` 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)
`
` 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. (5.3)
`
` 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 Nasal Spray slowly. (5.5)
`
` Potential reduction in growth velocity in children. Monitor growth
`
`routinely in pediatric patients receiving Dymista Nasal Spray. (5.7, 8.4)
`
`____________________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.
`
`
` Ritanovir: Coadministration is not recommended. (5.6, 7.2)
`
`
`
`
` Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with
`coadministration. (5.6, 7.2)
`
`
`USE IN SPECIFIC POPULATIONS _______________
`_______________
`
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: 4/2012
`
`
`17
`
`
`PATIENT COUNSELING INFORMATION
`
`
`17.1 Somnolence
`
`17.2 Concurrent Use of Alcohol and other Central Nervous System
`
`
`Depressants
`
`
`17.3 Local Nasal Effects
`
`
`17.4 Cataracts and Glaucoma
`
`
`17.5
`Immunosuppression
`
`
`17.6 Priming
`
`
`17.7 Keep Spray Out of Eyes
`
`
`17.8 Keep Out of Children’s Reach
`
`
`17.9 Potential Drug Interactions
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`DYMISTA™ Nasal Spray safely and effectively. See full prescribing
`information for DYMISTA Nasal Spray.
`DYMISTA (azelastine hydrochloride and fluticasone propionate) Nasal
`Spray
`
`Initial U.S. Approval: 2012
`
`
`
`_________________
`__________________ INDICATIONS AND USAGE
`Dymista Nasal Spray, containing an H1-receptor antagonist and a
`corticosteroid, is indicated for the relief of symptoms of seasonal allergic
`rhinitis in patients 12 years of age and older who require treatment with both
`
`azelastine hydrochloride and fluticasone propionate for symptomatic relief.
`(1.1)
` _______________
`
`DOSAGE AND ADMINISTRATION
`
`
`
` For intranasal use only. (2.1)
`
` Recommended dose is 1 spray per nostril twice daily in adults and
`
`adolescents 12 years of age and older (2.1)
`
` Prime before initial use and when it has not been used for 14 or more days.
`(2.2)
`
`_____________
`______________ DOSAGE FORMS AND STRENGTHS
`Dymista Nasal Spray: 137 mcg of azelastine hydrochloride and 50 mcg of
`
`
`fluticasone propionate (137 mcg/50 mcg) in each 0.137 mL spray. (3)
`
`____________________
`CONTRAINDICATIONS
`
`None.
`
`_______________
`_______________
`WARNINGS AND PRECAUTIONS
`
` Somnolence: Avoid engaging in hazardous occupations requiring complete
`mental alertness such as driving or operating machinery when taking
`Dymista Nasal Spray. (5.1)
`
`
`
` Avoid concurrent use of alcohol or other central nervous system (CNS)
`depressants with Dymista Nasal Spray because further decreased alertness
`
`and impairment of CNS performance may occur. (5.1)
`
`______________
`
`___________________
`
`
`
`
`6
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Information
`
`
`2.2
`Important Administration Instructions
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1
`Somnolence
`
`
`5.2 Local Nasal Effects
`
`
`5.3 Glaucoma and Cataracts
`
`
`5.4
`Immunosuppression
`
`
`5.5 Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects
`
`
`5.6 Use of Cytochrome P450 3A4 Inhibitors
`
`
`5.7 Effect on Growth
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`7.1 Central Nervous System Depressants
`
`
`
`7.2 Cytochrome P450 3A4
`
`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
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`CLINICAL STUDIES
`14
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`7
`
`
`8
`
`Reference ID: 3124523
`
`
`
`1
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`2
`3 Dymista Nasal Spray is indicated for the relief of symptoms of seasonal allergic rhinitis in
`4
`patients 12 years of age and older who require treatment with both azelastine hydrochloride and
`5
`fluticasone propionate for symptomatic relief.
`
`6
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Dosing Information
`2.1
`7
`The recommended dose of Dymista Nasal Spray, 137 mcg/50 mcg, is 1 spray per nostril twice
`8
`daily for seasonal allergic rhinitis. Each spray contains 137 mcg of azelastine hydrochloride and
`9
`50 mcg of fluticasone propionate (137 mcg/50 mcg).
`10
`
`11
`12 Administer Dymista Nasal Spray by the intranasal route only.
