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`EXHIBIT G
`
`EXHIBIT G
`
`

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`
`FLONASE- fluticas one propionate spray, metered
`Glaxo SmithKline LLC
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use FLONASE safely and effectively. See full
`prescribing information for FLONASE.
`Initial U.S. Approval: 1994
`- -------------------------------------- - - RECENT MAJOR CHANGES ---------------------------------------- --
`
`Indications and Usage (1)
`
`01/2015
`
`— -------------------------------------- - - INDICATIONS AND USAGE ---------------------------------------- --
`
`FLONASE Nasal Spray is a corticosteroid indicated for the management ofthe nasal symptoms ofperennialnonallergic
`rhinitis in adult and pediatric patients aged 4 years and older. (1)
`- ---------------------------------- -- DOSAGE AND ADMINISTRATION ------------------------------------ --
`
`For intranasal use only. Recommended starting dosages:
`
`' Adults: 2 sprays per nostril once daily (200 mcg per day). (2.1)
`' Adolescents and children aged 4 years and older: 1 spray per nostril once daily (100 mcg per day). (2.2)
`
`- ---------------------------------- --DOSAGE FORMS AND STRENGTHS ------------------------------------ --
`
`Nasal spray. 50 mcg of fluticasone propionate in each 100-mg spray. (3)
`— --------------------------------------- -- CONTRAINDICATIONS ----------------------------------------- --
`
`Hypersensitivity to any ingredient. (4)
`- ----------------------------------- - - WARNINGS AND PRECAUTIONS ------------------------------------- --
`
`' Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired wound healing. Monitor
`patients periodically for signs of adverse effects on the nasalmucosa. Avoid use in patients with recent nasal ulcers,
`nasal surgery, or nasal trauma. (5.1)
`' Close monitoring for glaucoma and cataracts is warranted. (5.2)
`Hypersensitivity reactions (e .g., anaphylaxis, angioe de ma, urticaria, contact dermatitis, and rash) have been reported
`after administration of FLONASE Nasal Spray. Discontinue FLONASE Nasal Spray if such reactions occur. (5.3)
`Potential worsening ofinfections (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 FLONASE Nasal Spray slowly. (5.5)
`' Monitor growth ofpediatric patients. (5.7)
`
`'
`
`- ---------------------------------------- --ADVERSE REACTIONS ------------------------------------------ --
`
`The most common adverse reactions (>3%) are headache, pharyngitis, epistaxis, nasalburning/nasalirritation,
`nausea/vomiting, asthma symptoms, and cough. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKlineat 1-888-825-5249 or FDA at 1-800-
`FDA-1088 or www.fda.goV/medwatch.
`- ---------------------------------------- - - DRUG INTERACTIONS ------------------------------------------ --
`
`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: 10/2011
`
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Adults
`
`2.2 Adolescents and Children (Aged 4 Years and Older)
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`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 Hypercorticism and Adrenal Suppression
`5.6 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors
`5.7 Effect on Growth
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`7.1 Inhibitors of Cytochrome P450 3A4
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`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 TOXIC OLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`LONASE® Nasal Spray is indicated for the management of the nasal symptoms of perennial
`onallergic rhinitis in adult and pediatric patients aged 4 years and older.
`
`2 DOSAGE AND ADMINISTRATION
`
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`Administer FLONASE Nasal Spray by the intranasal route or1ly. Prime FLONASE Nasal Spray before
`using for the first time or after a period of non-use (1 week or more) by shaking the contents well and
`releasing 6 sprays into the air away from the face. Shake FLONASE Nasal Spray gently before each
`use.
`
`Patients should use FLONASE Nasal Spray at regular intervals since its effectiveness depends onits
`regular use. Maximum effect may take several days and individual patients will experience a variable
`time to onset and different degree of symptom relief.
`
`2.1 Adults
`
`The recommended starting dosage in adults is 2 sprays (50 mcg of fluticasone propionate each) in each
`nostril once daily (total daily dose, 200 mcg). The same total daily dose, 1 spray in each nostril
`administered twice daily (e.g., 8 a.m and 8 p.m) is also effective. After the first few days, patients may
`be able to reduce their dose to 1 spray in each nostril once daily for maintenance therapy.
`
`Maximum total daily doses should not exceed 2 sprays in each nostril (total dose, 200 mcg/day). There
`is no evidence that exceeding the recommended dose is more effective.
