` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`DYMISTA® safely and effectively. See full prescribing information for
`
`
`
`
`DYMISTA.
`
`
`DYMISTA (azelastine hydrochloride and fluticasone propionate) nasal
`
`spray
`
`Initial U.S. Approval: 2012
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`Indications and Usage (1)
`04/2021
`
`
`
`-------------------------INDICATIONS AND USAGE----------------------------­
`
`DYMISTA contains an H1-receptor antagonist and a corticosteroid, and is
`
`
`
`indicated for the relief of symptoms of seasonal allergic rhinitis in adult and
`
`
`
`
`pediatric patients 6 years of age and older. (1)
`
`
`
`
`
`
`------------------DOSAGE AND ADMINISTRATION---------------------------­
`
`
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`
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`Recommended dosage: 1 spray per nostril twice daily (2.1)
`•
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`
`
`For nasal use only. (2.2)
`•
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`
`
`
`
`
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`Prime before initial use and when it has not been used for 14 or more
`•
`
`days. (2.2)
`
`
`
`
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`-----------------DOSAGE FORMS AND STRENGTHS-------------------------­
`
`
`
`
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`Nasal spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone
`
`propionate in each spray. (3)
`
`
`----------------------------CONTRAINDICATIONS--------------------------------­
`
`
`None. (4)
`
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`
`
`
`
`Somnolence: Avoid engaging in hazardous occupations requiring
`•
`
`
`complete mental alertness such as driving or operating machinery when
`
`taking DYMISTA. (5.1)
`
`
`
`
`Avoid concurrent use of alcohol or other central nervous system (CNS)
`
`
`
`
`depressants with DYMISTA because further decreased alertness and
`
`
`
`impairment of CNS performance may occur. (5.1)
`
`
`•
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`
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`
`
`3
`
`4
`
`5
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`Recommended Dosage
`2.1
`
`
`Important Administration Instructions
`2.2
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Somnolence
`
`
`5.2
`Local Nasal Effects
`
`
`5.3
`Glaucoma and Cataracts
`
`
`5.4
`Immunosuppression and Risk of Infections
`
`
`5.5
`Hypercorticism and Adrenal Suppression
`
`
`5.6
`Use of Cytochrome P450 3A4 Inhibitors
`
`
`
`
`5.7
`Effect on Growth
`
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`
`Postmarketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`7.1
`Central Nervous System Depressants
`
`
`6
`
`
`7
`
`
`
`
`
`
`
`Reference ID: 4780656
`
`
`
`
`Epistaxis, nasal ulcerations, nasal septal perforation, impaired wound
`
`
`
`healing, Candida albicans infection: Monitor patients periodically for
`
`
`
`
`
`signs of adverse effects on the nasal mucosa. Avoid use in patients with
`
`
`recent nasal ulcers, nasal surgery, or nasal trauma. (5.2)
`
`
`
`
`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. (5.3)
`
`
`
`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
`
`
`
`patients with the above because of the potential for worsening of these
`
`infections. (5.4)
`
`
`
`Hypercorticism and adrenal suppression with very high dosages or at the
`
`
`
`regular dosage in susceptible individuals. If such changes occur,
`
`discontinue DYMISTA slowly. (5.5)
`
`
`
`Potential reduction in growth velocity in children. Monitor growth
`
`
`
`
`routinely in pediatric patients receiving DYMISTA. (5.7, 8.4)
`
`
`•
`
`
`•
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`
`•
`
`
`•
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`
`•
`
`
`•
`
`•
`
`
`
`-----------------------------ADVERSE REACTIONS-------------------------------­
`
`
`
`
`The most common adverse reactions (≥2% incidence) are: dysgeusia,
`
`
`epistaxis, and headache. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Meda
`
`
`
`
`Pharmaceuticals Inc. at 1-888-939-6478 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`--------------------------------DRUG INTERACTIONS----------------------------­
`
`
`
`
`
`
`Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood
`•
`
`
`levels of fluticasone propionate.
`
`
`
`Ritonavir: Coadministration is not recommended. (5.6, 7.2)
`
`
`
`
`
`Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with
`
`coadministration. (5.6, 7.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`
`
`
`
`Revised: 04/2021
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`
`Cytochrome P450 3A4
`7.2
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`Mechanism of Action
`12.1
`
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`13
`
`14
`
`16
`
`17
`
`
`*Sections or subsections omitted from the full prescribing information are
`
`
`
`
`not listed.
`
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`
`
`
`
` 1
`
`

