HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XHANCE® safely and effectively. See full prescribing information for
`XHANCE®.
`
`XHANCE® (fluticasone propionate) nasal spray, for intranasal use
`Initial U.S. Approval: 1994
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
`XHANCE is a corticosteroid indicated for the treatment of nasal polyps in
`patients 18 years of age or older. (1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
`
`
`
`For intranasal use only. 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)
`Recommended adult dosage: One spray per nostril twice daily (total
`daily dose of 372 mcg). Two sprays per nostril twice daily may also be
`effective in some patients (total daily dose of 744 mcg). (2.1)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`Nasal spray: 93 mcg of fluticasone propionate in each 106-mg spray. (3)
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
`
`
`
`
`
`
`
`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: 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)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`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)
`
`To report SUSPECTED ADVERSE REACTIONS, contact OptiNose US,
`Inc. at 1-833-678-6673 and safety@optinose.com or FDA at 1-800-FDA-
`1088 or www.fda.gov/medwatch.
`
`Hypersensitivity to any ingredient in XHANCE. (4)
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`
`
`
`
`Local Nasal Effects: 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)
`Close monitoring for glaucoma and cataracts is warranted. (5.2)
`
`Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir, ketoconazole): Use
`not recommended. May increase risk of systemic corticosteroid effects. (7.1)
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`
`
`Hepatic impairment: Monitor patients for signs of increased drug
`exposure. (8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 09/2017
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Nasal Polyps
`2.2 Administration Information
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Local Nasal Effects
`5.2 Glaucoma and Cataracts
`5.3 Hypersensitivity Reactions Including Anaphylaxis
`5.4
`Immunosuppression
`5.5 Hypothalamic-Pituitary-Adrenal Axis Suppression
`5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors
`5.7 Reduction in Bone Mineral Density
`5.8 Effect on Growth
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`7.1
`Inhibitors of Cytochrome P450 3A4
`
`6
`
`7
`
`8
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Nasal Polyps in Adults 18 Years of Age and Older
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`_______________________________________________________________________________________________________________________________________
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`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`XHANCE® nasal spray is indicated for the treatment of nasal polyps in patients 18 years of age or older.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Nasal Polyps
`
`Adults (18 years and older): The recommended dosage of XHANCE nasal spray is 1 spray (93 mcg of
`fluticasone propionate per spray) in each nostril twice daily (total daily dose, 372 mcg). A dose of 2 sprays (93
`mcg of fluticasone propionate per spray) in each nostril twice daily may also be effective in some patients (total
`daily dose, 744 mcg). The maximum total daily dosage should not exceed 2 sprays in each nostril twice daily
`(total daily dose, 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
`
`Administer XHANCE by the intranasal route only, avoiding spraying directly on the nasal septum. Shake
`XHANCE before each use. 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.
`
`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. 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.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Nasal spray: Each 106-mg spray delivers 93 mcg of fluticasone propionate. One unit provides 120 metered
`sprays.
`
`4 CONTRAINDICATIONS
`
`XHANCE is contraindicated in patients with hypersensitivity to any of the ingredients [see Warnings and
`Precautions (5.3) and Description (11)].
`
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`5 WARNINGS AND PRECAUTIONS
`
`5.1 Local Nasal Effects
`
`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 intranasal application of XHANCE. In
`placebo-controlled clinical trials of 16 weeks duration, nasal septal perforations were 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.
`
`5.3 Hypersensitivity Reactions Including Anaphylaxis
`
`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)].
`
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`5.4
`
`Immunosuppression
`
`Persons who are using drugs that suppress the immune system 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 package inserts for complete VZIG and IG prescribing information.)
`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 Hypothalamic-Pituitary-Adrenal Axis Effects
`
`Hypercorticism and adrenal suppression may occur when intranasal 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)].
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`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 subjects (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
`
`Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients.
`The safety and efficacy of XHANCE has not been established in pediatric patients [see Use in Specific
`Populations (8.4)].