`13
`
`
`14
`15
`16
`17
`18
`19
`
`Important Administration Instructions
`2.2
`Shake the bottle gently before each use.
`Priming: Prime Dymista Nasal Spray before initial use by releasing 6 sprays or until a fine mist
`appears. When Dymista Nasal Spray has not been used for 14 or more days, reprime with 1 spray
`or until a fine mist appears. Avoid spraying Dymista Nasal Spray into the eyes. If sprayed in the
`eyes, flush eyes with water for at least 10 minutes.
`
`DOSAGE FORMS AND STRENGTHS
`3
`20
`21 Dymista is a nasal spray suspension. Each spray delivers a volume of 0.137 mL suspension
`22
`containing 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate (137
`23 mcg/50 mcg).
`
`4
`24
`25 None.
`
`CONTRAINDICATIONS
`
`26
`
`27
`28
`29
`30
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Somnolence
`5.1
`In clinical trials, the occurrence of somnolence has been reported in some patients (6 of 853
`patients) taking Dymista Nasal Spray [see Adverse Reactions (6.1)]. Patients should be cautioned
`against engaging in hazardous occupations requiring complete mental alertness and motor
`
`Reference ID: 3124523
`
`
`
`coordination such as operating machinery or driving a motor vehicle after administration of
`31
`32 Dymista Nasal Spray. Concurrent use of Dymista Nasal Spray with alcohol or other central
`33
`nervous system depressants should be avoided because additional reductions in alertness and
`additional impairment of central nervous system performance may occur [see Drug Interactions
`34
`(7.1)].
`35
`
`Local Nasal Effects
`5.2
`36
`In clinical trials of 2 to 52 weeks’ duration, epistaxis was observed more frequently in patients
`37
` treated with Dymista Nasal Spray than those who received placebo [see Adverse Reactions (6)].
`
`38
`Instances of nasal ulceration and nasal septal perforation have been reported in patients
`39
`following the intranasal application of corticosteroids. There were no instances of nasal
`40
`ulceration or nasal septal perforation observed in clinical trials with Dymista Nasal Spray.
`41
`42 Because of the inhibitory effect of corticosteroids on wound healing, patients who have
`43
`experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Dymista Nasal
`44
`Spray until healing has occurred.
`45
`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
`46
`47
`infection develops, it may require treatment with appropriate local therapy and discontinuation of
`48
`treatment with Dymista Nasal Spray. Patients using Dymista Nasal Spray over several months
`or longer should be examined periodically for evidence of Candida infection or other signs of
`49
`50
`adverse effects on the nasal mucosa.
`
`Glaucoma and Cataracts
`5.3
`51
`52 Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts.
`53
`Therefore, close monitoring is warranted in patients with a change in vision or with a history of
`54
`increased intraocular pressure, glaucoma, and/or cataracts.
`55 Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit
`56
`lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12
`57
`years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled
`58
`in the study, 405 were randomized to receive Dymista Nasal Spray (1 spray per nostril twice
`59
`daily) and 207 were randomized to receive fluticasone propionate nasal spray (2 sprays per
`60
`nostril once daily). In the Dymista Nasal Spray group, one patient had increased intraocular
`61
`pressure at month 6. In addition, three patients had evidence of posterior subcapsular cataract at
`62 month 6 and one at month 12 (end of treatment). In the fluticasone propionate group, three
`63
`patients had evidence of posterior subcapsular cataract at month 12 (end of treatment).
`
`64
`65
`66
`67
`68
`69
`70
`
`Immunosuppression
`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
`
`Reference ID: 3124523
`
`
`
`contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not
`71
`known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG)
`72
`73 may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin
`74
`(IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing
`75
`information.) If chickenpox develops, treatment with antiviral agents may be considered.
`76 Corticosteroids should be used with caution, if at all, in patients with active or quiescent
`77
`tuberculous infections of the respiratory tract; untreated local or systemic fungal or bacterial
`78
`infections; systemic viral or parasitic infections; or ocular herpes simplex because of the
`79
`potential for worsening of these infections.