`

`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1
` INDICATIONS AND USAGE
` DYMISTA is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and
`pediatric patients 6 years of age and older.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Recommended Dosage
`2.1
`
`
`The recommended dosage of DYMISTA is 1 spray (137 mcg of azelastine hydrochloride and 50
`
`mcg of fluticasone propionate) in each nostril twice daily.
`
`
`
`Important Administration Instructions
`2.2
`
`
`• Administer DYMISTA by the nasal route only.
`
`
`• Shake the bottle gently before each use.
`
`
`
`• Avoid spraying DYMISTA into the eyes. If sprayed in the eyes, flush eyes with water for at
`
`
`least 10 minutes.
`
`
`
`
`CONTRAINDICATIONS
`
`
`
`Priming
`
`Prime DYMISTA before initial use by releasing 6 sprays or until a fine mist appears.
`
`Repriming (as needed)
`
`When DYMISTA has not been used for 14 or more days, reprime with 1 spray or until a fine
`
`mist appears.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`Nasal spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate per spray
`
`
`
`
`
`
`4
`
`None.
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Somnolence
`
`
`In clinical trials, the occurrence of somnolence has been reported in some patients (6 of 853 adult
`
`and adolescent patients and 2 of 416 children) taking DYMISTA in placebo controlled trials [see
`
`Adverse Reactions (6.1)]. Patients should be cautioned against engaging in hazardous
`
`occupations requiring complete mental alertness and motor coordination such as operating
`
`machinery or driving a motor vehicle after administration of DYMISTA. Concurrent use of
`
`
`DYMISTA with alcohol or other central nervous system depressants should be avoided because
`
`
`additional reductions in alertness and additional impairment of central nervous system
`
`performance may occur [see Drug Interactions (7.1)].
`
`
`
`Local Nasal Effects
`5.2
`
`
`In clinical trials of 2 to 52 weeks' duration, epistaxis was observed more frequently in patients
`
`
`
`treated with DYMISTA than those who received placebo [see Adverse Reactions (6)].
`
`Instances of nasal ulceration and nasal septal perforation have been reported in patients
`
`
`following the nasal application of corticosteroids. There were no instances of nasal ulceration or
`
`
`nasal septal perforation observed in clinical trials with DYMISTA.
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 2
`
`

`

`
`Because of the inhibitory effect of corticosteroids on wound healing, patients who have
`
`
`
`experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid use of DYMISTA
`
`
`
`until healing has occurred.
`
`
`In clinical trials with fluticasone propionate administered nasally, 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
`
`treatment with DYMISTA. Patients using DYMISTA over several months or longer should be
`
`
`examined periodically for evidence of Candida infection or other signs of adverse effects on the
`
`
`
`
`
`nasal mucosa.
`
`
`5.3 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.
`
`
`Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit
`
`
`
`lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12
`years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled
`in the study, 405 were randomized to receive DYMISTA (1 spray per nostril twice daily) and
`207 were randomized to receive fluticasone propionate nasal spray (2 sprays per nostril once
`
`
`daily). In the DYMISTA group, one patient had increased intraocular pressure at month 6. In
`
`addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at
`
`
`month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of
`
`posterior subcapsular cataract at month 12 (end of treatment).
`
`
`
`Immunosuppression and Risk of Infections
`5.4
`
`
`
`Persons who are using drugs, such as corticosteroids, 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 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 Prescribing Information for VZIG and IG) If
`
`
`
`chickenpox develops, treatment with antiviral agents may be considered.
`
`
`
`Corticosteroids should be used with caution, if at all, in patients with active or quiescent
`
`tuberculous 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.
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 3
`
`

