XHANCE

1 INDICATIONS AND USAGE XHANCE is a corticosteroid indicated for the treatment of: Chronic rhinosinusitis with nasal polyps (CRSwNP) in adults. ( 1.1 ) Chronic rhinosinusitis without nasal polyps (CRSsNP) in adults. ( 1.2 ) 1.1 Chronic Rhinosinusitis with Nasal Polyps XHANCE is indicated for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) in adults. 1.2 Chronic Rhinosinusitis without Nasal Polyps XHANCE is indicated for the treatment of chronic rhinosinusitis without nasal polyps (CRSsNP) in adults.

2 DOSAGE AND ADMINISTRATION Recommended Dosage : 186 mcg (1 spray per nostril) or 372 mcg (2 sprays per nostril) twice daily. ( 2.1 ) For nasal use only. Shake before use. Prime before initial use. ( 2.2 ) XHANCE is delivered into the nose by actuating the pump spray into one nostril while simultaneously blowing into the mouthpiece of the device. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of XHANCE is 186 mcg (1 spray per nostril) or 372 mcg (2 sprays per nostril) twice daily (total daily dose of 372 mcg or 744 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril twice daily (total daily dose of 744 mcg). Patients should use XHANCE at regular intervals since its effectiveness depends on regular use. Individual patients will experience a variable time to onset and different degrees of symptom relief. The safety and efficacy of XHANCE when administered in excess of recommended doses have not been established. 2.2 Administration Information Shake XHANCE before each use. Administer XHANCE by the nasal route only. Avoid spraying directly on the nasal septum. Priming Before initial use, prime XHANCE by first gently shaking and then pressing the bottle 7 times or until a fine mist appears. Direct the spray into the air, away from the face. When XHANCE has not been used for ≥ 7 days, prime the pump again by shaking and releasing 2 sprays into the air, away from the face. Administration Instructions XHANCE is delivered into the nose by actuating the pump spray into one nostril while simultaneously blowing (exhaling) into the mouthpiece of the device. To administer XHANCE, insert the tapered tip of the cone-shaped nosepiece deep into one nostril and form a tight seal between the nosepiece and the nostril. Next, place the flexible mouthpiece into the mouth, bending it as necessary to maintain a tight seal with the nostril. Blow into the mouthpiece, and while continuing to blow, push the bottle up to actuate the spray pump. Continuing to blow through the mouth, but not inhaling or exhaling through the nose, at the time of actuation is important to achieve intended drug deposition. Repeat the process in the other nostril for a full dose [see Instructions for Use ] .

4 CONTRAINDICATIONS XHANCE is contraindicated in patients with hypersensitivity to any of the ingredients [see Warnings and Precautions ( 5.3 ) and Description ( 11 )] . Hypersensitivity to any ingredient in XHANCE. ( 4 )

