`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, for intranasal use
`Initial U.S. Approval: 2012
`
`------RECENT MAJOR CHANGES-----(cid:173)
`• Indications and Usage, Allergic Rhinitis (I)
`212015
`
`------INDICATIONS AND USAGE-----(cid:173)
`DYMISTA contains an H1-receptor antagonist and a corticosteroid, and is
`indicated for the relief of symptoms of seasonal allergic rhinitis in patients 6
`years of age and older who require treahnent with both azelastine
`hydrochloride and fluticasone propionate for symptomatic relief. (1.1)
`
`-----DOSAGE AND ADMINISTRATION-----
`• Recommended dosage: 1 spray per nostril twice daily (2.1)
`• For intranasal use only. (2.2)
`• Prime before initial use and when it has not been used tor 14 or more days.
`(2.2)
`
`-----DOSAGEFORMSANDSTRENGTHS----(cid:173)
`DYMIST A: Nasal spray suspension delivers 137 meg of azelastine
`hydrochloride and 50 meg offluticasone propionate (137 meg/50 meg) in
`each 0.137 mL 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)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`2
`
`3
`4
`5
`
`6
`
`INDICATIONS AND lJSAGE
`1.1 Seasonal Allergic Rhiniti s
`DOSAGE AND ADMINISTRATION
`2.1
`Dosing Information
`2.2
`Important Administration Instructions
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICA TIONS
`WARNINGS AND PRECAUTIONS
`5 .1
`Somnolence
`5.2
`Local Nasal Elfects
`5 .3 Glaucoma and Catm·acts
`5.4
`Immunosuppression
`5.5 Hypothalamic-Pituitary-Adrenal (HPA) Axis Eflects
`5.6 Use of Cytochrome P450 3A4 Inhibitors
`5.7
`Elfect on Growth
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Poshnarketing Experience
`DRUG INTERACTIONS
`7.1
`Central Nervous System Depressants
`
`• 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 or 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 ofthe potential lor worsening orthese
`infections. (5.4)
`• Hypercorticism and adrenal suppression with very high dosages or at the
`regular dosage in susceptible individuals. If such changes occur,
`discontinue DYMIST A slowly. (5 .5)
`• Potential reduction in growth velocity in children. Monitor growth
`routinely in pediatric patients receiving DYMISTA. (5.7, 8.4)
`
`-------ADVERSE REACTIONS - - - - - - (cid:173)
`Tlle most common adverse reactions G:2% incidence) are: dysgeusia,
`epistaxis, and headache. (6.1)
`To •·epot1 SUSPECTED ADVERSE REACTIONS, contact Meda
`Pharmaceuticals Inc. at 1-888-939-6478 or FDA at 1-800-FDA-1088 m·
`www. {da.gOI'.imedwatch.
`
`--------DRUG INTERACTION . .._ ______ _
`• Potent inhibitors of cytochrome P450 (CYP) 3A4: May increase blood
`levels offluticasone 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-----(cid:173)
`Pregnancy: Based on animal data, may cause fetal harm. (8 .1)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 2/2015
`
`7.2 C)1ochrome I'450 3A4
`VSE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Moth ers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Phmmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, J'v[utagenesis, Impainnent of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`8
`
`10
`11
`12
`
`13
`
`14
`16
`17
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`1
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`PLAINTIFFS' 8
`TRIAL EXHIBIT~ .E
`PTX0154
`~
`
`:0
`
`MEDA_APTX02330761
`
`PTX0154-00001
`
`1
`
`CIP2114
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Seasonal Allergic Rhinitis
`1.1
`DYMISTA nasal spray is indicated for the relief of symptoms of seasonal allergic rhinitis in
`patients 6 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 dosage ofDYMISTA is 1 spray in each nostril twice daily.
`
`Important Administration Instructions
`2.2
`Administer DYMISTA by the intranasal route only.
`
`Shake the bottle gently before each use.
`
`Priming: Prime DYMIST A before initial use by releasing 6 sprays or until a fine mist appears.
`When DYMISTA has not been used for 14 or more days, reprime with 1 spray or until a fine
`mist appears.
`
`Avoid spraying DYMISTA 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 0.13 7 mL suspension
`containing 137 meg ofazelastine hydrochloride and 50 meg offluticasone propionate (137
`meg/50 meg).
`
`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 adult
`and adolescent patients and 2 of 416 children) taking DYMISTA in 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 ofDYMISTA. Concurrent use ofDYMISTA with
`alcohol or other central nervous system depressants should be avoided because additional
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`2
`
`MEDA_APTX02330762
`
`PTX0154-00002
`
`2
`
`
`
`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 intranasal application of corticosteroids. There were no instances of nasal
`ulceration or nasal septal perforation observed in clinical trials with DYMISTA.
`
`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 ofDYMISTA
`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. 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.
`
`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 (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
`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
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`3
`
`MEDA_APTX02330763
`
`PTX0154-00003
`
`3
`
`
`
`(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 ofDYMISTA 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 ofhypercorticism and/or suppression of the HPA
`ax1s.
`
`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 ofDYMISTA
`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 ofDYMISTA 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)].