`

`5.5 Hypercorticism and Adrenal Suppression
`
`
`When nasal 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 DYMISTA should be discontinued
`
`slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The
`concomitant use of nasal corticosteroids with other inhaled corticosteroids could increase the risk
`
`of signs or symptoms of hypercorticism and/or suppression of the HPA axis.
`
`
`The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied
`
`by signs of adrenal insufficiency, and in addition some patients may experience symptoms of
`
`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, too rapid a decrease in systemic corticosteroids may cause a
`
`severe exacerbation of their symptoms.
`
`
`
`Use of Cytochrome P450 3A4 Inhibitors
`5.6
`
`
`Ritonavir and other strong cytochrome P450 3A4 (CYP3A4) inhibitors can significantly increase
`
`plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol
`
`
`concentrations [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. During
`
`postmarketing use, there have been reports of clinically significant drug interactions in patients
`
`
`receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects
`
`
`including Cushing syndrome and adrenal suppression. Therefore, coadministration of DYMISTA
`
`and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of
`
`systemic corticosteroid side effects.
`
`
`Use caution with the coadministration of DYMISTA and other potent CYP3A4 inhibitors, such
`as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
`
`Effect on Growth
`5.7
`
`
`Corticosteroids may cause a reduction in growth velocity when administered to pediatric
`
`patients. Monitor the growth routinely of pediatric patients receiving DYMISTA [see Use in
`
`
`
`Specific Populations (8.4)].
`
`
`ADVERSE REACTIONS
`6
`
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`
`Somnolence [see Warnings and Precautions (5.1)]
`
`
`
`•
`Local nasal effects, including epistaxis, nasal ulceration, nasal septal perforation,
`
`
`•
`impaired wound healing, and Candida albicans infection [see Warnings and Precautions
`
`
`
`(5.2)]
`Glaucoma and Cataracts [see Warnings and Precautions (5.3)]
`
`
`
`Immunosuppression and Risk of Infections [see Warnings and Precautions (5.4)]
`
`
`
`
`Hypercorticism and Adrenal Suppression, including growth reduction [see Warnings and
`
`
`Precautions (5.5 and 5.7), Use in Specific Populations (8.4)]
`
`
`
`•
`
`•
`
`•
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 4
`
`

`

` Clinical Trials Experience
` 6.1
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
` observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`
`
` another drug and may not reflect rates observed in practice.
`
`
`Adults and Adolescents 12 Years of Age and Older: The safety data described below in adults
`
`
`and adolescents 12 years of age and older reflect exposure to DYMISTA in 853 patients (12
`
`
`years of age and older; 36% male and 64% female) with seasonal allergic rhinitis in 3 double-
`
`blind, placebo-controlled clinical trials of 2-week duration. The racial distribution for the 3
`
`clinical trials was 80% white, 16% black, 2% Asian, and 1% other.
`
`In the 3 placebo controlled clinical trials of 2-week duration, 3411 patients with seasonal allergic
`rhinitis were treated with 1 spray per nostril of DYMISTA, azelastine hydrochloride nasal spray,
`
`fluticasone propionate nasal spray, or placebo, twice daily. The azelastine hydrochloride and
`
`
`
`
`fluticasone propionate comparators use the same vehicle and device as DYMISTA and are not
`
`
`commercially marketed. Overall, adverse reactions were 16% in the DYMISTA treatment
`
`groups, 15% in the azelastine hydrochloride nasal spray groups, 13% in the fluticasone
`propionate nasal spray groups, and 12% in the placebo groups. Overall, 1% of patients in both
`
`the DYMISTA and placebo groups discontinued due to adverse reactions.
`
`
`Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and
`
`more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis
`
`controlled clinical trials.
`
`
`
`Table 1. Adverse Reactions with ≥ 2% Incidence and More Frequently than Placebo in
`
`
`Placebo-Controlled Trials of 2 Weeks Duration with DYMISTA in Adult and Adolescent
`
`Patients with Seasonal Allergic Rhinitis
` 1 spray per nostril twice daily
`
`
`Azelastine
`Fluticasone
`
`Hydrochloride
` Propionate
` Nasal Spray†
`
`
` Nasal Spray†
`
`
`
` (N = 846)
`
`
`
` (N = 851)
`
`
`
`
` 4 (1%)
` 44 (5%)
`
`
` 30 (4%)
`
` Dysgeusia
`
`
`
`
` 20 (2%)
`
`
` 20 (2%)
`
` 18 (2%)
`Headache
`
`
`
`
`
` 14 (2%)
`
` 14 (2%)
`
` 16 (2%)
`Epistaxis
` * Safety population N = 853, intent-to-treat population N = 848
`
`
`
`
` † Not commercially marketed
`
`
`In the above trials, somnolence was reported in < 1% of patients treated with DYMISTA (6 of
`
`
`
`
`853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)].
`
`
`
`
`Pediatric Patients 6-11 Years of Age: The safety data described below in children 6-11 years of
`
`
`age reflect exposure to DYMISTA in 152 patients (6-11 years of age; 57% male and 43%
`
`
`
`female) with seasonal allergic rhinitis in one double-blind, placebo-controlled clinical trial of 2­
`
`week duration. The racial distribution for the clinical trial was 69% white, 31% black, 2% Asian
`
`and 2% other.
`
`
`Vehicle
`
` Placebo
` (N = 861)
`
`
`
`
`
`
`
`
` 2 (< 1%)
`
`
`
` 10 (1%)
`
`
`
` 15 (2%)
`
` DYMISTA
`
`
`
`
` (N = 853)*
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 5
`
`

