1% of subjects were: abdominal pain, burning at application site, cellulitis, dermatitis, dizziness, pruritus, secondary wound infection, and ulcerative stomatitis. In a supportive trial in the treatment of secondarily infected eczema, 82 subjects were treated with mupirocin cream. The incidence of adverse reactions was as follows: nausea (4.9%), headache and burning at application site (3.6% each), pruritus (2.4%), and 1 report each of abdominal pain, bleeding secondary to eczema, pain secondary to eczema, hives, dry skin, and rash. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of mupirocin cream. 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 mupirocin cream. Immune System Disorders Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash [see Warnings and Precautions ( 5.1 )] .

8.1 Pregnancy Risk Summary There are insufficient human data to establish whether there is a drug-associated risk with mupirocin cream in pregnant women. Systemic absorption of mupirocin through intact human skin is minimal following topical administration of mupirocin cream [see Clinical Pharmacology (12.3)] . No developmental toxicity was observed in rats or rabbits treated with 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 miscarriage 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 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 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. 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.