` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`DYMISTA® safely and effectively. See full prescribing information for
`
`
`
`
`
`
`DYMISTA.
`
`
`DYMISTA (azelastine hydrochloride and fluticasone propionate) nasal
`
`
`spray, for intranasal use
`
`
`Initial U.S. Approval: 2012
`
`
` _________________
` _________________
`RECENT MAJOR CHANGES
`2/2015
`• Indications and Usage, Allergic Rhinitis (1)
`
`
`
`
`
`
` __________________
` _________________
`INDICATIONS AND USAGE
`DYMISTA contains an H1-receptor antagonist and a corticosteroid, and is
`
`
`
`indicated for the relief of symptoms of seasonal allergic rhinitis in patients 6
`
`
`
`
`years of age and older who require treatment 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 for 14 or more days.
`
`
`
`
`
`(2.2)
`
` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`DYMISTA: Nasal spray suspension delivers 137 mcg of azelastine
`
`
`
`
`hydrochloride and 50 mcg of fluticasone propionate (137 mcg/50 mcg) in
`
`
`
`each 0.137 mL spray. (3)
`
`
`
` ___________________
`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)
`
`
`
` ___________________
`CONTRAINDICATIONS
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`
`
`2
`
`INDICATIONS AND USAGE
`
`1.1 Seasonal Allergic Rhinitis
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Information
`
`
`Important Administration Instructions
`2.2
`
`
`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
`
`
`Postmarketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`7.1 Central Nervous System Depressants
`
`
`6
`
`
`7
`
`
`
`• Epistaxis, nasal ulcerations, nasal septal perforation, impaired wound
`
`
`healing, Candida albicans infection: Monitor patients periodically for signs
`
`
`
`
`of adverse effects on the nasal mucosa. Avoid use in patients with recent
`
`
`
`nasal ulcers, nasal surgery, or nasal trauma. (5.2)
`
`• Glaucoma or posterior subcapsular cataracts: Monitor patients closely with
`
`
`
`
`
`a change in vision or with a history of increased intraocular pressure,
`
`
`glaucoma, and/or cataracts. (5.3)
`
`• Potential worsening of existing tuberculosis; fungal, bacterial, viral, or
`
`
`parasitic infections; or ocular herpes simplex. More serious or even fatal
`
`
`course of chickenpox or measles in susceptible patients. Use caution in
`
`
`patients with the above because of the potential for worsening of these
`infections. (5.4)
`
`• Hypercorticism and adrenal suppression with very high dosages or at the
`
`
`
`
`regular dosage in susceptible individuals. If such changes occur,
`
`
`discontinue DYMISTA slowly. (5.5)
`
`
`
`• Potential reduction in growth velocity in children. Monitor growth
`
`
`
`routinely in pediatric patients receiving DYMISTA. (5.7, 8.4)
`
`
`
`
`
`
`___________________ 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: 2/2015
`
`
`8
`
`
`
`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
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`
`
`are not listed.
`
`
`
`Reference ID: 3705083
`
`
` 1
`
`
`CIPLA LTD. EXHIBIT 2006 PAGE 1
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`CIPLA LTD. EXHIBIT 2006 PAGE 1
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`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
` 1.1
`
`
`
` Seasonal Allergic Rhinitis
`
`
` 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
`
` 2.1
`
`
` Dosing Information
` The recommended dosage of DYMISTA is 1 spray in each nostril twice daily.
`
`
`
`
`
`
`
`
`
`
` 2.2
`
`
` Important Administration Instructions
` Administer DYMISTA by the intranasal route only.
`
`
`
`
` Shake the bottle gently before each use.
`
`
` Priming: Prime DYMISTA 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 0.137 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 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 of DYMISTA. Concurrent use of DYMISTA with
`
`
`
` alcohol or other central nervous system depressants should be avoided because additional
`
`
`
`
`
`
`Reference ID: 3705083
`
`2
`
`
`
`
`
`
`
`CIPLA LTD. EXHIBIT 2006 PAGE 2
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`

`

`
`
`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 of DYMISTA
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 5.3
`
`
` Glaucoma and Cataracts
`
` Nasal and inhaled corticosteroids may result in the development of glaucoma and/or cataracts.
`
` Therefore, close monitoring is warranted in patients with a change in vision or with a history of
`
`
`
`
` increased intraocular pressure, glaucoma, and/or cataracts.
` Glaucoma and cataract formation were evaluated with intraocular pressure measurements and slit
`
`
`
` lamp examinations in a controlled 12-month study in 612 adolescent and adult patients aged 12
`years and older with perennial allergic or vasomotor rhinitis (VMR). Of the 612 patients enrolled
`
`
`in the study, 405 were randomized to receive DYMISTA (1 spray per nostril twice daily) and
`
`
`207 were randomized to receive fluticasone propionate nasal spray (2 sprays per nostril once
`
`
`daily). In the DYMISTA group, one patient had increased intraocular pressure at month 6. In
`
`
`addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at
`
`
`month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of
`
`
`posterior subcapsular cataract at month 12 (end of treatment).
`
`
`
` Immunosuppression
` 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
`
`3
`
`
`
`
`
`
`
`CIPLA LTD. EXHIBIT 2006 PAGE 3
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`