`

`
`
`In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis
`were treated with 1 spray per nostril of DYMISTA or placebo, twice daily. Overall, adverse
`reactions were 16% in the DYMISTA treatment group, and 12% in the placebo group. Overall,
` 1% of patients in both the DYMISTA and placebo groups discontinued due to adverse reactions.
`
`
`
`
`Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and
`
`more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis
`
`controlled clinical trial.
`
`
`Table 2. Adverse Reactions with ≥ 2% Incidence and More Frequently than Placebo in
`
`Placebo-Controlled Trials of 2 Weeks Duration with DYMISTA in Children 6 to 11 Years
`
`
`of Age with Seasonal Allergic Rhinitis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 spray per nostril twice daily
`
` Vehicle Placebo
`
` DYMISTA
` (N = 152)*
`
`
`
`
`
`
` (N = 152)
`
`
`
`6 (4%)
`0 (0%)
`Dysgeusia
`
`
`
`6 (4%)
`4 (3%)
`Epistaxis
` * Safety population N = 152, intent-to-treat population N = 152
`
`
`
` In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)].
`
` Long-Term (12-Month) Safety Trial in Adults and Adolescents 12 Years of Age and Older: In the
`
`
`12-month open-label, active-controlled clinical trial, 404 Asian patients (240 males and 164
`
` females) with perennial allergic rhinitis or vasomotor rhinitis were treated with DYMISTA, 1
`
` spray per nostril twice daily.
`
`
` In the 12-month, open-label, active-controlled, long-term safety trial in adults and adolescents 12
`
`
` years of age and older, 404 patients with perennial allergic rhinitis or vasomotor rhinitis were
` treated with DYMISTA 1 spray per nostril twice daily and 207 patients were treated with
`
`
`
`
` fluticasone propionate nasal spray, 2 sprays per nostril once daily. Overall, adverse reactions
`were 47% in the DYMISTA treatment group and 44% in the fluticasone propionate nasal spray
`
` group. The most frequently reported adverse reactions (≥ 2%) with DYMISTA were headache,
`pyrexia, cough, nasal congestion, rhinitis, dysgeusia, viral infection, upper respiratory tract
`
`
`infection, pharyngitis, pain, diarrhea, and epistaxis. In the DYMISTA treatment group, 7 patients
`
`
`(2%) had mild epistaxis and 1 patient (< 1%) had moderate epistaxis. In the fluticasone
`
`
`propionate nasal spray treatment group 1 patient (< 1%) had mild epistaxis. No patients had
`
`
`reports of severe epistaxis. Focused nasal examinations were performed and no nasal ulcerations
`
`
`or septal perforations were observed. Eleven of 404 patients (3%) treated with DYMISTA and 6
`
`
`of 207 patients (3%) treated with fluticasone propionate nasal spray discontinued from the trial
`
`
`due to adverse reactions.
`
`Long-Term (3-Month) Safety Trial in Pediatric Patients 6-11 Years of Age: In the 3-month open
`
`
`
`
`label active-controlled clinical trial, 264 patients (60% male, 40% female) (80% white, 19%
`
`
`
`black, 4% Asian and 2% other) with allergic rhinitis were treated with DYMISTA, 1 spray per
`
`nostril twice daily.
`
`
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 6
`
`

