NASACORT AQ- triamcinolone acetonide spray, metered
`sanofi-aventis U.S. LLC
`----------
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use NASACORT AQ safely and effectively. See
`full prescribing information for NASACORT AQ.
`
`®
` AQ (triamcinolone acetonide)
`Nasacort
`Nasal Spray
`Initial U.S. Approval: 1957
`
`INDICATIONS AND USAGE
`NASACORT AQ Nasal Spray is a corticosteroid indicated for treatment of nasal symptoms of seasonal and perennial
`allergic rhinitis in adults and children 2 years of age and older. (1)
`
`DOSAGE AND ADMINISTRATION
`Adults and adolescents ≥ 12 years: Starting and maximum dose is 220 mcg/day (two sprays in each nostril once daily).
`(2.1)
`Children 6 to 12 years of age: Starting dose is 110 mcg/day (one spray in each nostril once daily). Maximum dose is 220
`mcg/day (two sprays per nostril once daily). (2.2)
`Children 2 to 5 years of age: Starting and maximum dose 110 mcg/day (one spray in each nostril once daily). (2.2)
`Priming/Use: For intranasal use only. Shake well before each use. Before using for the first time, release 5 sprays into
`the air away from the face. If the product is not used for more than 2 weeks, release 1 spray into the air before using.
`(2.3)
`
`DOSAGE FORMS AND STRENGTHS
`Nasal Spray: 55 mcg triamcinolone acetonide in each spray. (3)
`
`CONTRAINDICATIONS
`Do not administer to patients with history of hypersensitivity to triamcinolone acetonide or any ingredients of this
`product. (4)
`
`WARNINGS AND PRECAUTIONS
`Epistaxis, nasal septal perforation, Candida albicans infection, impaired wound healing. Monitor patients periodically for
`signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal septal ulcers, nasal surgery, or
`trauma. (5.1)
`Development of glaucoma or posterior subcapsular cataracts. Monitor patients closely with a change in vision or with a
`history of increased intraocular pressure, glaucoma, and/or cataracts. (5.2)
`Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
`More serious or even fatal course of chickenpox or measles in susceptible patients. Use caution in patient with the
`above because of the potential for worsening of these infections. (5.3)
`Hypercorticism and adrenal suppression with very high dosages or at the regular dosage in susceptible individuals. If
`such changes occur, discontinue NASACORT AQ Nasal Spray slowly. (5.4)
`Potential reduction in growth velocity in children. Monitor growth routinely in pediatric patients receiving NASACORT
`AQ Nasal Spray. (5.5, 8.4)
`
`ADVERSE REACTIONS
`Most common adverse reactions (>2% incidence) were pharyngitis, epistaxis, flu syndrome, cough increased,
`bronchitis, dyspepsia, tooth disorder, headache, pharyngolaryngeal pain, nasopharyngitis, abdominal upper pain,
`diarrhea, and excoriation. (6.1)
`Other adverse reactions, including serious adverse reactions, have been reported. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-
`800-FDA-1088 or www.fda.gov/medwatch.
`USE IN SPECIFIC POPULATIONS
`NASACORT AQ should be used during pregnancy only if potential benefit justifies potential risk to fetus. (8.1)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
`Revised: 7/2013
`Exhibit 1047
`IPR2017-00807
`ARGENTUM
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Adults and Adolescents 12 Years of Age and Older
`2.2 Children 2 to 12 Years of Age
`2.3 Administration Information
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Local Nasal Effects
`5.2 Glaucoma and Cataracts
`5.3 Immunosuppression
`5.4 Hypothalamic-Pituitary-Adrenal Axis Effects
`5.5 Effect on Growth
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-Marketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`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
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`17. PATIENT COUNSELING INFORMATION
`*
`Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`NASACORT AQ Nasal Spray is indicated for the treatment of the nasal symptoms of seasonal and
`perennial allergic rhinitis in adults and children 2 years of age and older.