`
`6 ADVERSE REACTIONS
`
`Systemic and local corticosteroid use may result in the following:
`
` Local nasal effects: epistaxis, erosion, ulceration, septal perforation, Candida albicans infection, and
`impaired wound healing [see Warnings and Precautions (5.1)]
` Cataracts and glaucoma [see Warnings and Precautions (5.2)]
` Hypersensitivity reactions including anaphylaxis [see Contraindications (4) and Warnings and
`Precautions (5.3)]
`
`Immunosuppression [see Warnings and Precautions (5.4)]
` HPA axis effects, including growth reduction [see Warnings and Precautions (5.5 and 5.8)]
` Reduction in bone mineral density [see Warnings and Precautions (5.7)]
` Effect on Growth [see Warnings and Precautions (5.8)]
`
`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 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 subjects 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%) subjects classified as Other.
`Of these patients, 45 (7%) were 65 years of age or older.
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`Table 1 displays adverse reactions with an incidence of ≥ 3% in the XHANCE 186 mcg and 372 mcg twice
`daily subjects, and more common than placebo.
`
` Table 1.
`
`
`
`
`
`Summary of Adverse Reactions with XHANCE Reported in  3% of Subjects with Nasal
`Polyps and More Common Than Placebo in Placebo-Controlled Studies
`XHANCE
`186 mcg bid
`372 mcg bid
`(N = 160)
`(N = 161)
`n (%)
`n (%)
`19 (11.9)
`16 (9.9)
`3 (1.9)
`12 (7.5)
`11 (6.9)
`12 (7.5)
`7 (4.4)
`9 (5.6)
`7 (4.4)
`8 (5.0)
`8 (5.0)
`6 (3.7)
`2 (1.3)
`5 (3.1)
`6 (3.8)
`4 (2.5)
`9 (5.6)
`8 (5.0)
`6 (3.8)
`7 (4.3)
`
`Placebo
`(N = 161)
`n (%)
`4 (2.5)
`8 (5.0)
`3 (1.9)
`6 (3.7)
`6 (3.7)
`5 (3.1)
`2 (1.2)
`2 (1.3)
`6 (3.7)
`3 (1.9)
`
`Adverse Reaction
` Epistaxis1
` Nasopharyngitis
` Nasal septal ulceration2
` Nasal congestion
` Acute sinusitis
` Headache
` Pharyngitis
` Nasal mucosal ulceration2
` Nasal mucosal erythema
` Nasal septal erythema
` bid = twice daily.
`1Includes spontaneous adverse reaction reports
`2Include ulcerations and erosions
`
`
`
`
`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 subjects treated with XHANCE 186 mcg twice daily and 1.2% of subjects 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 subjects 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.
`
`The adverse reactions observed during uncontrolled, open-label trials of 3 to 12 months duration in subjects
`with chronic sinusitis with and without nasal polyps receiving XHANCE 372 mcg twice daily were similar to
`the adverse reactions reported in clinical trials in patients with nasal polyps.
`
`7 DRUG INTERACTIONS
`
`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.
`
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`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.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summary
`
`Available data from published literature on the use of inhaled or intranasal 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis with a maternal subcutaneous dose of
`15 mcg/kg/day).
`
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`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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis with maternal subcutaneous doses up to
`50 mcg/kg/day).
`
`8.2 Lactation
`
`Risk Summary
`
`There are no available data on the presence of fluticasone propionate in human milk, the effects on the breastfed
`child, or the effects on milk production. Fluticasone propionate is present in rat milk (see Data). Other
`corticosteroids have been detected in human milk. However, fluticasone propionate concentrations in plasma
`after orally inhaled therapeutic doses are low, and therefore, concentrations in human breast milk are likely to
`be correspondingly low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of
`breastfeeding should be considered along with the mother’s clinical need for XHANCE and any potential
`adverse effects on the breastfed child from XHANCE or from the underlying maternal condition.
`
`Data
`
`Subcutaneous administration of tritiated fluticasone propionate at a dose in lactating rats approximately
`0.1 times the MRHDID for adults (on a mcg/m2 basis) resulted in measurable levels in milk.