`

` (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.
`
`
`
` 5.5
`
`
` Hypothalamic-Pituitary-Adrenal (HPA) Axis Effects
` 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 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
`
`
` and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of
`
` systemic corticosteroid side effects.
`
`
` Use caution with the coadministration of DYMISTA and other potent CYP3A4 inhibitors, such
` as ketoconazole [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
` Effect on Growth
` 5.7
`
`
`
`
` Corticosteroids may cause a reduction in growth velocity when administered to pediatric
` patients. Monitor the growth routinely of pediatric patients receiving DYMISTA [see Use in
`
`
`
` Specific Populations (8.4)].
`
`
`
`
`Reference ID: 3705083
`
`4
`
`
`
`
`
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`
`CIPLA LTD. EXHIBIT 2006 PAGE 4
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`

`

` 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)]
` • 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 of DYMISTA, azelastine hydrochloride nasal spray,
`
`fluticasone propionate nasal spray, or placebo, twice daily. The azelastine hydrochloride and
`
`
`
`fluticasone propionate comparators use the same vehicle and device as DYMISTA and are not
`
`
`commercially marketed. Overall, adverse reactions were 16% in the DYMISTA treatment
`
`
`groups, 15% in the azelastine hydrochloride nasal spray groups, 13% in the fluticasone
`
`
`propionate nasal spray groups, and 12% in the placebo groups. Overall, 1% of patients in both
`
`
`the DYMISTA and placebo groups discontinued due to adverse reactions.
`
`
`Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and
`
`
`more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis
`
`controlled clinical trials.
`
`
`Reference ID: 3705083
`
`
`5
`
`
`
`
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`CIPLA LTD. EXHIBIT 2006 PAGE 5
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`

`
`
`
`
`
`
`
` Table 1. Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled
`Trials of 2 Weeks Duration with DYMISTA in Adult and Adolescent Patients with Seasonal Allergic
`
`
`
`
`
`Rhinitis
`
`
`
`
`
`
`Dysgeusia
`
`
`Headache
`
`Epistaxis
`
`
`
` DYMISTA
`
` (N=853)*
`
`
`30(4%)
`
`
`18(2%)
`
`16(2%)
`
`
`1 spray per nostril twice daily
`
`Fluticasone Propionate
`
`
` Azelastine
`Nasal Spray†
`
` Hydrochloride Nasal
`
`Spray†
`
`(N=846)
`
`(N=851)
`
`
`44(5%)
`
`
`4(1%)
`
`
`20(2%)
`
`14(2%)
`
`
`
`20(2%)
`
`14(2%)
`
`
`Vehicle Placebo
`
`(N=861)
`
`
`
`2(<1%)
`
`
`10(1%)
`
`15(2%)
`
`
`
`
`
` *Safety population N=853, intent-to-treat population N=848
`
` † Not commercially marketed
`
`
` In the above trials, somnolence was reported in <1% of patients treated with DYMISTA (6 of
`
`853) or vehicle placebo (1 of 861) [see Warnings and Precautions (5.1)].
`
`
`
`
` Pediatric Patients 6-11 Years of Age
`
`
`
`
`
`
`
`
`The safety data described below in children 6-11 years of age reflect exposure to DYMISTA in
`
`
`
`
`
`152 patients (6-11 years of age; 57% male and 43% female) with seasonal allergic rhinitis in one
`
`double-blind, placebo-controlled clinical trial of 2-week duration. The racial distribution for the
`
`
`
`
`clinical trial was 69% white, 31% black, 2% Asian and 2% other.
`
`In the placebo-controlled clinical trial of 2-week duration, patients with seasonal allergic rhinitis
`
`
`
`were treated with 1 spray per nostril of DYMISTA or placebo, twice daily. Overall, adverse
`
`
`reactions were 16% in the DYMISTA treatment group, and 12% in the placebo group. Overall,
`
`
`
`1% of patients in both the DYMISTA and placebo groups discontinued due to adverse reactions.
`
`
`Table 2 contains adverse reactions reported with frequencies greater than or equal to 2% and
`
`
`more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis
`
`controlled clinical trial.
` Table 2. Adverse Reactions with ≥2% Incidence and More Frequently than Placebo in Placebo-Controlled
`
`
`
`
`
`
`
`
`
`
`
`
`Trials of 2 Weeks Duration with DYMISTA in Children 6 to 11 Years of Age with Seasonal Allergic Rhinitis
`
`
`
`
`
`
`Dysgeusia
`
`
`Epistaxis
`
`
`1 spray per nostril twice daily
`
`
` DYMISTA
`
` (N=152)*
`
`
`6 (4%)
`
`
`6 (4%)
`
`
` Vehicle Placebo
`
` (N=152)
`
`0 (0%)
`
`
`
`4 (3%)
`
`
`
` *Safety population N=152, intent-to-treat population N=152
`
` In the above trial, somnolence was not reported [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3705083
`
`
`
` 6
`
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`CIPLA LTD. EXHIBIT 2006 PAGE 6
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`