`
`Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects
`5.5
`80
`81 When intranasal steroids are used at higher than recommended dosages or in susceptible
`82
`individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and
`83
`adrenal suppression may appear. If such changes occur, the dosage of Dymista Nasal Spray
`84
`should be discontinued slowly, consistent with accepted procedures for discontinuing oral
`85
`corticosteroid therapy. The concomitant use of intranasal corticosteroids with other inhaled
`86
`corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or
`87
`suppression of the HPA axis.
`88
`The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied
`89
`by signs of adrenal insufficiency, and in addition some patients may experience symptoms of
`90 withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously
`91
`treated for prolonged periods with systemic corticosteroids and transferred to topical
`92
`corticosteroids should be carefully monitored for acute adrenal insufficiency in response to
`93
`stress. In those patients who have asthma or other clinical conditions requiring long-term
`94
`systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a
`95
`severe exacerbation of their symptoms.
`
`Use of Cytochrome P450 3A4 Inhibitors
`5.6
`96
`97 Ritonavir and other strong cytochrome P450 3A4 (CYP3A4) inhibitors can significantly increase
`98
`plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol
`concentrations [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. During
`99
`100
`postmarketing use, there have been reports of clinically significant drug interactions in patients
`101
`receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects
`102
`including Cushing syndrome and adrenal suppression. Therefore, coadministration of Dymista
`103 Nasal Spray and ritonavir is not recommended unless the potential benefit to the patient
`104
`outweighs the risk of systemic corticosteroid side effects.
`105 Use caution with the coadministration of Dymista Nasal Spray and other potent CYP3A4
`inhibitors, such as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`106
`
`Effect on Growth
`5.7
`107
`108 Corticosteroids may cause a reduction in growth velocity when administered to pediatric
`patients. Monitor the growth routinely of pediatric patients receiving Dymista Nasal Spray [see
`109
`110 Use in Specific Populations (8.4)].
`
`Reference ID: 3124523
`
`
`
`111
`112
`113
`114
`115
`116
`117
`118
`119
`120
`
`ADVERSE REACTIONS
`6
`Systemic and local corticosteroid use may result in the following:
` 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)]
` Cataracts and glaucoma [see Warnings and Precautions (5.3)]
`
`Immunosuppression [see Warnings and Precautions (5.4)]
` Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see
`Warnings and Precautions (5.5 and 5.7), Use in Specific Populations (8.4)]
`
`Clinical Trials Experience
`6.1
`121
`122 Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`123
`observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of
`124
`another drug and may not reflect rates observed in practice.
`125
`The safety data described below reflect exposure to Dymista Nasal Spray in 853 patients (12
`126
`years of age and older; 36% male and 64% female) with seasonal allergic rhinitis in 3 double
`127
`blind, placebo-controlled clinical trials of 2-week duration. The racial distribution for the 3
`128
`clinical trials was 80% white, 16% black, 2% Asian, and 1% other. In the 12-month open-label,
`129
`active-controlled clinical trial, 404 Asian patients (240 males and 164 females) with perennial
`130
`allergic rhinitis or vasomotor rhinitis were treated with Dymista Nasal Spray, 1 spray per nostril
`131
`twice daily.
`
`132 Adults and Adolescents 12 Years of Age and Older
`133
`In the 3 placebo controlled clinical trials of 2-week duration, 3411 patients with seasonal allergic
`134
`rhinitis were treated with 1 spray per nostril of Dymista Nasal Spray, azelastine hydrochloride
`135
`nasal spray, fluticasone propionate nasal spray, or placebo, twice daily. The azelastine
`136
`hydrochloride and fluticasone propionate comparators use the same vehicle and device as
`137 Dymista Nasal Spray and are not commercially marketed. Overall, adverse reactions were 16%
`138
`in the Dymista Nasal Spray treatment groups, 15% in the azelastine hydrochloride nasal spray
`139
`groups, 13% in the fluticasone propionate nasal spray groups, and 12% in the placebo groups.
`140 Overall, 1% of patients in both the Dymista Nasal Spray and placebo groups discontinued due to
`141
`adverse reactions.
`142
`Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and
`143 more frequently than placebo in patients treated with Dymista Nasal Spray in the seasonal
`144
`allergic rhinitis controlled clinical trials.