`
`2.2 Adolescents and Children (Aged 4 Years and Older)
`
`The recommended starting dosage in adolescents and children, aged 4 years and older is 1 spray in each
`nostril once daily (total daily dose, 100 mcg). Patients not adequately responding to 1 spray in each
`nostril may use 2 sprays in each nostril once daily (total daily dose, 200 mcg). Once adequate control is
`achieved, the dosage should be decreased to 1 spray in each nostril once daily.
`
`The maximum total daily dosage should not exceed 2 sprays in each nostril (200 mcg/day) There is no
`evidence that exceeding the recommended dose is more effective.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`FLONASE Nasal Spray is a nasal spray suspension. Each 100-mg spray delivers 50 mcg of fluticasone
`propionate.
`
`4 CONTRAINDICATIONS
`
`FLONASE Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see
`Warnings and Precautions (5.3), Description (11)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Local Nasal Effects
`
`E
`
`In clinical trials of 2 to 26 weeks’ duration, epistaxis was observed more frequently in subjects treated
`with FLONASE Nasal Spray than those who received placebo [see Adverse Reactions (6.1)].
`
`Nasal Ulceration
`
`Postmarketing cases of nasal ulceration have been reported in patients treated with FLONASE Nasal
`Spray [see Adverse Reactions (6.2)].
`
`Candida Infection
`
`In clinical trials with fluticasone propionate administered intranasally, the development of localized
`infections of the nose and pharynx with Candida albicans has occurred. When such an infection
`develops, it may require treatment with appropriate local therapy and discontinuation of FLONASE
`Nasal Spray. Patients using FLONASE Nasal Spray over several months or longer should be examined
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`periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.
`
`Nasal Septal Perforation
`
`Postmarketing cases of nasal septal perforation have been reported in patients treated with FLONASE
`Nasal Spray [see Adverse Reactions (6.2)].
`
`Impaired Wound Healing
`
`Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced
`recent nasal ulcers, nasal surgery, or nasaltrauma should avoid using FLONASE Nasal Spray until
`healing has occurred.
`
`5.2 Glaucoma and Cataracts
`
`Use of intranasal and inhaled corticosteroids may result in the development of glaucoma and/or
`cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history
`of increased intraocular pressure, glaucoma, and/or cataracts.
`
`5.3 Hypersensitivity Re actions including Anaphylaxis
`
`Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, contact dermatitis, and rash) have
`been reported after administration of FLONASE Nasal Spray. Discontinue FLONASE Nasal Spray if
`such reactions occur [see Contraindications (4)].Rarely, immediate hypersensitivity reactions may occur
`after the administration of FLONASE Nasal Spray.
`
`5.4 Immuno s uppre s s ion
`
`Persons who are using drugs that suppress the immune system are more susceptible to infections than
`healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course
`in susceptible children or adults using corticosteroids. In such children or 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 riskis 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 complete prescribing information for
`VZIG and IG.) If chickenpox develops, treatment with antiviral agents may be considered.
`
`Intranasal corticosteroids should be used with caution, if at all, in patients with active or quiescent
`tuberculous infections of the respiratory tract; systemic fungal, bacterial, viral or parasitic infections;
`or ocular herpes simplex.
`
`5.5 Hypercorticism and Adrenal Suppression
`
`When intranasal corticosteroids are used at higher than recommended dosages or in susceptible
`individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and
`adrenal suppression may appear. If such changes occur, the dosage of FLONASE Nasal Spray should
`be discontinued slowly consistent with accepted procedures for discontinuing oral corticosteroid
`therapy.
`
`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). 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. In patients who have asthma or
`other clinical conditions requiring longflterm systemic corticosteroid treatment, rapid decreases in
`systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.
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`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, nefazodone, voriconazole) with FLONASE Nasal Spray is not recommended
`because increased systemic corticosteroid adverse effects may occur [see Drug Interactions (7.1),
`Clinical Pharmacology (12.3)].
`
`5.7 Effect on Growth
`
`Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric
`patients [see Use in Specific Populations (8.4)]. Monitor the growth routinely of pediatric patients
`receiving FLONASE Nasal Spray. To minimize the systemic effects of intranasal corticosteroids,
`including FLONASE Nasal Spray, titrate each patient’s dose to the lowest dosage that effectively
`controls his/her symptoms [see Dosage and Administration (2), Use in Specific Populations (8.4)].
