b'XHANCE (fluticasone propionate) nasal spray for intranasal use. Rx only. with established standards of care. A 2-year trial in 160 subjects (females aged 18 to 40 years, males 45Brief Summary of Prescribing Information (PI) for XHANCE. See full PI. aged 18 to 50 years) with asthma receiving chlorofluorocarbon (CFC)-propelled fluticasone propionate IMPORTANT DOSING CONSIDERATIONS: inhalation aerosol 88 or 440 mcg twice daily demonstrated no statistically significant changes in BMD at Use Twice Daily for Best Effect: Inform patients that they should use XHANCE on a regular basis as directed.any time point (24, 52, 76, and 104 weeks of double-blind treatment) as assessed by dual-energy x-ray XHANCE, like other corticosteroids, does not have an immediate effect on nasal polyps or symptoms.absorptiometry at lumbar regions L1 through L4.Individual patients will experience a variable time to onset and degree of symptom relief and the full benefitEffect on Growth: Intranasal corticosteroids may cause a reduction in growth velocity when administered to may not be achieved until treatment has been administered for up to 16 weeks or longer. Maximum benefitpediatric patients. The safety and efficacy of XHANCE has not been established in pediatric patients.may not be reached for a period of months. Patients should not increase the prescribed dosage but shouldADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying contact their healthcare providers if symptoms do not improve or if the condition worsens. If a patientconditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates missed a dose, the patient should be advised to take the dose as soon as they remember. The patient shouldin the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described not take more than the recommended dose for the day. below are based on two placebo-controlled clinical trials evaluating doses of a fluticasone propionate exhalation Keep Spray Out of Eyes and Mouth: Inform patients to avoid spraying XHANCE in their eyes and mouth. delivery system from 93 mcg twice daily to 372 mcg twice daily. Both trials were 16-weeks in duration with an How to Use XHANCE nasal spray: It is important for patients to understand how to correctly administer XHANCEadditional 8-week open-label extension. The trials included a total of 643 adult subjects with bilateral nasal polyps nasal spray using the exhalation delivery system. Advise the patient to carefully read the patient Instructions forand associated moderate or severe nasal congestion of which 161 received 93 mcg twice daily, 160 received Use. The patient should note the difference in appearance of the cone-shaped, non-flexible nosepiece and the186 mcg twice daily, 161 received 372 mcg twice daily and 161 received placebo. The overall pooled safety data longer flexible mouthpiece. Patients should be advised not to try to inhale (e.g., sniff) when blowing (exhaling)included 296 (46.0%) Female, 347 (54.0%) Male, 584 (90.8%) White, 39 (6.1%) Black, 9 (1.4%) Asian, and 11 into the mouthpiece. Patients should be advised not to block the other nostril because the exhaled breath must(1.7%) subjects classified as Other. Of these patients, 45 (7%) were 65 years of age or older. All adverse reactions pass around the back of the nasal septum and out the other side of the nose. with an incidence of3% in the XHANCE 186 mcg (n = 160) and 372 mcg (n = 161) twice daily subjects, and CONTRAINDICATIONS: XHANCE should not be administered to patients with a history of hypersensitivity tomore common than placebo (n = 161) were as follows (% Placebo, % XHANCE 186 mcg, and % XHANCE 372 any ingredient in XHANCE. mcg): Epistaxis (2.5%, 11.9%, 9.9%), Nasopharyngitis (5.0%, 1.9%, 7.5%), Nasal septal erosion and ulceration (1.9%, 6.9%, 7.5%), Nasal congestion (3.7%, 4.4%, 5.6%), Acute sinusitis (3.7%, 4.4%, 5.0%), Headache (3.1%, WARNINGS & PRECAUTIONS: 5.0%, 3.7%), Pharyngitis (1.2%, 1.3%, 3.1%), Nasal mucosal erosion and ulceration (1.3%, 3.8%, 2.5%), Nasal Local Nasal Effects mucosal erythema (3.7%, 5.6%, 5.0%) and Nasal septal erythema (1.9%, 3.8%, 4.3%).Other adverse reactions Epistaxis, Nasal Erosions and Ulcerations: In placebo-controlled clinical trials of 16 weeks duration, epistaxis,with XHANCE observed with an incidence 3% but1% and more common than placebo included: nasal nasal erosions and nasal ulcerations were reported more frequently in patients treated with XHANCE thandryness, sinusitis, oropharyngeal pain, toothache, intraocular pressure increase, dizziness, abdominal discomfort, those who received placebo. and weight increase. 5.0% of subjects treated with XHANCE 186 mcg twice daily and 1.2% of subjects treated Nasal Septal Perforation: Nasal septal perforations have been reported in patients following the intranasalwith 372 mcg twice daily discontinued from the clinical trials prior to the open-label extension because of adverse application of XHANCE. In placebo-controlled clinical trials of 16 weeks duration, nasal septal perforationsreactions compared to 4.3% of subjects treated with placebo. There were no clinically relevant differences in the were reported in 1 (0.3%) patient treated with XHANCE compared with none treated with placebo.incidence of adverse reactions based on gender. Clinical trials did not include sufficient numbers of non-Caucasian The patient had a prior history of nasal/sinus surgery. Three (0.3%) patients treated