`
`2 DOSAGE AND ADMINISTRATION
`
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`Administer NASACORT AQ Nasal Spray by the intranasal route only. Shake NASACORT AQ Nasal
`Spray well before each use.
`
`2.1 Adults and Adolescents 12 Years of Age and Older
`The recommended starting and maximum dose is 220 mcg per day as two sprays in each nostril once
`daily. Titrate an individual patient to the minimum effective dose to reduce the possibility of side
`effects. When the maximum benefit has been achieved and symptoms have been controlled, reducing the
`dose to 110 mcg per day (one spray in each nostril once a day) has been shown to be effective in
`maintaining control of the allergic rhinitis symptoms.
`
`2.2 Children 2 to 12 Years of Age
`
`Children 6 to 12 years of age: The recommended starting dose is 110 mcg per day given as one spray in
`each nostril once daily. Children not responding adequately to 110 mcg per day may use 220 mcg (2
`sprays in each nostril) once daily. Once symptoms have been controlled, the dosage may be decreased
`to 110 mcg once daily [see Warnings and Precautions (5.5), Use in Specific Populations (8.4) and Clinical
`Pharmacology (12.2)].
`
`Children 2 to 5 years of age: The recommended and maximum dose is 110 mcg per day given as one
`spray in each nostril once daily [see Warnings and Precautions (5.5), Use in Specific Populations (8.4) and
`Clinical Pharmacology (12.2)].
`NASACORT AQ Nasal Spray is not recommended for children under 2 years of age.
`
`2.3 Administration Information
`
`Priming: Prime NASACORT AQ Nasal Spray before using for the first time by shaking the contents
`well and releasing 5 sprays into the air away from the face. It will remain adequately primed for two
`weeks. If the product is not used for more than 2 weeks, then it can be adequately reprimed with one
`spray. Shake NASACORT AQ Nasal Spray well before each use.
`If adequate relief of symptoms has not been obtained after 3 weeks of treatment, NASACORT AQ Nasal
`Spray should be discontinued [see Warnings and Precautions (5), Patient Counseling Information (17), and
`Adverse Reactions (6)].
`
`3 DOSAGE FORMS AND STRENGTHS
`NASACORT AQ Nasal Spray is a metered-dose pump spray containing the active ingredient
`triamcinolone acetonide. Each actuation delivers 55 mcg triamcinolone acetonide from the nasal actuator
`after an initial priming of 5 sprays. Each 16.5 gram bottle (120 actuations) contains 9.075 mg of
`triamcinolone acetonide. The bottle should be discarded when the labeled-number of actuations have
`been reached even though the bottle is not completely empty.
`
`4 CONTRAINDICATIONS
`NASACORT AQ should not be administered to patients with a history of hypersensitivity to
`triamcinolone acetonide or to any of the other ingredients of this preparation.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Local Nasal Effects
`
`Epistaxis: In clinical studies of 2 to 12 weeks duration, epistaxis was observed more frequently in
`patients treated with NASACORT AQ Nasal Spray than those who received placebo [see Adverse
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`Reactions (6)].
`
`Nasal Septal Perforation: In clinical trials, nasal septum perforation was reported in one adult patient
`treated with NASACORT AQ Nasal Spray.
`
`Candida Infection: In clinical studies with NASACORT AQ Nasal Spray, the development of localized
`infections of the nose and pharynx with Candida albicans has rarely occurred. When such an infection
`develops it may require treatment with appropriate local or systemic therapy and discontinuation of
`NASACORT AQ Nasal Spray. Therefore, patients using NASACORT AQ Nasal Spray over several
`months or longer should be examined periodically for evidence of Candida infection or other signs of
`adverse effects on the nasal mucosa.
`
`Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing,
`patients who have experienced recent nasal ulcers, surgery, or trauma should not use NASACORT AQ
`Nasal Spray until healing has occurred.
`
`5.2 Glaucoma and Cataracts
`Nasal 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 Immunosuppression
`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 children or adults who have not had these
`diseases or have not 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 exposed to chickenpox, prophylaxis with
`varicella zoster immune globulin (VZIG) may be indicated. If 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; untreated local or systemic fungal or bacterial infections; systemic
`viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these
`infections.