`
`6 ADVERSE REACTIONS
`
`Systemic and local corticosteroid use may result in the following:
`
`° Epistaxis, nasal ulceration, Candida albicans infection, nasal septal perforation, and impaired
`wound healing [see Warnings and Precautions (5.1)]
`
`Cataracts and glaucoma [see Warnings and Precautions (5.2)]
`
`Immunosuppression [see Warnings and Precautions (5.4)]
`
`Hypercorticism and adrenal suppression [see Warnings and Precautions (5.5)]
`
`Effect on growth [see Warnings and Precautions (5.7)]
`
`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 controlled US clinical trials, more than 3,300 subjects with allergic and nonallergic rhinitis received
`treatment with intranasal fluticasone propionate. In general, adverse reactions in clinical trials have been
`primarily associated with irritation of the nasal mucous membranes, and the adverse reactions were
`reported with approximately the same frequency by subjects treated with placebo. Less than 2% of
`subjects in clinical trials discontinued because of adverse reactions; this rate was similar for vehicle
`placebo and active comparators.
`
`The safety data described below are based on 7 placebo-controlled clinical trials in subjects with
`allergic rhinitis. The 7 trials included 536 subjects (57 girls and 108 boys aged 4 to 11 years, 137
`female and 234 male adolescents and adults) treated with FLONASE 200 mcg once daily over 2 to
`4 weeks and 2 placebo-controlled clinical trials which included 246 subjects (119 female and 127 male
`adolescents and adults) treated with FLONASE 200 mcg once daily over 6 months (Table 1). Also
`included in Table 1 are adverse reactions from2 trials in which 167 children (45 girls and 122 boys
`aged 4 to 11 years) were treated with FLONASE 100 mcg once daily for 2 to 4 weeks.
`
`Table 1. Adverse Reactions with FLONASE Nasal Spray with >3% Incidence and More Common
`than Placebo in Subjects 24 Years with Allergic Rhinitis
`
`FLONASE
`
`FLONASE
`
`100 mcg
`Once Daily
`(n = 167)
`
`200 mcg
`Once Daily
`(n = 782)
`
`Placebo
`(n = 758)
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`Adverse Reaction
`%
`%
`%
`
`Headache
`
`Pharyngitis
`
`Epistaxis
`
`Nasal burning/nasal irritation
`
`Nausea/vomiting
`
`Asthma symptoms
`
`Cough
`
`6.6
`
`6.0
`
`6.0
`
`2.4
`
`4.8
`
`7.2
`
`3.6
`
`16.1
`
`7.8
`
`6.9
`
`3.2
`
`2.6
`
`3.3
`
`3.8
`
`14.6
`
`7.2
`
`5.4
`
`2.6
`
`2.0
`
`2.9
`
`2.8
`
`Other adverse reactions with FLONASE Nasal Spray observed with an incidence less than or equal to
`3% but greater than or equal to 1% and more common than with placebo included: blood in nasal mucus,
`runny nose, abdominal pain, diarrhea, fever, flufllike symptoms, aches and pains, dizziness, and
`bronchitis.
`
`6.2 Postmarketjng Experience
`
`In addition to adverse events reported from clinical trials, the following adverse events have been
`identified during postapproval use of intranasal fluticasone propionate. 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. These events have been chosen for
`inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone
`propionate or a combination of these factors.
`
`General Disorders and Administration Site Conditions
`
`Hypersensitivity reactions, including angioedema, skin rash, edema of the face and tongue, pruritus,
`urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions, which in rare
`instances were severe.
`
`Ear and Labyrinth Disorders
`
`Alteration or loss of sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore
`throat, throat irritation and dryness, cough, hoarseness, and voice changes.
`
`Eye Disorders
`
`Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular pressure, and
`cataracts.
`
`Cases of growth suppression have been reported for intranasal corticosteroids, including FLONASE
`[see Warnings and Precautions (5.7)].
`
`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, nefazodone, voriconazole) with FLONASE Nasal Spray is not
`recommended because increased systemic corticosteroid adverse effects may occur.