with XHANCE inpatients or patients aged 65 years and older to determine whether they respond differently from Caucasian or uncontrolled, open-label trials of 3 to 12 months duration developed nasal septal perforations. younger patients, respectively. The adverse reactions observed during uncontrolled, open-label trials of 3 to As with any long term topical treatment of the nasal cavity, patients using XHANCE over several months or12 months duration in subjects with chronic sinusitis with and without nasal polyps receiving XHANCE 372 mcg longer should be examined periodically for possible changes in the nasal mucosa. If a septal perforation istwice daily were similar to the adverse reactions reported in clinical trials in patients with nasal polyps.noted, discontinue XHANCE. Avoid spraying XHANCE directly on the septum. DRUG INTERACTIONSInhibitors of Cytochrome P450 3A4Candida Infection: In clinical trials with XHANCE, localized infections with Candida albicans have been observed.Fluticasone propionate is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, Eight (0.9%) patients in uncontrolled, open-label trials of 3 to 12 months duration developed Candida albicansatazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, infections (nasal, pharyngeal, esophageal or intestinal). If such an infection develops, it may require treatmenttelithromycin, conivaptan, lopinavir, voriconazole) with XHANCE is not recommended because increased with appropriate local therapy and discontinuation of XHANCE. Patients using XHANCE should be examinedsystemic corticosteroid adverse effects may occur.periodically for evidence of Candida infection in the nasal and oropharyngeal mucosa. RitonavirImpaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients whoA drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that have experienced recent nasal ulcerations, nasal surgery, or nasal trauma should avoid using XHANCE untilritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, healing has occurred. resulting in significantly reduced serum cortisol concentrations. During postmarketing use, there have been Glaucoma and Cataracts: Nasal and inhaled corticosteroids, including fluticasone propionate may result in thereports of clinically significant drug interactions in patients receiving fluticasone propionate products with development of glaucoma and/or cataracts. In placebo-controlled clinical trials of 16 weeks duration, cataracts wereritonavir, resulting in systemic corticosteroid effects including Cushings syndrome and adrenal suppression. reported in 4 (1.2%) patients treated with XHANCE, compared with 3 (1.9%) patients treated with placebo. AmongKetoconazolethese patients, 2 patients treated with XHANCE reported subcapsular cataracts compared with none treated withCoadministration of orally inhaled fluticasone propionate (1000 mcg) and ketoconazole (200 mg once daily) placebo. Eleven patients (1.2%) in uncontrolled, open-label trials of 3 to 12 months duration developed new orresulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma worsening cataracts, of which none were subcapsular. Therefore, close monitoring is warranted in patients with acortisol area under the curve (AUC), but had no effect on urinary excretion of cortisol.change in vision or with a history of increased intraocular pressure (IOP), glaucoma, and/or cataracts. USE IN SPECIFIC POPULATIONSHypersensitivity Reactions Including Anaphylaxis: XHANCE is contraindicated in patients with knownPregnancy: Available data from published literature on the use of inhaled or intranasal fluticasone propionate hypersensitivity to fluticasone propionate or any of the ingredients of XHANCE. Discontinue XHANCEin pregnant women have not reported a clear association with adverse developmental outcomes. In animals, if such reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, rash, hypotension, andteratogenicity characteristic of corticosteroids, decreased fetal body weight, and/or skeletal variations in bronchospasm) occur. rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone Immunosuppression: Persons who are using drugs that suppress the immune system are more susceptiblepropionate less than the maximum recommended human daily inhaled dose (MRHDID) on a mcg/m2 basis. to infections than healthy individuals and may experience a worsening of existing infections. Chickenpox andHowever, fluticasone propionate administered via inhalation to rats decreased fetal body weight, but did not measles, for example, can have a more serious or even fatal course in susceptible adults using corticosteroids.induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m2 basis. Experience with In such adults who have not had these diseases or been properly immunized, care should be taken to avoidoral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing ahumans. The estimated background risk of major birth defects and miscarriage for the indicated population disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroidis unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicellaU.S. general population, the estimated risk of major birth defects and miscarriages in clinically recognized zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooledpregnancies is 2% to 4% and 15% to 20%, respectively.intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIGLactation: There are no available data on the presence