`
`5.4 Hypothalamic-Pituitary-Adrenal Axis Effects
`
`Hypercorticism and Adrenal Suppression: When intranasal steroids 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 NASACORT AQ 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, and
`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 those 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.
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`5.5 Effect on Growth
`Corticosteroids, including NASACORT AQ Nasal Spray, may cause a reduction in growth velocity
`when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving
`NASACORT AQ Nasal Spray. To minimize the systemic effects of intranasal corticosteroids,
`including NASACORT AQ Nasal Spray, titrate each patient's dose to the lowest dosage that effectively
`controls his/her symptoms [see Use in Specific Populations (8.4)].
`
`6 ADVERSE REACTIONS
`Systemic and local corticosteroid use may result in the following:
`Epistaxis, Candida albicans infection, nasal septal perforation, impaired wound healing [see
`Warnings and Precautions (5.1)]
`Glaucoma and Cataracts [see Warnings and Precautions (5.2)]
`Immunosuppression [see Warnings and Precautions (5.3)]
`Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see Warnings and
`Precautions (5.4, 5.5), Use in Specific Populations (8.4) and Clinical Pharmacology (12.2)]
`
`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 to rates in the clinical trials of another drug
`and may not reflect the rates observed in clinical practice.
`In placebo-controlled, double-blind, and open-label clinical studies, 1483 adults and children 12 years
`and older received treatment with NASACORT AQ Nasal Spray. These patients were treated for an
`average duration of 51 days. In the controlled trials (2–5 weeks duration) from which the following
`adverse reaction data are derived, 1394 patients were treated with NASACORT AQ Nasal Spray for an
`average of 19 days. In a long-term, open-label study, 172 patients received treatment for an average
`duration of 286 days. Adverse reactions from 12 studies in adults and adolescent patients 12 to 17 years
`of age receiving NASACORT AQ Nasal Spray 27.5 mcg to 440 mcg once daily are summarized in
`Table 1.
`In clinical trials, nasal septum perforation was reported in one adult patient who received NASACORT
`AQ Nasal Spray.
`
`Table 1 - Adverse drug reactions > 2% and greater than placebo with
`NASACORT AQ Nasal Spray 220 mcg treatment in studies in adults and
`adolescents 12 years and older
`Placebo
`NASACORT AQ 220 mcg
`(N=962)
`(N=857)
`%
`%
`Adverse reaction
`3.6
`5.1
`Pharyngitis
`0.8
`2.7
`Epistaxis
`Cough increased
`1.5
`2.1
`Coding dictionary for adverse events is Coding Symbols for Thesaurus of Adverse
`Reaction Terms (COSTART).
`
`A total of 602 children 6 to 12 years of age were studied in 3 double-blind, placebo-controlled clinical
`trials. Of these, 172 received 110 mcg/day and 207 received 220 mcg/day of NASACORT AQ Nasal
`Spray for two, six, or twelve weeks. The longest average durations of treatment for patients receiving
`110 mcg/day and 220 mcg/day were 76 days and 80 days, respectively. One percent of patients treated
`with NASACORT AQ were discontinued due to adverse experiences. No patient receiving 110
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`mcg/day and one patient receiving 220mcg/day discontinued due to a serious adverse event. A similar
`adverse reaction profile was observed in pediatric patients 6–12 years of age as compared to
`adolescents and adults with the exception of epistaxis which occurred in less than 2% of the children
`studied. Adverse reactions from 2 studies in children 4 to 12 years of age receiving NASACORT AQ
`Nasal Spray 110 mcg once daily are summarized in Table 2.