`145
`
`146
`
`
`Reference ID: 3124523
`
`
`
` Table 1. Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled
`
`Trials of 2 Weeks Duration with Dymista Nasal Spray in Adult and Adolescent Patients With Seasonal
`Allergic Rhinitis
`1 spray per nostril twice daily
`
`Fluticasone Propionate
`Azelastine
`Nasal Spray†
`
`Hydrochloride Nasal
`Spray†
`
`
`(N=846)
`
`(N=851)
`
`Dymista Nasal Spray
`
`
`(N=853)*
`
`
`
`
`
`
`Vehicle Placebo
`
`
`
`
`(N=861)
`2(<1%)
`
`
`10(1%)
`
`
`15(2%)
`
`
`Dysgeusia
`
`Headache
`
`Epistaxis
`
`30(4%)
`
`
`18(2%)
`
`
`16(2%)
`
`
`44(5%)
`
`
`20(2%)
`
`
`14(2%)
`
`
`4(1%)
`
`
`20(2%)
`
`
`14(2%)
`
`
`147
`
`*Safety population N=853, intent-to-treat population N=848
`148
`† Not commercially marketed
`In the above trials, somnolence was reported in <1% of patients treated with Dymista Nasal
`149
`Spray (6 of 853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)].
`150
`
`151
`
`Long-Term (12-Month) Safety Trial:
`152
`In the 12-month, open-label, active-controlled, long-term safety trial, 404 patients (12 years of
`153
`age and older) with perennial allergic rhinitis or vasomotor rhinitis were treated with Dymista
`154
`155 Nasal Spray 1 spray per nostril twice daily and 207 patients were treated with fluticasone
`156
`propionate nasal spray, 2 sprays per nostril once daily. Overall, adverse reactions were 47% in
`157
`the Dymista Nasal Spray treatment group and 44% in the fluticasone propionate nasal spray
`158
`group. The most frequently reported adverse reactions (≥ 2%) with Dymista Nasal Spray were
`159
`headache, pyrexia, cough, nasal congestion, rhinitis, dysgeusia, viral infection, upper respiratory
`160
`tract infection, pharyngitis, pain, diarrhea, and epistaxis. In the Dymista Nasal Spray treatment
`161
`group, 7 patients (2%) had mild epistaxis and 1 patient (<1%) had moderate epistaxis. In the
`162
`fluticasone propionate nasal spray treatment group 1 patient (<1%) had mild epistaxis. No
`163
`patients had reports of severe epistaxis. Focused nasal examinations were performed and no
`164
`nasal ulcerations or septal perforations were observed. Eleven of 404 patients (3%) treated with
`165 Dymista Nasal Spray and 6 of 207 patients (3%) treated with fluticasone propionate nasal spray
`166
`discontinued from the trial due to adverse events.
`
`167
`
`Postmarketing Experience
`6.2
`168
`169 Because these reactions are reported voluntarily from a population of uncertain size, it is not
`170
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`171
`exposure.
`172
`The following spontaneous adverse events have been reported during the marketing of azelastine
`173
`hydrochloride nasal spray and causal relationship with the drug is unknown: anaphylactoid
`174
`reaction, application site irritation, atrial fibrillation, chest pain, confusion, dyspnea, facial
`175
`edema, involuntary muscle contractions, nasal sores, palpitations, paresthesia, parosmia, pruritus,
`
`Reference ID: 3124523
`
`
`
`rash, disturbance or loss of sense of smell and/or taste, tolerance, urinary retention, vision
`176
`abnormal and xerophthalmia.
`177
`In addition, the following events have been identified during post-approval use of fluticasone
`178
`propionate nasal spray. These events have been chosen for inclusion due to either their
`179
`seriousness, frequency of reporting, or causal connection to fluticasone propionate or a
`180
`combination of these factors.
`181
`182 General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and
`183
`tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid
`184
`reactions, which in rare instances were severe.
`Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal
`185
`186
`perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice
`187
`changes.
`Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular
`188
`189
`pressure, and cataracts.
`190 Cases of growth suppression have been reported for intranasal corticosteroids, including
`fluticasone propionate [see Use in Specific Populations (8.4)].
`191
`
`DRUG INTERACTIONS
`7
`192
`193 No formal drug interaction studies have been performed with Dymista Nasal Spray. The drug
`194
`interactions of the combination are expected to reflect those of the individual components.