5 WARNINGS AND PRECAUTIONS Local Nasal Adverse Reactions: epistaxis, erosion, ulceration, septal perforation, Candida albicans infection, and impaired wound healing. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcerations, nasal surgery, or nasal trauma. ( 5.1 ) Glaucoma and Cataracts may occur with long-term use. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use XHANCE long-term. ( 5.2 ) Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, rash, hypotension, and bronchospasm) have been reported after administration of fluticasone propionate. Discontinue XHANCE if such reactions occur. ( 5.3 ) Immunosuppression and Risk of Infection: potential increased susceptibility to or 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. ( 5.4 ) Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue XHANCE slowly. ( 5.5 ) Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.7 ) 5.1 Local Nasal Adverse Reactions Epistaxis, Nasal Erosions and Ulcerations In placebo-controlled clinical trials of 16 weeks duration, epistaxis, nasal erosions, and nasal ulcerations were reported more frequently in patients treated with XHANCE than those who received placebo [see Adverse Reactions ( 6.1 )] . Nasal Septal Perforation Nasal septal perforations have been reported in patients following the nasal application of XHANCE. In placebo-controlled clinical trials of 16 weeks duration, nasal septal perforation was reported in 1 (0.3%) patient treated with XHANCE compared with none treated with placebo. The patient had a prior history of nasal/sinus surgery. Three (0.3%) patients treated with XHANCE in uncontrolled, open-label trials of 3 to 12 months duration developed nasal septal perforations. As with any long term topical treatment of the nasal cavity, patients using XHANCE over several months or longer should be examined periodically for possible changes in the nasal mucosa. If a septal perforation is noted, discontinue XHANCE. Avoid spraying XHANCE directly on the septum. Candida Infection In clinical trials with XHANCE, localized infections with Candida albicans have been observed. Eight (0.9%) patients in uncontrolled, open-label trials of 3 to 12 months duration developed Candida albicans infections (nasal, pharyngeal, esophageal or intestinal). If such an infection develops, it may require treatment with appropriate local therapy and discontinuation of XHANCE. Patients using XHANCE should be examined periodically for evidence of Candida infection in the nasal and oropharyngeal mucosa. Impaired Wound Healing Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcerations, nasal surgery, or nasal trauma should avoid using XHANCE until healing has occurred. 5.2 Glaucoma and Cataracts Nasal and inhaled corticosteroids, including fluticasone propionate, may result in the development of glaucoma and/or cataracts. In placebo-controlled clinical trials of 16 weeks duration, cataracts were reported in 4 (1.2%) patients treated with XHANCE, compared with 3 (1.9%) patients treated with placebo. Among these patients, 2 patients treated with XHANCE reported subcapsular cataracts compared with none treated with placebo. Eleven patients (1.2%) in uncontrolled, open-label trials of 3 to 12 months duration developed new or worsening cataracts, of which none were subcapsular. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure (IOP), glaucoma, and/or cataracts. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use XHANCE long-term. 5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, rash, hypotension, and bronchospasm) have been reported after administration of fluticasone propionate. XHANCE is contraindicated in patients with known hypersensitivity to fluticasone propionate or any of the ingredients of XHANCE. Discontinue XHANCE if such reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, rash, hypotension, and bronchospasm) occur [see Contraindications ( 4 ) and Adverse Reactions ( 6.1 )] . 5.4 Immunosuppression and Risk of Infection Persons who are using drugs that suppress the immune system, such as corticosteroids, including XHANCE, are more susceptible to infections than healthy individuals and may experience a worsening of existing infections. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible adults using corticosteroids. In such adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex [see Adverse Reactions ( 6.1 )] . 5.5 Hypercorticism and Adrenal Suppression Hypercorticism and adrenal suppression may occur when nasal corticosteroids, such as XHANCE, are used at higher than recommended dosages or in susceptible individuals at recommended dosages. Since fluticasone propionate is absorbed into the circulation and can be systemically active at higher doses, recommended dosages of XHANCE should not be exceeded to avoid hypothalamic-pituitary-adrenal (HPA) dysfunction. A relationship between plasma levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after 4 weeks of pulmonary treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing XHANCE. Patients treated with XHANCE should be observed carefully for any evidence of systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis). If such effects occur, the dosage of XHANCE should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of nasal symptoms should be considered. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression). After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA function. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress such as trauma, surgery, infection (particularly gastroenteritis), or other conditions associated with severe electrolyte loss. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms [see Adverse Reactions ( 6.1 ) and Clinical Pharmacology ( 12.2 )] . 5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, voriconazole) with XHANCE is not recommended because increased systemic corticosteroid adverse effects may occur [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 5.7 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term oral inhalation of products containing corticosteroids into the lungs. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids), should be monitored and treated with established standards of care. A 2-year trial in 160 patients (females aged 18 to 40 years, males aged 18 to 50 years) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray absorptiometry at lumbar regions L1 through L4. 5.8 Effect on Growth Nasal corticosteroids, including XHANCE, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of XHANCE has not been established in pediatric patients [see Use in Specific Populations ( 8.4 )] .