of fluticasone propionate in human milk, the effects and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.on the breastfed child, or the effects on milk production. Fluticasone propionate is present in rat milk. Other Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infectionscorticosteroids have been detected in human milk. However, fluticasone propionate concentrations in plasma of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. after orally inhaled therapeutic doses are low, and therefore, concentrations in human breast milk are likely Hypothalamic-Pituitary-Adrenal Axis Effects: Hypercorticism and adrenal suppression may occurto be correspondingly low. The developmental and health benefits of breastfeeding should be considered when intranasal corticosteroids, such as XHANCE, are used at higher than recommended dosages oralong with the mothers clinical need for XHANCE and any potential adverse effects on the breastfed child in susceptible individuals at recommended dosages. Since fluticasone propionate is absorbed into thefrom XHANCE or from the underlying maternal condition.circulation and can be systemically active at higher doses, recommended dosages of XHANCE should not Pediatric Use: The safety and efficacy of XHANCE in pediatric patients have not been established.be exceeded to avoid hypothalamic-pituitary-adrenal (HPA) dysfunction. A relationship between plasmaGeriatric Use: Clinical trials of XHANCE did not include sufficient numbers of subjects aged 65 years and older levels of fluticasone propionate and inhibitory effects on stimulated cortisol production has been shown after to determine whether they responded differently than younger subjects. Other reported clinical experience with 4 weeks of pulmonary treatment with fluticasone propionate inhalation aerosol. Since individual sensitivity tofluticasone administered intranasal or orally inhaled has not identified differences in responses between the effects on cortisol production exists, physicians should consider this information when prescribing XHANCE.elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.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, theHepatic Impairment: Formal pharmacokinetic trials using XHANCE have not been conducted in subjects dosage of XHANCE should be reduced slowly, consistent with accepted procedures for reducing systemicwith hepatic impairment. Since fluticasone propionate is predominantly cleared by hepatic metabolism, corticosteroids, and other treatments for management of nasal symptoms should be considered. Particularimpairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, care should be taken in observing patients postoperatively or during periods of stress for evidence ofpatients with hepatic disease should be closely monitored.inadequate adrenal response. The replacement of a systemic corticosteroid with a topical corticosteroid canRenal Impairment: Formal pharmacokinetic trials using XHANCE have not been conducted in subjects with be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptomsrenal impairment.of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression). After withdrawal fromOVERDOSAGE: Chronic overdosage may result in signs/symptoms of hypercorticism. An intranasal dose systemic corticosteroids, a number of months are required for recovery of HPA function. Patients previouslyof 2 mg (2.7 to 5.4 times the recommended daily dose) of fluticasone propionate twice daily for 7 days treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids shouldwas administered to healthy human volunteers. Adverse events reported with fluticasone propionate were be carefully monitored for acute adrenal insufficiency in response to stress such as trauma, surgery,similar to placebo, and no clinically significant abnormalities in laboratory safety tests were observed. Single infection (particularly gastroenteritis), or other conditions associated with severe electrolyte loss. In patientsoral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Oral who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapidinhalation by healthy volunteers of a single dose of 1.76 or 3.52 mg of fluticasone propionate was well decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. tolerated. Fluticasone propionate given by pulmonary inhalation administration at dosages of 1.32 mg twice Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors: The use of strong cytochromedaily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, voriconazole) with XHANCE is nottolerated. Adverse reactions were of mild or moderate severity, and incidences were similar in active and recommended because increased systemic corticosteroid adverse effects may occur. placebo treatment groups.Reduction in Bone Mineral Density: Decreases in bone mineral density (BMD) have been observed withTo report SUSPECTED ADVERSE REACTIONS contact OptiNose US, Inc. at 1-833-678-6673, safety@long-term oral inhalation of products containing corticosteroids into the lungs. The clinical significance ofoptinose.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients withXHANCE and OptiNose are registered trademarks of OptiNose AS.major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of2022 OptiNose US, Inc. All rights reserved. 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 XHA-22-10061_Pharmacy Differentiation Ad-US Medicine Compendia_DR.indd 2 5/4/22 1:18 PM'