CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202236Orig1s000
`
`LABELING
`
`
`
`
`

`

`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 ______________
`(cid:120) For intranasal use only. (2.1)
`(cid:120) Recommended dose is 1 spray per nostril twice daily in adults and
`adolescents 12 years of age and older (2.1)
`(cid:120) 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_______________
`(cid:120) Somnolence: Avoid engaging in hazardous occupations requiring complete
`mental alertness such as driving or operating machinery when taking
`Dymista Nasal Spray. (5.1)
`(cid:120) 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)
`
`
`
`(cid:120) 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)
`(cid:120) 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)
`(cid:120) 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)
`(cid:120) 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)
`(cid:120) 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 ((cid:149)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____________________
`(cid:120) Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood
`levels of fluticasone propionate.
`(cid:120) Ritanovir: Coadministration is not recommended. (5.6, 7.2)
`(cid:120) Other potent CYP3A4 inhibitors, such as ketoconazole: use caution with
`coadministration. (5.6, 7.2)
`
`_______________ USE IN SPECIFIC POPULATIONS _______________
`(cid:120) 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.
`
`3
`4
`5
`
`6
`
`7
`
`8
`
`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
`CONTRAINDICATIONS
`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
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`
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`11
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`13
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`16
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`Reference ID: 3124523
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`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`Dymista Nasal Spray 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.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Dosing Information
`2.1
`The recommended dose of Dymista Nasal Spray, 137 mcg/50 mcg, is 1 spray per nostril twice
`daily for seasonal allergic rhinitis. Each spray contains 137 mcg of azelastine hydrochloride and
`50 mcg of fluticasone propionate (137 mcg/50 mcg).
`
`Administer Dymista Nasal Spray by the intranasal route only.
`
`
`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
`Dymista is a nasal spray suspension. Each spray delivers a volume of 0.137 mL suspension
`containing 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate (137
`mcg/50 mcg).
`
`CONTRAINDICATIONS
`
`4
`None.
`
`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
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`coordination such as operating machinery or driving a motor vehicle after administration of
`Dymista Nasal Spray. Concurrent use of Dymista Nasal Spray 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 Nasal Spray than those who received placebo [see Adverse Reactions (6)].
`Instances of nasal ulceration and nasal septal perforation have been reported in patients
`following the intranasal application of corticosteroids. There were no instances of nasal
`ulceration or nasal septal perforation observed in clinical trials with Dymista Nasal Spray.
`Because of the inhibitory effect of corticosteroids on wound healing, patients who have
`experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use Dymista Nasal
`Spray until healing has occurred.
`In clinical trials with fluticasone propionate administered intranasally, the development of
`localized infections of the nose and pharynx with Candida albicans has occurred. When such an
`infection develops, it may require treatment with appropriate local therapy and discontinuation of
`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
`adverse effects on the nasal mucosa.
`
`Glaucoma and Cataracts
`5.3
`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 Nasal Spray (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 Nasal Spray 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
`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
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`Reference ID: 3124523
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`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
`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.
`
`Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects
`5.5
`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 Dymista Nasal Spray
`should be discontinued slowly, consistent with accepted procedures for discontinuing oral
`corticosteroid therapy. The concomitant use of intranasal 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
`Nasal Spray 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 Nasal Spray 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 Nasal Spray [see
`Use in Specific Populations (8.4)].
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`ADVERSE REACTIONS
`6
`Systemic and local corticosteroid use may result in the following:
`(cid:120) Somnolence [see Warnings and Precautions (5.1)]
`(cid:120) Local nasal effects, including epistaxis, nasal ulceration, nasal septal perforation,
`impaired wound healing, and Candida albicans infection [see Warnings and
`Precautions (5.2)]
`(cid:120) Cataracts and glaucoma [see Warnings and Precautions (5.3)]
`Immunosuppression [see Warnings and Precautions (5.4)]
`(cid:120)
`(cid:120) 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
`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.
`The safety data described below reflect exposure to Dymista Nasal Spray 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 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 Nasal Spray, 1 spray per nostril
`twice daily.