`
`Table 2 - Adverse drug reactions > 2% and greater than placebo with
`NASACORT AQ Nasal Spray 110 mcg treatment in US studies in patients 4 to 12
`years of age
`NASACORT AQ 110 mcg
`Placebo
`(N=179)
`(N=202)
`%
`%
`Adverse reaction
`8.9
`7.4
`Flu syndrome
`8.4
`6.4
`Cough increased
`7.8
`6.4
`Pharyngitis
`3.4
`1.0
`Bronchitis
`3.4
`1.0
`Dyspepsia
`Tooth disorder
`1.0
`3.4
`Coding dictionary for adverse events is Coding Symbols for Thesaurus of Adverse
`Reaction Terms (COSTART).
`
`A total of 474 children 2 to 5 years of age were studied in a 4-week double-blind, placebo-controlled
`clinical trial. Of these, 236 received 110 mcg/day of NASACORT AQ Nasal Spray for a mean duration
`of 28 days. No patient discontinued due to a serious adverse event. Adverse reactions from the single
`placebo-controlled study in children 2 to 5 years of age receiving NASACORT AQ Nasal Spray 110
`mcg once daily are summarized in Table 3.
`
`Table 3 - Adverse drug reactions > 2% and greater than placebo with
`NASACORT AQ Nasal Spray 110 mcg treatment in children 2 to 5 years of age
`Placebo
`NASACORT AQ 110 mcg
`(N=238)
`(N=236)
`%
`%
`Adverse reactions
`4.2
`5.5
`Headache
`4.2
`5.5
`Pharyngolaryngeal pain
`5.0
`5.1
`Epistaxis
`3.8
`5.1
`Nasopharyngitis
`0.8
`4.7
`Abdominal upper pain
`1.3
`3.0
`Diarrhea
`2.1
`2.5
`Asthma
`1.7
`2.5
`Rash
`0.0
`2.5
`Excoriation
`Rhinorrhea
`1.7
`2.1
`Coding dictionary for adverse events is Medical Dictionary for Regulatory Activities
`terminology (MedDRA) Version 8.1
`
`In the event of accidental overdose, an increased potential for these adverse experiences may be
`expected, but acute systemic adverse experiences are unlikely [see Overdosage (10)].
`
`6.2 Post-Marketing Experience
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`In addition to the adverse drug reactions reported during clinical studies and listed above, the following
`adverse reactions have been identified during post-approval use of NASACORT AQ Nasal Spray.
`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.
`Reactions that have been reported during post-marketing experience include: nasal discomfort and
`congestion, sneezing, alterations of taste and smell, nausea, insomnia, dizziness, fatigue, dyspnea,
`decreased blood cortisol, cataract, glaucoma, increased ocular pressure, pruritus, rash, and
`hypersensitivity.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Teratogenic Effects: Pregnancy Category C
`There are no adequate and well-controlled studies of NASACORT AQ Nasal Spray in pregnant women.
`Triamcinolone acetonide was teratogenic in rats, rabbits, and monkeys. NASACORT AQ Nasal Spray,
`like other corticosteroids, should be used during pregnancy only if the potential benefit justifies the
`potential risk to the fetus. Since their introduction, experience with oral corticosteroids in
`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
`glucocorticoid production during pregnancy, most women will require a lower exogenous
`corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
`In reproduction studies in rats and rabbits, triamcinolone acetonide administered by inhalation produced
`cleft palate and/or internal hydrocephaly and axial skeletal defects at exposures less than and 2 times,
`2
`respectively, the maximum recommended daily intranasal dose in adults on a mcg/m basis. In a monkey
`reproduction study, triamcinolone acetonide administered by inhalation produced cranial malformations
`at an exposure approximately 37 times the maximum recommended daily intranasal dose in adults on a
`2
`mcg/m basis.
`
`8.3 Nursing Mothers
`It is not known whether triamcinolone acetonide is excreted in human milk. Because other
`corticosteroids are excreted in human milk, caution should be exercised when NASACORT AQ Nasal
`Spray is administered to nursing women.
`
`8.4 Pediatric Use
`The safety and effectiveness of NASACORT AQ Nasal Spray has been evaluated in 464 children 2 to 5
`years of age, 518 children 6 to 12 years of age, and 176 adolescents 12 to 17 years of age [see Clinical
`Studies (14)]. The safety and effectiveness of NASACORT AQ Nasal Spray in children below 2 years
`of age have not been established.
`Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth
`velocity in pediatric patients. This effect has been 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 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, including NASACORT AQ Nasal Spray,
`should be monitored routinely (e.g., via stadiometry). The potential growth effects of treatment should
`be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives. To
`minimize the systemic effects of intranasal corticosteroids, including NASACORT AQ Nasal Spray,
`each patient's dose should be titrated to the lowest dosage that effectively controls his/her symptoms.
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`The effect of NASACORT AQ Nasal Spray on growth velocity in children was assessed in a 12 month
`randomized, placebo controlled study conducted in 299 prepubescent children age 3 to 9 years (173
`males, 126 females) with perennial allergic rhinitis. Treatment groups were NASACORT AQ 110 mcg
`once daily and placebo. Growth velocity was estimated for each patient using the slope of the linear
`regression of height over time using observed data in the intent to treat population who had at least 3
`height measurements after randomization. Growth velocities were significantly lower in the
`NASACORT AQ group compared to placebo, with a mean growth velocity of 6.09 cm/year in the
`placebo group and 5.65 cm/year in the NASACORT AQ treated group (difference from placebo -0.45
`cm/year; 95% CI: -0.78, -0.11).
`
`8.5 Geriatric Use
`Clinical studies of NASACORT AQ did not include sufficient numbers of subjects aged 65 and over to
`determine whether they respond differently from younger subjects. Other reported clinical experience
`has not identified differences in responses between the elderly and 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.
`
`10 OVERDOSAGE
`Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions
`(5.4)]. There are no data on the effects of acute or chronic overdosage with NASACORT AQ Nasal
`Spray. Because of low systemic bioavailability and an absence of acute drug-related systemic findings
`in clinical studies overdose is unlikely to require any therapy other than observation.
`Acute overdosing with the intranasal dosage form is unlikely in view of the total amount of active
`ingredient present and low bioavailability of triamcinolone acetonide. In the event that the entire contents
`of the bottle were administered all at once, via either oral or nasal application, clinically significant
`systemic adverse events would most likely not result.
`
`11 DESCRIPTION
`Triamcinolone acetonide, USP, the active ingredient in NASACORT AQ Nasal Spray, is a
`corticosteroid with a molecular weight of 434.51 and with the chemical designation 9-Fluoro-
`11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone
`(C H FO ).
`24 31
`6
`
`NASACORT AQ Nasal Spray is a thixotropic, water-based metered-dose pump spray formulation unit
`containing a microcrystalline suspension of triamcinolone acetonide in an aqueous medium.
`Microcrystalline cellulose, carboxymethylcellulose sodium, polysorbate 80, dextrose, benzalkonium
`chloride, and edetate disodium are contained in this aqueous medium; hydrochloric acid or sodium
`hydroxide may be added to adjust the pH to a target of 5.0 within a range of 4.5 and 6.0.
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`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Triamcinolone acetonide is a synthetic fluorinated corticosteroid with approximately 8 times the
`potency of prednisone in animal models of inflammation.
`Although the precise mechanism of corticosteroid antiallergic action is unknown, corticosteroids have
`been shown to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils,
`neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes,
`cytokines) involved in inflammation.
`
`12.2 Pharmacodynamics
`In order to determine if systemic absorption plays a role in the effect of NASACORT AQ Nasal Spray
`on allergic rhinitis symptoms, a two week double-blind, placebo-controlled clinical study was
`conducted comparing NASACORT AQ, orally ingested triamcinolone acetonide, and placebo in 297
`adult patients with seasonal allergic rhinitis. The study demonstrated that the therapeutic efficacy of
`NASACORT AQ Nasal Spray can be attributed to the topical effects of triamcinolone acetonide.
`
`Adrenal Function: In order to evaluate the effects of systemic absorption on the Hypothalamic-
`Pituitary-Adrenal (HPA) axis, 4 clinical studies, one each in adults and in children 6–12 years of age, 2–
`5 years of age, and 2–11 years of age, were conducted.