`

`
`In the 3-month, open label, active-controlled, safety trial in pediatric patients 6-11 years of age
`
`
`264 patients (128 patients ≥ 6 to < 9 years of age, and 136 patients ≥ 9 to < 12 years of age) with
`
`
`
`
`
`
`
`allergic rhinitis (based on the Investigator’s assessment) were treated with DYMISTA, 1 spray
`
`per nostril twice daily and 89 patients (44 patients ≥ 6 to < 9 years of age, and 45 patients ≥ 9 to
`
`
`
`
`
`< 12 years of age) were treated with fluticasone propionate nasal spray, 1 spray per nostril twice
`
`
`daily. Overall, adverse reactions were 40% in the DYMISTA treatment group and 36% in the
`
`
`
`fluticasone propionate nasal spray group. The most frequently reported adverse reactions (≥ 2%)
`
`with DYMISTA were epistaxis, headache, oropharyngeal pain, vomiting, upper abdominal pain,
`
`cough, pyrexia, otitis media, upper respiratory tract infection, diarrhea, nausea, otitis externa, and
`urticaria. In the DYMISTA treatment group 23 patients (9%) had mild epistaxis and 3 patients
`
`
`(1%) had moderate epistaxis. In the fluticasone propionate nasal spray treatment group 8 patients
`
`
`(9%) had mild epistaxis. No patients had reports of severe epistaxis. Focused nasal examinations
`
`were performed and no ulcerations or septal perforations were observed. Four of 264 patients
`
`
`(2%) treated with DYMISTA and 3 of 89 (3%) treated with fluticasone propionate nasal spray
`discontinued from the trial due to adverse reactions. There were two reports of somnolence, one
`
`
`severe, among children taking DYMISTA [see Warnings and Precautions (5.1)].
`
`
`
`
`Postmarketing Experience
`6.2
`
`
`The following spontaneous adverse reactions have been reported with DYMISTA or one of the
`
`
`
`components (azelastine and fluticasone). 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.
`
`
`
`Cardiac Disorders: atrial fibrillation, increased heart rate, palpitations
`
`
`
`
`Eye Disorder: blurred vision, cataracts, conjunctivitis, dryness and irritation, eye swelling,
`
`glaucoma, increased intraocular pressure, vision abnormal, xerophthalmia
`
`
`Gastrointestinal Disorders: nausea, vomiting
`
`
`
`General Disorders and Administration Site Condition: aches and pain, application site irritation,
`
`
`
`chest pain, edema of face and tongue, fatigue, tolerance
`
`
`Immune System Disorders: anaphylaxis/anaphylactoid reactions which in rare instances were
`
`
`
`
`severe, hypersensitivity reactions
`
`
`Musculoskeletal and Connective Tissue Disorders: growth suppression [see Use in Specific
`
`
`
`Populations (8.4)]
`
`Nervous System Disorders: disturbance or loss of smell and/ or taste, dizziness, involuntary
`
`
`
`muscle contractions, paresthesia, parosmia
`
`
`Psychiatric Disorders: anxiety, confusion, nervousness
`
`
`
`Renal and Urinary Disorders: urinary retention
`
`
`
`
`
`
`Reference ID: 4780656
`
`
`
` 7
`
`

`

`
`
`Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, cough, dysphonia, dyspnea,
`
`
`
`hoarseness, nasal septal perforation, nasal discomfort, nasal dryness, nasal sores, nasal ulcer, sore
`
`throat, throat dryness and irritation, voice changes, wheezing
`
`
`Skin and Subcutaneous Tissue Disorder: angioedema, erythema, face swelling, pruritus, rash,
`
`
`
`urticaria
`
`
`
`Vascular Disorder: hypertension
`
`
`
`
`DRUG INTERACTIONS
`7
`
`No formal drug interaction studies have been performed with DYMISTA. The drug interactions
`
`
`of the combination are expected to reflect those of the individual components.
`
`
`
`Central Nervous System Depressants
`7.1
`
`
`Concurrent use of DYMISTA with alcohol or other central nervous system depressants should be
`
`avoided because somnolence and impairment of central nervous system performance may occur
`
`[see Warnings and Precautions (5.1)].
`
`
`
`Cytochrome P450 3A4
`7.2
`
`Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate
`
`exposure following administration of fluticasone propionate aqueous nasal spray, 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 and ritonavir, resulting in systemic corticosteroid effects
`
`including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone
`
`propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs
`
`the risk of systemic corticosteroid side effects.
`
`Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to
`steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC,
`but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg
`
`dose of fluticasone propionate by oral inhalation route.
`
`
`Caution should be exercised when DYMISTA is coadministered with ketoconazole and other
`
`known strong CYP3A4 inhibitors.
`
`
`
`USE IN SPECIFIC POPULATIONS
`8
`
`
`Pregnancy
`8.1
`
`Risk Summary
`
`
`Limited data from postmarketing experience with DYMISTA in pregnant women have not
`
`identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or
`fetal outcomes. The individual components of DYMISTA have been marketed for decades.
`
`While the data regarding the use of nasal preparations of fluticasone propionate in pregnancy are
`limited, data from clinical studies of inhaled fluticasone propionate do not indicate an increased
`
`
`risk of adverse maternal or fetal outcomes.
`
`
`
`Reference ID: 4780656
`
`
`
` 8
`
`