`
`
`
`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, including FLONASE, with ritonavir, resulting in
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`systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
`
`Ketoconazole
`
`Coadministration of orally inhaled fluticasone propionate (1,000 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
`
`Teratogenic Effects
`
`Pregnancy Category C. There are no adequate and well-controlled trials with FLONASE Nasal Spray in
`pregnant women. Corticosteroids have been shown to be teratogenic inlaboratory animals when
`administered systemically at relatively low dosage levels. Because animal reproduction studies are not
`always predictive of human response, FLONASE Nasal Spray should be used during pregnancy only if
`the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their
`physicians if they become pregnant while taking FLONASE Nasal Spray.
`
`Mice and rats at fluticasone propionate doses approximately 1 and 4 times, respectively, the maximum
`recommended human daily intranasal dose (MRHDID) for adults (on a mg/m2 basis at maternal
`subcutaneous doses of 45 and 100 mcg/kg/day, respectively) showed fetal toxicity characteristic of
`potent corticosteroid compounds, including embryonic growth retardation, omphalocele, cleft palate,
`and retarded cranial ossification. No teratogenicity was seenin rats at doses up to 3 times the MRHDID
`(on a mg/m2 basis at maternal inhalation doses up to 68.7 mcg/kg/day).
`
`In rabbits, fetal weight reduction and cleft palate were observed at a fluticasone propionate dose
`approximately 0.3 times the MRHDID for adults (on a mg/m2 basis at a maternal subcutaneous dose of
`4mcg/kg/day). However, no teratogenic effects were reported at fluticasone propionate doses up to
`approximately 20 times the MRHDID for adults (on a mg/m2 basis at a maternal oral dose up to 300
`mcg/kg/day). No fluticasone propionate was detected in the plasma in this study, consistent with the
`established low bioavailability following oral administration [see Clinical Pharmacology (12.3)].
`
`Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and
`oral administration to rabbits.
`
`Experience with oral corticosteroids since their introductionin pharmacologic, as opposed to
`physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids
`than humans. In addition, because there is a natural increase in corticosteroid production during
`pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need
`corticosteroid treatment during pregnancy.
`
`Nonteratogenic Effects
`
`Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such
`infants should be carefully monitored.
`
`8.3 Nursing Mothers
`
`It is not known whether fluticasone propionate is excreted in human breast milk However, other
`corticosteroids have been detected in human milk. Subcutaneous administration to lactating rats of
`tritiated fluticasone propionate at a dose approximately 0.4 times the MRHDID for adults on a mg/m2
`basis resulted in measurable radioactivity in milk
`
`Since there are no data from controlled trials on the use of intranasal FLONASE Nasal Spray by nursing
`mothers, caution should be exercised when FLONASE Nasal Spray is administered to a nursing woman.
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`8.4 Pediatric Use
`
`The safety and effectiveness of FLONASE Nasal Spray in children aged 4 years and older have been
`established [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. Six hundred fifty (650) subjects
`aged 4 to 11 years and 440 subjects aged 12 to 17 years were studied in US clinical trials with
`fluticasone propionate nasal spray. The safety and effectiveness of FLONASE Nasal Spray in children
`younger than 4 years 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 hypothalamic-pituitary-adrenal (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 longflterm effects of this reductionin growth velocity
`associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The
`potential for “catchflup” growth following discontinuation of treatment with intranasal corticosteroids
`has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids,
`including FLONASE Nasal Spray, 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. To minimize the systemic effects of intranasal
`corticosteroids, including FLONASE Nasal Spray, each patient’s dosage should be titrated to the
`lowest dosage that effectively controls his/her symptoms.
`
`A 1Dyear placeboflcontrolled trial was conducted in 150 pediatric subjects (aged 3 to 9 years) to assess
`the effect of FLONASE Nasal Spray (single daily dose of 200 mcg) on growth velocity. From the
`primary population receiving FLONASE Nasal Spray (n = 56) and placebo (n = 52), the point estimate
`for growth velocity with FLONASE Nasal Spray was 0.14 cm/year lower than placebo (9 5% CI: -0.54,
`0.27 cm/year). Thus, no statistically significant effect on growth was noted compared with placebo. No
`evidence of clinically relevant changes in HPA axis function or bone mineral density was observed as
`assessed by 12Dhour urinary cortisol excretion and dualflenergy xDray absorptiometry, respectively.
`
`The potential for FLONASE Nasal Spray to cause growth suppressionin susceptible patients or when
`given at higher than recommended dosages cannot be ruled out.