`The adult clinical study compared 220 mcg or 440 mcg NASACORT AQ per day, or 10 mg prednisone
`per day with placebo for 42 days. Adrenal response to a six-hour 250 mcg cosyntropin stimulation test
`showed that NASACORT AQ administered at doses of 220 mcg and 440 mcg had no statistically
`significant effect on HPA activity versus placebo. Conversely, oral prednisone at 10 mg/day
`significantly reduced the response to ACTH.
`A study evaluating plasma cortisol response thirty and sixty minutes after 250 mcg cosyntropin
`stimulation in 80 pediatric patients 6 to 12 years of age who received 220 mcg or 440 mcg (twice the
`maximum recommended daily dose) daily for six weeks was conducted. No abnormal response to
`cosyntropin infusion (peak serum cortisol <18 mcg/dL) was observed in any pediatric patient after six
`weeks of dosing with NASACORT AQ at 440 mcg per day.
`In pediatric patients 2 to 5 years of age (n = 61) receiving Nasacort AQ 110 mcg per day intranasally,
`HPA axis function was assessed by cosyntropin stimulation test; however, the results were
`inconclusive.
`An effect of Nasacort AQ Nasal Spray on adrenal function in children 2 to 5 years of age cannot be
`ruled out.
`In a 6-week trial in 140 children 2 to 11 years of age with allergic rhinitis, a daily dose of 110 or 220
`mcg of NASACORT AQ Nasal Spray was compared to placebo nasal spray. A subset of 24 children 6
`to 11 years of age received a higher dose of 220 mcg of NASACORT AQ Nasal Spray. A positive
`control was not included in this trial. Adrenal function was assessed by measurement of 24 hour serum
`cortisol levels before and after the treatment. The difference from placebo in the change from baseline
`in LS mean serum cortisol AUC
` at the end of week 6 for the NASACORT AQ Nasal Spray
`(0–24 hr)
`treatment groups (110 mcg and 220 mcg) was -4.2 mcg·hour/dL (95% CI: -14.7, 6.4).
`
`12.3 Pharmacokinetics
`Based upon intravenous dosing of triamcinolone acetonide phosphate ester in adults, the half-life of
`triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported was
`99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for triamcinolone acetonide. The plasma
`half-life of corticosteroids does not correlate well with the biologic half-life.
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`Pharmacokinetic characterization of the NASACORT AQ Nasal Spray formulation was determined in
`both normal adult subjects and patients with allergic rhinitis. Single dose intranasal administration of 220
`mcg of NASACORT AQ Nasal Spray in normal adult subjects and patients demonstrated minimal
`absorption of triamcinolone acetonide. The mean peak plasma concentration was approximately 0.5
`ng/mL (range: 0.1 to 1.0 ng/mL) and occurred at 1.5 hours post dose. The mean plasma drug
`concentration was less than 0.06 ng/mL at 12 hours, and below the assay detection limit (the minimum
`LOQ of the assay was 0.025 ng/ml) at 24 hours. The average terminal half-life was 3.1 hours. The
`range of mean AUC
` values was 1.4 ng·hr/mL to 4.7 ng·hr/mL between doses of 110 mcg to 440 mcg
`0–∞
`in both patients and healthy volunteers. Dose proportionality was demonstrated in both normal adult
`subjects and in allergic rhinitis patients following single intranasal doses of 110 mcg or 220 mcg
`NASACORT AQ Nasal Spray. The C
` and AUC
` of the 440 mcg dose increased less than
`max
`0–∞
`proportionally when compared to 110 and 220 mcg doses.