`

`
`
`
`Animal reproduction studies with DYMISTA are not available; however, studies are available
`
`
`with its individual components, azelastine hydrochloride and fluticasone propionate. In animal
`
`
`reproduction studies, there was no evidence of fetal harm in animals at oral doses of azelastine
`
`hydrochloride approximately 10 times the clinical daily dose. Oral administration of azelastine
`hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced
`
` developmental toxicity that included structural abnormalities, decreased embryo-fetal survival,
`
` and decreased fetal body weights at doses 530 times and higher than the maximum
`
`
` recommended human daily nasal dose (MRHDID) of 0.548 mg. However, the relevance of these
`
` findings in animals to pregnant women was considered questionable based upon the high animal
`
`to human dose multiple.
`
`
`In animal reproduction studies, fluticasone propionate administered via nose-only 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. 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
`MRHDID of 200 mcg on a mcg/m2 basis (see Data). Experience with 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
`
`
`
` populations is unknown. All pregnancies have a background risk of birth defect, loss, or other
`
`
`
` adverse outcomes. In the U.S. general population, the estimated background risk of major birth
`
`
`
`
`
` defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
`
`
`
`
`Data
`Animal Data: Azelastine Hydrochloride: In an embryo-fetal development study in mice dosed
`during the period of organogenesis, azelastine hydrochloride caused embryo-fetal death,
`
`structural abnormalities (cleft palate; short or absent tail; fused, absent or branched ribs), delayed
`
`ossification, and decreased fetal weight at approximately 610 times the MRHDID in adults (on a
`
`
`
` mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day), which also caused maternal toxicity as
` evidenced by decreased maternal body weight. Neither fetal nor maternal effects occurred in
`
`
`
` mice at approximately 25 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose
`
`
`of 3 mg/kg/day).
`
`
`In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis
`
`from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo-and
`brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity,
`
`at approximately 530 times the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of
`
`
`30 mg/kg/day). Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight
`
`
`and severe maternal toxicity at approximately 1200 times the MRHDID (on a mg/m2 basis at a
`
`
`maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at
`
`
`approximately 55 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 3 mg/kg/day).
`
`
`
`
`In an embryo-fetal development study in pregnant rabbits dosed during the period of
`
`
`organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed
`
`
`
`
`Reference ID: 4780656
`
`
`
` 9
`
`

`

`ossification and decreased fetal weight and severe maternal toxicity at approximately 1100 times
`
`the MRHDID in adults (on a mg/m2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal
`
`nor maternal effects occurred at approximately 10 times the MRHDID (on a mg/m2 basis at a
`
`
`
`
`
`maternal oral dose of 0.3 mg/kg/day).
`
`
`In a prenatal and postnatal development study in pregnant rats dosed from late in the gestation
`period and through the lactation period from gestation day 17 through lactation day 21,
`
`
`azelastine hydrochloride produced no adverse developmental effects on pups at maternal doses
`up to approximately 530 times the MRHDID (on mg/m2 basis at a maternal dose of 30
`
`
`
`
`mg/kg/day).
`
`
`Fluticasone Propionate: 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 5 times the
`MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). Neither
`
`
`fetal nor maternal effects occurred in rats at approximately 1 times the MRHDID (on a mg/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 1 times the MRHDID (on a
`mg/m2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). Neither fetal nor maternal
`
`
`effects occurred in mice with a dose approximately 0.4 times the MRHDID (on a mg/m2 basis
`
`
`
`with a maternal subcutaneous dose of 15 mcg/kg/day).
`
`
`
`
`In an embryofetal development study with pregnant rats dosed by the nose-only 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 1
`times the MRHDID (on a mg/m2 basis with a maternal nose-only inhalation dose of 25.7
`
`
`
`
`mcg/kg/day); however, there was no evidence of teratogenicity. Neither fetal nor maternal effects
`occurred in rats with a dose approximately 0.25 times the MRHDID (on a mg/m2 basis with a
`
`
`
`
`
`
`maternal nose-only inhalation dose of 5.5 mcg/kg/day).
`
`
`In an embryofetal development study in pregnant rab