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`4
`
`MEDA_APTX02330764
`
`PTX0154-00004
`
`4
`
`
`
`ADVERSE REACTIONS
`6
`Systemic and local corticosteroid use may result in the following:
`
`• Somnolence [see Warnings and Precautions (5. J)]
`
`• 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 [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
`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 ofDYMISTA, 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.
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`5
`
`MEDA_APTX02330765
`
`PTX0154-00005
`
`5
`
`
`
`Table 1. Adverse Reactions with 2::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
`
`DYMISTA
`(N=853)*
`
`30(4%)
`
`18(2%)
`
`16(2%)
`
`1 spray per nostril twice daily
`
`Azelastine
`Hydrochloride Nasal
`Spray1
`(N=851)
`
`Fluticasone Pmpionate
`Nasal Spray1
`(N=846)
`
`44(5%)
`
`20(2%)
`
`14(2%)
`
`4(1%)
`
`20(2%)
`
`14(2%)
`
`V chicle Placebo
`(N=861)
`
`2(<1%)
`
`10(1%)
`
`15(2%)
`
`Dysgeusia
`
`Headache
`
`Epistaxis
`
`*Safety population N=853, intent-to-treat population N=848
`t Not commercially marketed
`
`In the above trials, somnolence was reported in <1% of patients treated with DYMISTA (6 of
`853) or vehicle placebo (1 of861) [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.
`
`In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis
`were treated with 1 spray per nostril ofDYMISTA 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::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
`
`Dysgeusia
`
`Epistaxis
`
`DYMISTA
`(N=152)*
`
`6 (4%)
`
`6 (4%)
`
`Vehicle Placebo
`(N=152)
`
`0 (0%)
`
`4(3%)
`
`*Safety population N= l52, intent-to-treat population N= l 52
`
`In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)].
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`6
`
`MEDA_APTX02330766
`
`PTX0154-00006
`
`6
`
`
`
`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 events.
`
`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.
`
`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 extema, 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 of89 (3%) treated with fluticasone propionate nasal spray
`discontinued from the trial due to adverse events. 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 events have been reported with DYMISTA or one of the
`components (azelastine and fluticasone). Because these reactions are reported voluntarily from a
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`7
`
`MEDA_APTX02330767
`
`PTX0154-00007
`
`7
`
`
`
`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
`
`Respiratorv, 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
`
`DRUGINTERACTIONS
`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 ofDYMISTA 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 offluticasone 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
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`8
`
`MEDA_APTX02330768
`
`PTX0154-00008
`
`8
`
`
`
`receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects
`including Cushing syndrome and adrenal suppression. Therefore, coadministration offluticasone
`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 offluticasone propionate, reduced plasma cortisol AUC,
`but had no effect on urinary excretion of cortisol, following administration of a single 1000 meg
`dose offluticasone propionate by oral inhalation route.
`
`Caution should be exercised when DYMISTA is coadministered with ketoconazole and other
`known strong CYP3A4 inhibitors.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`DYMISTA: Teratogenic Effects: Pregnancy Category C:
`
`There are no adequate and well-controlled clinical trials ofDYMISTA, 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 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/m 2 basis
`at a maternal dose of68.6 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 of30
`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 of30 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 of0.3 mg/kg).
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`9
`
`MEDA_APTX02330769
`
`PTX0154-00009
`
`9
`
`
`
`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 meg/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 meg/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 of300 meg/kg) offluticasone 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 (1 2.3)].
`
`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 meg/kg and 300 meg/kg to rats and rabbits, respectively).
`
`Nursing Mothers
`8.3
`DYMISTA: It is not known whether DYMISTA is excreted in human breast milk. Because many
`drugs are excreted in human milk, caution should be exercised when DYMISTA is administered
`to a nursing woman. Since there are no data from well-controlled human studies on the use of
`DYMISTA by nursing mothers, based on data from the individual components, a decision should
`be made whether to discontinue nursing or to discontinue DYMISTA, taking into account the
`importance ofDYMISTA 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 meg/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
`Use ofDYMISTA for seasonal allergic rhinitis in pediatric patients 6 to 11 years of age is
`supported by safety and efficacy data from clinical studies ( 416 patients 6 to 11 years of age with
`allergic rhinitis were treated with DYMISTA in controlled clinical trials) and the established
`efficacy and safety of azelastine hydrochloride nasal spray and fluticasone propionate nasal spray
`in this age group [see Adverse Reactions (6.1) and Clinical Studies (14)].
`
`Reference ID: 3705083
`
`HIGHLY CONFIDENTIAL-
`SUBJECT TO STIPULATED PROTECTIVE ORDER
`
`10
`
`MEDA_APTX02330770
`
`PTX0154-0001 0
`
`10
`
`
`
`Sixty-one patients ages 4-5 years of age were treated with DYMISTA in the pediatric studies
`described above. Safety findings in children 4-5 years of age were similar to those in children 6-
`11 years of age, but efficacy was not established.
`
`Safety and effectiveness ofDYMISTA has not been studied in pediatric patients below the age
`of 4 years.
`
`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 ofHP A axis suppression, suggesting that growth velocity is a more sensitive indicator
`of systemic corticosteroid exposure in pediatric patients than some commonly used tests ofHP A
`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, 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 ofDYMISTA did not include sufficient numbers of patients 65 years of age and
`older to determine wheth