`Following multiple dose administration of NASACORT AQ 440 mcg once daily in pediatric patients 6
`to 12 years of age, plasma drug concentrations, AUC
`, C
` and T
` were similar to those values
`0–∞ max
`max
`observed in adult patients receiving the same dose. Intranasal administration of NASACORT AQ 110
`mcg once daily in pediatric patients 2 to 5 years of age exhibited similar systemic exposure to that
`achieved in adult patients 20 to 49 years of age with intranasal administration of NASACORT AQ at a
`dose of 220 mcg once daily. Based on the population pharmacokinetic modeling, the apparent clearance
`and volume of distribution following intranasal administration of NASACORT AQ in pediatric patients
`2 to 5 years of age were found to be approximately half of that in adults.
`In animal studies using rats and dogs, three metabolites of triamcinolone acetonide have been identified.
`They are 6β-hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-
`hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less active than
`the parent compound due to (a) the dependence of anti-inflammatory activity on the presence of a 21-
`hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and (c) the markedly
`increased water solubility favoring rapid elimination. There appeared to be some quantitative
`differences in the metabolites among species. No differences were detected in metabolic pattern as a
`function of route of administration.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a two-year study in rats, triamcinolone acetonide caused no treatment-related carcinogenicity at oral
`doses up to 1.0 mcg/kg (less than the maximum recommended daily intranasal dose in adults and children
`2
`on a mcg/m basis, respectively). In a two-year study in mice, triamcinolone acetonide caused no
`treatment-related carcinogenicity at oral doses up to 3.0 mcg/kg (less than the maximum recommended
`2
`daily intranasal dose in adults and children on a mcg/m basis, respectively).
`No evidence of mutagenicity was detected from in vitro tests (a reverse mutation test in Salmonella
`bacteria and a forward mutation test in Chinese hamster ovary cells) conducted with triamcinolone
`acetonide.
`In male and female rats, triamcinolone acetonide caused no change in pregnancy rate at oral doses up to
`2
`15.0 mcg/kg (less than the maximum recommended daily intranasal dose in adults on a mcg/m basis).
`Triamcinolone acetonide caused increased fetal resorptions and stillbirths and decreases in pup weight
`and survival at doses of 5.0 mcg/kg and above (less than the maximum recommended daily intranasal
`dose in adults on a mcg/m basis). At 1.0 mcg/kg (less than the maximum recommended daily intranasal
`dose in adults on a mcg/m basis), it did not induce the above mentioned effects.
`
`22
`
`13.2 Animal Toxicology and/or Pharmacology
`Triamcinolone acetonide was teratogenic in rats, rabbits, and monkeys. In rats, triamcinolone acetonide
`was teratogenic at an inhalation dose of 20 mcg/kg and above (approximately 7/10 of the maximum
`2
`
`000010
`
`

`

`2 2
`
`recommended daily intranasal dose in adults on a mcg/m basis). In rabbits, triamcinolone acetonide was
`teratogenic at inhalation doses of 20 mcg/kg and above (approximately 2 times the maximum
`recommended daily intranasal dose in adults on a mcg/m basis). In monkeys, triamcinolone acetonide
`was teratogenic at an inhalation dose of 500 mcg/kg (approximately 37 times the maximum recommended
`2
`daily intranasal dose in adults on a mcg/m basis). Dose-related teratogenic effects in rats and rabbits
`included cleft palate and/or internal hydrocephaly and axial skeletal defects, whereas the effects
`observed in the monkey were cranial malformations.
`Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such
`infants should be carefully observed.
`
`14 CLINICAL STUDIES
`The safety and efficacy of NASACORT AQ Nasal Spray have been evaluated in 10 double-blind,
`placebo-controlled clinical studies of two- to four-weeks duration in adults and children 12 years and
`older with seasonal or perennial allergic rhinitis. The number of patients treated with NASACORT AQ
`Nasal Spray in these studies was 1266; of these patients, 675 were males and 591 were females.
`Overall, the results of these clinical studies in adults and children 12 years and older demonstrated that
`NASACORT AQ Nasal Spray 220 mcg once daily (2 sprays in each nostril), when compared to
`placebo, provides statistically significant relief of nasal symptoms of seasonal or perennial allergic
`rhinitis including sneezing, stuffiness, discharge, and itching.
`The saf