`
`8.5 Geriatric Use
`
`A limited number of subjects aged 65 years and older (n = 129) or 75 years and older (n = 11) have been
`treated with FLONASE Nasal Spray in clinical trials. While the number of subjects is too small to
`permit separate analysis of efficacy and safety, the adverse reactions reported in this population were
`similar to those reported by younger patients. In general, dose selection for an elderly patient should be
`cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of
`decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
`
`8.6 Hepatic Impairment
`
`Formal pharmacokinetic trials using FLONASE Nasal Spray 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 FLONASE Nasal Spray have not been conducted in subjects with
`renal impairment.
`
`10 OVERDOSAGE
`
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`Chronic overdosage may result in signs/syrnptorns of hypercorticism [see Warnings and Precautions
`(5.5)]. Intranasal administration of 2 mg (10 times the recommended 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 inlaboratory
`safety tests were observed. Single oral doses up to 16 mg have been studied in human volunteers with
`no acute toxic effects reported. 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. Acute
`overdosage with this dosage formis unlikely since 1 bottle of FLONASE Nasal Spray contains
`approximately 8 mg of fluticasone propionate.
`
`11 DE SCRIPT ION
`
`The active component of FLONASE Nasal Spray is fluticasone propionate, a corticosteroid having the
`chemical name S- (fluoromethyl) 60(,9-difluoro-11[3,17-dihydroxy- 160(-methyl-3-oxoandrosta- 1,4-
`diene-17B-carbothioate, 17-propionate and the following chemical structure:
`
`,:|:'.’'-.:":'=: I 5-nscng
`_15.'..mur.:::::;,H,
`
`:|:II...::|.1
`
`H
`
`Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula
`is C25H31F3O5S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and
`dimethylformamide, and slightly soluble in methanol and 95% ethanol.
`
`FLONASE Nasal Spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for
`topical administration to the nasal mucosa by means of a metering, atomizing spray pump. FLONASE
`Nasal Spray also contains microcrystalline cellulose and carboxymethylcellulose sodium, dextrose,
`0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a pH
`between 5 and 7.
`
`After initial priming, each actuation delivers 50 mcg of fluticasone propionate in 100 mg of formulation
`through the nasal adapter.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflarnrnatory activity.
`Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human
`glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of
`beclomethasonefl17Dmonopropionate (BMP), the active metabolite of beclomethasone dipropionate, and
`over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent
`with these results. The clinical significance of these findings is unknown.
`
`The precise mechanism through which fluticasone propionate affects rhinitis symptoms is not known.
`Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast
`cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids,
`leukotrienes, cytokines) involved in inflammation. In 7 trials in adults, FLONASE Nasal Spray has
`decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of
`
`APOTEX_AZFL 0130292
`
`

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`patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not
`known.
`
`12.2 Pharmacodynamics
`
`HPA Axis Effect
`
`The potential systemic effects of FLONASE Nasal Spray on the HPA axis were evaluated. FLONASE
`Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral
`prednisone 7.5 or 15 mg givenin the morning. FLONASE Nasal Spray at either dosage for 4 weeks did
`not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral
`prednisone significantly reduced the response to cosyntropin.
`
`Cardiac Electrophysiology
`
`A study specifically designed to evaluate the effect of FLONASE on the QT interval has not been
`conducted.
`
`12.3 Pharmacokinetics
`
`The activity of FLONASE Nasal Spray is due to the parent drug, fluticasone propionate. Due to the low
`bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other
`routes of administration.
`
`Absorption
`
`Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an
`absolute bioavailability averaging less than 2%.Trials using oral dosing of labeled and unlabeled drug
`have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%),
`primarily due to incomplete absorption and presystemic metabolismin the gut and liver. After intranasal
`treatment of patients with rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above
`the level of detection (50 pg/mL) only when recommended doses were exceeded and then only in
`occasional samples atlow plasma levels.
`
`mlnmlbrl
`
`Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid
`and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged
`4.2 L/kg.
`
`The percentage of fluticasone propionate bound to human plasma proteins averaged 99%. Fluticasone
`propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human
`transcortin.
`
`Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a
`terminal elimination halfDlife of approximately 7.8 hours. The total blood clearance of fluticasone
`propionate is high (average: 1,093 mL/min), with renal clearance accounting for less than 0.02% of the
`total.
`
`Metabolism: The only circulating metabolite detected in manis the 17B-carboxylic acid derivative of
`fluticasone propionate, which is formed through the CYP3A4 pathway. This metabolite had less affinity
`(approximately