`
`Adults and Adolescents 12 Years of Age and Older
`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 Nasal Spray, 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 Nasal Spray and are not commercially marketed. Overall, adverse reactions were 16%
`in the Dymista Nasal Spray 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 Nasal Spray 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 Nasal Spray in the seasonal
`allergic rhinitis controlled clinical trials.
`
`
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`Reference ID: 3124523
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`

`Table 1. Adverse Reactions with (cid:149)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%)
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`*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 Nasal
`Spray (6 of 853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)].
`
`Long-Term (12-Month) Safety Trial:
`In the 12-month, open-label, active-controlled, long-term safety trial, 404 patients (12 years of
`age and older) with perennial allergic rhinitis or vasomotor rhinitis were treated with Dymista
`Nasal Spray 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 Nasal Spray treatment group and 44% in the fluticasone propionate nasal spray
`group. The most frequently reported adverse reactions ((cid:149) 2%) with Dymista Nasal Spray were
`headache, pyrexia, cough, nasal congestion, rhinitis, dysgeusia, viral infection, upper respiratory
`tract infection, pharyngitis, pain, diarrhea, and epistaxis. In the Dymista Nasal Spray 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 Nasal Spray and 6 of 207 patients (3%) treated with fluticasone propionate nasal spray
`discontinued from the trial due to adverse events.
`
`
`Postmarketing Experience
`6.2
`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.
`The following spontaneous adverse events have been reported during the marketing of azelastine
`hydrochloride nasal spray and causal relationship with the drug is unknown: anaphylactoid
`reaction, application site irritation, atrial fibrillation, chest pain, confusion, dyspnea, facial
`edema, involuntary muscle contractions, nasal sores, palpitations, paresthesia, parosmia, pruritus,
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`Reference ID: 3124523
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`rash, disturbance or loss of sense of smell and/or taste, tolerance, urinary retention, vision
`abnormal and xerophthalmia.
`In addition, the following events have been identified during post-approval use of fluticasone
`propionate nasal spray. These events have been chosen for inclusion due to either their
`seriousness, frequency of reporting, or causal connection to fluticasone propionate or a
`combination of these factors.
`General: Hypersensitivity reactions, including angioedema, skin rash, edema of the face and
`tongue, pruritus, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid
`reactions, which in rare instances were severe.
`Ear, Nose, and Throat: Alteration or loss of sense of taste and/or smell and, rarely, nasal septal
`perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice
`changes.
`Eye: Dryness and irritation, conjunctivitis, blurred vision, glaucoma, increased intraocular
`pressure, and cataracts.
`Cases of growth suppression have been reported for intranasal corticosteroids, including
`fluticasone propionate [see Use in Specific Populations (8.4)].
`
`DRUG INTERACTIONS
`7
`No formal drug interaction studies have been performed with Dymista Nasal Spray. 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 Nasal Spray 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 Nasal Spray is coadministered with ketoconazole and
`other known strong CYP3A4 inhibitors.
`
`Reference ID: 3124523
`
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`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Dymista Nasal Spray: Teratogenic Effects: Pregnancy Category C:
`There are no adequate and well-controlled clinical trials of Dymista Nasal Spray, azelastine
`hydrochloride only, or fluticasone propionate only in pregnant women. Animal reproductive
`studies of azelastine hydrochloride and fluticasone propionate in mice, rats, and/or rabbits
`revealed evidence of teratogenicity as well as other developmental toxic effects. Because animal
`reproduction studies are not always predictive of human response, Dymista Nasal Spray should
`be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`Azelastine hydrochloride: Teratogenic Effects: In mice, azelastine hydrochloride caused
`embryo-fetal death, malformations (cleft palate; short or absent tail; fused, absent or branched
`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
`at a maternal dose of 68.6 mg/kg). This dose also caused maternal toxicity as evidenced by
`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).
`In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed
`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
`mg/kg). At a dose approximately 1200 times the MRHDID (on a mg/m2 basis at a maternal dose
`of 68.6 mg/kg), azelastine hydrochloride also caused embryo-fetal death and decreased fetal
`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
`3 mg/kg).
`In rabbits, azelastine hydrochloride caused abortion, delayed ossification, and decreased fetal
`weight at oral doses approximately 1100 times the MRHDID in adults (on a mg/m2 basis at a
`maternal dose of 30 mg/kg); however, these doses also resulted in severe maternal toxicity.