`
`Central Nervous System Depressants
`7.1
`195
`196 Concurrent use of Dymista Nasal Spray with alcohol or other central nervous system depressants
`197
`should be avoided because somnolence and impairment of central nervous system performance
`198 may occur [see Warnings and Precautions (5.1)].
`
`Cytochrome P450 3A4
`7.2
`199
`200 Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate
`201
`exposure following administration of fluticasone propionate aqueous nasal spray, resulting in
`significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During
`202
`203
`postmarketing use, there have been reports of clinically significant drug interactions in patients
`204
`receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects
`205
`including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone
`206
`propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs
`207
`the risk of systemic corticosteroid side effects.
`208 Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to
`209
`steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC,
`210
`but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg
`211
`dose of fluticasone propionate by oral inhalation route.
`212 Caution should be exercised when Dymista Nasal Spray is coadministered with ketoconazole and
`213
`other known strong CYP3A4 inhibitors.
`
`Reference ID: 3124523
`
`
`
`214
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`215
`216 Dymista Nasal Spray: Teratogenic Effects: Pregnancy Category C:
`217
`There are no adequate and well-controlled clinical trials of Dymista Nasal Spray, azelastine
`218
`hydrochloride only, or fluticasone propionate only in pregnant women. Animal reproductive
`219
`studies of azelastine hydrochloride and fluticasone propionate in mice, rats, and/or rabbits
`220
`revealed evidence of teratogenicity as well as other developmental toxic effects. Because animal
`221
`reproduction studies are not always predictive of human response, Dymista Nasal Spray should
`222
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`223 Azelastine hydrochloride: Teratogenic Effects: In mice, azelastine hydrochloride caused
`224
`embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched
`225
`ribs), delayed ossification, and decreased fetal weight at an oral dose approximately 610 times
`the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m2 basis
`226
`227
`at a maternal dose of 68.6 mg/kg). This dose also caused maternal toxicity as evidenced by
`228
`decreased body weight. Neither fetal nor maternal effects occurred at a dose that was
`approximately 26 times the MRHDID (on a mg/m2 basis at a maternal dose of 3 mg/kg).
`229
`230
`In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed
`231
`ossification and skeletal variations, in the absence of maternal toxicity, at an oral dose
`approximately 530 times the MRHDID in adults (on a mg/m2 basis at a maternal dose of 30
`232
`233 mg/kg). At a dose approximately 1200 times the MRHDID (on a mg/m2 basis at a maternal dose
`234
`of 68.6 mg/kg), azelastine hydrochloride also caused embryo-fetal death and decreased fetal
`235 weight; however, this dose caused severe maternal toxicity. Neither fetal nor maternal effects
`occurred at a dose approximately 53 times the MRHDID (on a mg/m2 basis at a maternal dose of
`236
`237
`3 mg/kg).
`238
`In rabbits, azelastine hydrochloride caused abortion, delayed ossification, and decreased fetal
`239 weight at oral doses approximately 1100 times the MRHDID in adults (on a mg/m2 basis at a
`240 maternal dose of 30 mg/kg); however, these doses also resulted in severe maternal toxicity.
`241 Neither fetal nor maternal effects occurred at a dose approximately 11 times the MRHDID (on a
`242 mg/m2 basis at a maternal dose of 0.3 mg/kg).
`Fluticasone propionate: Teratogenic Effects: Corticosteroids have been shown to be
`243
`244
`teratogenic in laboratory animals when administered systemically at relatively low dosage levels.
`245
`Subcutaneous studies in the mouse and rat at doses approximately equivalent to and 4 times,
`respectively, the MRHDID in adults (on a mcg/m2 basis at maternal doses of 45 and 100 mcg/kg,
`246
`247
`respectively), revealed fetal toxicity characteristic of potent corticosteroid compounds, including
`248
`embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
`249
`In the rabbit, fetal weight reduction and cleft palate were observed at a subcutaneous dose less
`than the MRHDID in adults (on a mcg/m2 basis at a maternal dose of 4 mcg/kg). However, no
`250
`251
`teratogenic effects were reported at oral doses up to approximately 25 times the MRHDID in
`adults (on a mcg/m2 basis at a maternal dose of 300 mcg/kg) of fluticasone propionate to the
`252
`253
`rabbit. 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)].