`

` 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 externa, and
`urticaria. In the DYMISTA treatment group 23 patients (9%) had mild epistaxis and 3 patients
`
`
`
`
`
`
`
`(1%) had moderate epistaxis. In the fluticasone propionate nasal spray treatment group 8 patients
`
`
`
`
`(9%) had mild epistaxis. No patients had reports of severe epistaxis. Focused nasal examinations
`
`
`
`were performed and no ulcerations or septal perforations were observed. Four of 264 patients
`
`
`
`
`(2%) treated with DYMISTA and 3 of 89 (3%) treated with fluticasone propionate nasal spray
`
`
`
`
`
`discontinued from the trial due to adverse 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
`
`7
`
`
`
`
`
`
`
`CIPLA LTD. EXHIBIT 2006 PAGE 7
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`CIPLA LTD. EXHIBIT 2006 PAGE 7
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`

`

`
`
`
`
` 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
`
`
`Respiratory, thoracic and mediastinal disorders: bronchospasm, cough, dysphonia, dyspnea,
`
`
`
`hoarseness, nasal septal perforation, nasal discomfort, nasal dryness, nasal sores, nasal ulcer, sore
`
`
`
`
`throat, throat dryness and irritation, voice changes, wheezing
`
`
`
`Skin and subcutaneous tissue disorder: angioedema, erythema, face swelling, pruritus, rash,
`
`
`urticaria
`
`
`Vascular disorder: hypertension
`
`
` DRUG INTERACTIONS
` 7
`
`
`
` No formal drug interaction studies have been performed with DYMISTA. The drug interactions
` of the combination are expected to reflect those of the individual components.
`
`
`
`
`
` Central Nervous System Depressants
` 7.1
`
`
`
`
`
` Concurrent use of DYMISTA with alcohol or other central nervous system depressants should be
` avoided because somnolence and impairment of central nervous system performance may occur
`
`
` [see Warnings and Precautions (5.1)].
`
`
`
`
` Cytochrome P450 3A4
` 7.2
`
`
`Ritonavir (a strong CYP3A4 inhibitor) significantly increased plasma fluticasone propionate
`exposure following administration of fluticasone propionate aqueous nasal spray, resulting in
`
`significantly reduced serum cortisol concentrations [see Clinical Pharmacology (12.3)]. During
`
`
` postmarketing use, there have been reports of clinically significant drug interactions in patients
`
`
`
`Reference ID: 3705083
`
`8
`
`
`
`
`
`
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`CIPLA LTD. EXHIBIT 2006 PAGE 8
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`CIPLA LTD. EXHIBIT 2006 PAGE 8
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`

`

` receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects
`
`
`
` including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone
`
` propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs
`
` the risk of systemic corticosteroid side effects.
` Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to
`
`steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC,
`but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg
`
`dose of fluticasone propionate by oral inhalation route.
`
`Caution should be exercised when DYMISTA is coadministered with ketoconazole and other
`
`
`known strong CYP3A4 inhibitors.
`
`
`
`
` 8
`
`
`
` USE IN SPECIFIC POPULATIONS
`
` 8.1
` Pregnancy
`
`
`
`
`
` DYMISTA: Teratogenic Effects: Pregnancy Category C:
`
`
`
`There are no adequate and well-controlled clinical trials of DYMISTA, 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/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).
`
`
`
`
`Reference ID: 3705083
`
`
`9
`
`
`
`
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`CIPLA LTD. EXHIBIT 2006 PAGE 9
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`

`

`
`
` 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)].
`
`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).
`
`
`
`
`
`
`
` 8.3
`
`
` Nursing Mothers
` 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 of DYMISTA 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.
`
`
`
`
`
` 8.4
`
`
` Pediatric Use
` Use of DYMISTA 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 a