`Neither fetal nor maternal effects occurred at a dose approximately 11 times the MRHDID (on a
`mg/m2 basis at a maternal dose of 0.3 mg/kg).
`Fluticasone propionate: Teratogenic Effects: Corticosteroids have been shown to be
`teratogenic in laboratory animals when administered systemically at relatively low dosage levels.
`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,
`respectively), revealed fetal toxicity characteristic of potent corticosteroid compounds, including
`embryonic growth retardation, omphalocele, cleft palate, and retarded cranial ossification.
`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
`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
`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)].
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`Reference ID: 3124523
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`Experience with oral corticosteroids since their introduction 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 corticosteroid
`production during pregnancy, most women will require a lower exogenous corticosteroid dose
`and many will not need corticosteroid treatment during pregnancy.
`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
`maternal doses of 100 mcg/kg and 300 mcg/kg to rats and rabbits, respectively).
`
`Nursing Mothers
`8.3
`Dymista Nasal Spray: It is not known whether Dymista Nasal Spray is excreted in human
`breast milk. Because many drugs are excreted in human milk, caution should be exercised when
`Dymista Nasal Spray is administered to a nursing woman. Since there are no data from well-
`controlled human studies on the use of Dymista Nasal Spray by nursing mothers, based on data
`from the individual components, a decision should be made whether to discontinue nursing or to
`discontinue Dymista Nasal Spray, taking into account the importance of Dymista Nasal Spray to
`the mother.
`Azelastine hydrochloride: It is not known if azelastine hydrochloride is excreted in human
`milk.
`Fluticasone propionate: It is not known if fluticasone propionate is excreted in human milk.
`However, other corticosteroids are excreted in human milk. Subcutaneous administration to
`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
`radioactivity in the milk.
`
`Pediatric Use
`8.4
`Safety and effectiveness of Dymista Nasal Spray in pediatric patients below the age of 12 years
`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 this reduction in growth velocity associated with
`intranasal corticosteroids, including the impact on final adult height, are unknown. The potential
`for “catch-up” growth following discontinuation of treatment with intranasal corticosteroids has
`not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids,
`including Dymista Nasal Spray, should be monitored routinely (e.g., via stadiometry). The
`potential growth effects of prolonged treatment should be weighed against the clinical benefits
`obtained and the risks/benefits of treatment alternatives.
`
`Geriatric Use
`8.5
`Clinical trials of Dymista Nasal Spray did not include sufficient numbers of patients 65 years of
`age and older to determine whether they respond differently from younger patients. Other
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`Reference ID: 3124523
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`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
`Dymista Nasal Spray: Dymista Nasal Spray contains both azelastine hydrochloride and
`fluticasone propionate; therefore, the risks associated with overdosage for the individual
`components described below apply to Dymista Nasal Spray.
`Azelastine hydrochloride: There have been no reported overdosages with azelastine
`hydrochloride. Acute azelastine hydrochloride overdosage by adults with this dosage form is
`unlikely to result in clinically significant adverse events, other than increased somnolence, since
`one (1) 23 g bottle of Dymista Nasal Spray contains approximately 23 mg of azelastine
`hydrochloride. Clinical trials in adults with single doses of the oral formulation of azelastine
`hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events.
`General supportive measures should be employed if overdosage occurs. There is no known
`antidote to Dymista Nasal Spray. Oral ingestion of antihistamines has the potential to cause
`serious adverse effects in children. Accordingly, Dymista Nasal Spray should be kept out of the
`reach of children
`Fluticasone propionate: Chronic fluticasone propionate overdosage may result in
`signs/symptoms of hypercorticism [see Warnings and Precautions (5.2)]. Intranasal
`administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily
`for 7 days to healthy human volunteers was well tolerated. Single oral fluticasone propionate
`doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported.
`Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg
`daily for 14 days in patients were well tolerated. Adverse reactions were of mild or moderate
`severity, and incidences were similar in active and placebo treatment groups. Acute overdosage
`with this dosage form is unlikely since one (1) 23 g bottle o