`
`254
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`Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to
`255
`physiologic, doses suggests that rodents are more prone to teratogenic effects from
`256
`corticosteroids than humans. In addition, because there is a natural increase in corticosteroid
`257
`production during pregnancy, most women will require a lower exogenous corticosteroid dose
`258
`and many will not need corticosteroid treatment during pregnancy.
`259
`260 Nonteratogenic Effects: Fluticasone propionate crossed the placenta following oral
`administration of approximately 4 and 25 times the MRHDID in adults (on a mcg/m2 basis at
`261
`262 maternal doses of 100 mcg/kg and 300 mcg/kg to rats and rabbits, respectively).
`
`Nursing Mothers
`8.3
`263
`264 Dymista Nasal Spray: It is not known whether Dymista Nasal Spray is excreted in human
`265
`breast milk. Because many drugs are excreted in human milk, caution should be exercised when
`266 Dymista Nasal Spray is administered to a nursing woman. Since there are no data from well
`267
`controlled human studies on the use of Dymista Nasal Spray by nursing mothers, based on data
`268
`from the individual components, a decision should be made whether to discontinue nursing or to
`269
`discontinue Dymista Nasal Spray, taking into account the importance of Dymista Nasal Spray to
`270
`the mother.
`271 Azelastine hydrochloride: It is not known if azelastine hydrochloride is excreted in human
`272 milk.
`Fluticasone propionate: It is not known if fluticasone propionate is excreted in human milk.
`273
`274 However, other corticosteroids are excreted in human milk. Subcutaneous administration to
`275
`lactating rats of 10 mcg/kg of tritiated fluticasone propionate (less than the maximum
`recommended daily intranasal dose in adults on a mcg/m2 basis) resulted in measurable
`276
`277
`radioactivity in the milk.
`
`Pediatric Use
`8.4
`278
`Safety and effectiveness of Dymista Nasal Spray in pediatric patients below the age of 12 years
`279
`have not been established.
`280
`281 Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in
`282
`growth velocity in pediatric patients. This effect has been observed in the absence of laboratory
`283
`evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator
`284
`of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA
`285
`axis function. The long-term effects of this reduction in growth velocity associated with
`286
`intranasal corticosteroids, including the impact on final adult height, are unknown. The potential
`287
`for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has
`288
`not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids,
`289
`including Dymista Nasal Spray, should be monitored routinely (e.g., via stadiometry). The
`290
`potential growth effects of prolonged treatment should be weighed against the clinical benefits
`291
`obtained and the risks/benefits of treatment alternatives.
`
`Geriatric Use
`8.5
`292
`293 Clinical trials of Dymista Nasal Spray did not include sufficient numbers of patients 65 years of
`294
`age and older to determine whether they respond differently from younger patients. Other
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`Reference ID: 3124523
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`
`
`295
`296
`297
`298
`
`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.
`
`OVERDOSAGE
`10
`299
`300 Dymista Nasal Spray: Dymista Nasal Spray contains both azelastine hydrochloride and
`301
`fluticasone propionate; therefore, the risks associated with overdosage for the individual
`302
`components described below apply to Dymista Nasal Spray.
`303 Azelastine hydrochloride: There have been no reported overdosages with azelastine
`304
`hydrochloride. Acute azelastine hydrochloride overdosage by adults with this dosage form is
`305
`unlikely to result in clinically significant adverse events, other than increased somnolence, since
`306
`one (1) 23 g bottle of Dymista Nasal Spray contains approximately 23 mg of azelastine
`307
`hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine
`308
`hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events.
`309 General supportive measures should be employed if overdosage occurs. There is no known
`310
`antidote to Dymista Nasal Spray. Oral ingestion of antihistamines has the potential to cause
`311
`serious adverse effects in children. Accordingly, Dymista Nasal Spray should be kept out of the
`312
`reach of children
`Fluticasone propionate: Chronic fluticasone propionate overdosage may result in
`313
`signs/symptoms of hypercorticism [see Warnings and Precautions (5.2)]. Intranasal
`314
`315
`administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily
`316
`for 7 days to healthy human volunteers was well tolerated. Single oral fluticasone propionate
`317
`doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported.
`318 Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg
`319
`daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate
`320
`severity, and incidences were similar in active and placebo treatment groups. Acute overdosage
`321 with this dosage form is unlik