7 DRUG INTERACTIONS Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use not recommended. May increase risk of systemic corticosteroid effects. ( 7.1 ) 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, voriconazole) with XHANCE is not recommended because increased systemic corticosteroid adverse effects may occur. Ritonavir A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see Clinical Pharmacology ( 12.3 )] . During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate products with ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Ketoconazole Coadministration of orally inhaled fluticasone propionate (1000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Local Nasal Adverse Reactions: [see Warnings and Precautions ( 5.1 )] Glaucoma and Cataracts [see Warnings and Precautions ( 5.2 )] Hypersensitivity Reactions including Anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] Immunosuppression and Risk of Infection [see Warnings and Precautions ( 5.4 )] Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.5 )] Reduction in Bone Mineral Density [see Warnings and Precautions ( 5.7 )] Effect on Growth [see Warnings and Precautions ( 5.8 )] CRSwNP: The most common adverse reactions (incidence ≥ 3%) are epistaxis, nasal septal ulceration, nasopharyngitis, nasal mucosal erythema, nasal mucosal ulcerations, nasal congestion, acute sinusitis, nasal septal erythema, headache, and pharyngitis. ( 6.1 ) CRSsNP: The most common adverse reactions (incidence ≥ 3%) are epistaxis, headache, and nasopharyngitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Paratek Pharmaceuticals, Inc. at 1-833-678-6673 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. Chronic Rhinosinusitis with Nasal Polyps The safety data described below are based on two placebo-controlled clinical trials evaluating doses of a fluticasone propionate nasal spray with an exhalation delivery system from 93 mcg twice daily to 372 mcg twice daily. Both trials were 16-weeks in duration with an additional 8-week open-label extension. The trials included a total of 643 adult patients with bilateral nasal polyps and associated moderate or severe nasal congestion of which 161 received 93 mcg twice daily, 160 received 186 mcg twice daily, 161 received 372 mcg twice daily and 161 received placebo. The overall pooled safety data included 296 (46.0%) Female, 347 (54.0%) Male, 584 (90.8%) White, 39 (6.1%) Black, 9 (1.4%) Asian, and 11 (1.7%) patients classified as Other. Of these patients, 45 (7%) were 65 years of age or older. Table 1 displays adverse reactions with an incidence of ≥ 3% in the XHANCE 186 mcg and 372 mcg twice daily patients, and more common than placebo. Table 1. Summary of Adverse Reactions with XHANCE Reported in ≥ 3% of Patients with CRSwNP and More Common Than Placebo in Placebo-Controlled Studies XHANCE Adverse Reaction Placebo (N = 161) n (%) 186 mcg bid* (N = 160) n (%) 372 mcg bid^ (N = 161) n (%) *186 mcg bid = 1 spray per nostril twice daily ^372 mcg bid = 2 sprays per nostril twice daily 1 Includes spontaneous adverse reaction reports 2 Include ulcerations and erosions Epistaxis 1 4 (2.5) 19 (11.9) 16 (9.9) Nasopharyngitis 8 (5.0) 3 (1.9) 12 (7.5) Nasal septal ulceration 2 3 (1.9) 11 (6.9) 12 (7.5) Nasal congestion 6 (3.7) 7 (4.4) 9 (5.6) Acute sinusitis 6 (3.7) 7 (4.4) 8 (5.0) Headache 5 (3.1) 8 (5.0) 6 (3.7) Pharyngitis 2 (1.2) 2 (1.3) 5 (3.1) Nasal mucosal ulceration 2 2 (1.3) 6 (3.8) 4 (2.5) Nasal mucosal erythema 6 (3.7) 9 (5.6) 8 (5.0) Nasal septal erythema 3 (1.9) 6 (3.8) 7 (4.3) Other adverse reactions with XHANCE observed with an incidence < 3% but ≥ 1% and more common than placebo included: nasal dryness, sinusitis, oropharyngeal pain, toothache, intraocular pressure increase, dizziness, abdominal discomfort, and weight increase. 5.0% of patients treated with XHANCE 186 mcg twice daily and 1.2% of patients treated with 372 mcg twice daily discontinued from the clinical trials prior to the open-label extension because of adverse reactions compared to 4.3% of patients treated with placebo. There were no clinically relevant differences in the incidence of adverse reactions based on gender. Clinical trials did not include sufficient numbers of non-Caucasian patients or patients aged 65 years and older to determine whether they respond differently from Caucasian or younger patients, respectively. Chronic Rhinosinusitis without Nasal Polyps The safety of XHANCE was based on a pooled safety population that reflect the exposure of XHANCE in 367 adults with chronic rhinosinusitis with (CRSwNP) or without nasal polyps (CRSsNP) exposed for 24 weeks duration. XHANCE was studied in two randomized, placebo-controlled, multicenter trials (Trial 3 and Trial 4). Patients received either XHANCE 186 mcg (1 spray per nostril) twice daily, XHANCE 372 mcg (2 sprays per nostril) twice daily, or placebo delivered with an exhalation delivery system. The pooled safety population had a mean age of 49 years [age range: 18 to 87], and were 55% male, 94% White, 96% non-Hispanic or Latino, 4% Black or African American, and 2% Asian. In these trials, 1.6% of patients treated with XHANCE 186 mcg (1 spray per nostril) twice daily and 1.6% of patients treated with 372 mcg (2 sprays per nostril) twice daily discontinued treatment due to adverse reactions compared to 2.7% of patients treated with placebo. The most common adverse reactions that occurred at a rate of ≥ 3% in patients treated with XHANCE and at a higher rate in at least one treatment group than placebo from the pooled safety population (Trials 3 and 4) are shown in Table 2 . Table 2. Summary of Adverse Reactions with XHANCE Reported in ≥ 3% of Patients and More Common Than Placebo from Pooled Safety Population (Trials 3 and 4) 1 XHANCE Adverse Reaction Placebo (N = 187) n (%) 186 mcg bid* (N = 184) n (%) 372 mcg bid^ (N = 183) n (%) *186 mcg bid = 1 spray per nostril twice daily ^372 mcg bid = 2 sprays per nostril twice daily 1 Patients in Trial 3 included adults with CRSsNP and Trial 4 included adults with CRSsNP and CRSwNP Epistaxis 1 (0.5%) 9 (4.9%) 20 (10.9%) Headache 7 (3.7%) 4 (2.2%) 10 (5.5%) Nasopharyngitis 8 (4.3%) 9 (4.9%) 7 (3.8%) 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of XHANCE. Because these 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. Eye disorders: central serous chorioretinopathy Respiratory, thoracic, and mediastinal disorders: dysphonia, nasal discomfort, and nasal dryness Skin and subcutaneous tissue disorders: pruritus, rash

8.1 Pregnancy Risk Summary Available data from published literature on the use of inhaled or nasal fluticasone propionate in pregnant women have not reported a clear association with adverse developmental outcomes. In animals, teratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m 2 basis. However, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis ( see Data ). Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). The rat no observed adverse effect level (NOAEL) was observed at approximately 0.4 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day). Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 0.3 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). The mouse NOAEL was observed with a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 0.34 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity. The NOAEL was observed with a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.02 times the MRHDID and higher (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at a dose approximately 0.1 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). The NOAEL was observed in rabbit fetuses with a dose approximately 0.002 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 0.08 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.7 times the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).