`
`8.4 Pediatric Use
`
`The safety and efficacy of XHANCE in pediatric patients have not been established.
`
`Effects on Growth
`
`Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity
`when administered to pediatric patients. This effect was observed in the absence of laboratory evidence of HPA
`axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid
`exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of
`
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`this reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult
`height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with
`intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal
`corticosteroids should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged
`treatment should be weighed against the clinical benefits obtained and the risks associated with alternative
`therapies.
`
`Controlled clinical trials have shown that corticosteroids orally inhaled into the lungs may cause a reduction in
`growth in pediatric patients. In these trials, the mean reduction in growth velocity was approximately 1 cm/year
`(range: 0.3 to 1.8 cm/year) and appeared to depend upon dose and duration of exposure. The effects on growth
`velocity of treatment with corticosteroids orally inhaled into the lungs for over 1 year, including the impact on
`final adult height, are unknown. The growth of children and adolescents receiving corticosteroids should be
`monitored routinely (e.g., via stadiometry) [see Warnings and Precautions (5.8)].
`
`8.5 Geriatric Use
`
`Clinical trials of XHANCE did not include sufficient numbers of subjects aged 65 years and older to determine
`whether they responded differently than younger subjects. Other reported clinical experience with fluticasone
`administered intranasal or orally inhaled has not identified differences in responses between the elderly and
`younger patients, but greater sensitivity of some older individuals cannot be ruled out.
`
`8.6 Hepatic Impairment
`
`Formal pharmacokinetic trials using XHANCE have not been conducted in subjects with hepatic impairment.
`Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may
`lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be
`closely monitored.
`
`8.7 Renal Impairment
`
`Formal pharmacokinetic trials using XHANCE have not been conducted in subjects with renal impairment.
`
`10 OVERDOSAGE
`
`Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.5)]. An
`intranasal dose of 2 mg (2.7 to 5.4 times the recommended daily dose) of fluticasone propionate twice daily for
`7 days was administered to healthy human volunteers. Adverse events reported with fluticasone propionate
`were similar to placebo, and no clinically significant abnormalities in laboratory safety tests were observed.
`Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Oral
`inhalation by healthy volunteers of a single dose of 1.76 or 3.52 mg of fluticasone propionate was well
`tolerated. Fluticasone propionate given by pulmonary inhalation administration at dosages of 1.32 mg twice
`daily for 7 to 15 days to healthy human volunteers was also well tolerated. Repeat oral doses up to 80 mg daily
`for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated.
`Adverse reactions were of mild or moderate severity, and incidences were similar in active and placebo
`treatment groups.
`
`11 DESCRIPTION
`
`The active component of XHANCE is fluticasone propionate, a corticosteroid, having the chemical name S-
`(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3oxoandrosta-1,4-diene-17β-carbothioate,
`17-propionate and the following chemical structure:
`
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`Fluticasone propionate is a white powder with a molecular weight of 500.57, and the empirical formula is
`C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethylformamide, sparingly soluble in
`acetone and dichloromethane, and slightly soluble in 96% ethanol.
`
`XHANCE (fluticasone propionate) nasal spray, 93 mcg, for intranasal administration, with an exhalation
`delivery system that delivers an aqueous suspension of microfine fluticasone propionate having a particle size
`distribution in the range of 0 to 5 microns for topical intranasal administration by means of a metering,
`atomizing spray pump and exhaled breath. XHANCE also contains microcrystalline cellulose and
`carboxymethylcellulose sodium, dextrose, benzalkonium chloride, polysorbate 80, edetate disodium dihydrate,
`and purified water, and has a pH between 5 and 7.
`
`Before initial use, prime XHANCE by gently shaking and then pressing the amber glass bottle 7 times or until a
`fine mist appears. Once primed, XHANCE contains 120 metered sprays. When XHANCE has not been used
`for ≥ 7 days, prime again by releasing 2 sprays into the air, away from the face [see Dosage and Administration
`(2.2) and patient I