Dymista Drug Information

DYMISTA is indicated for the relief of symptoms of seasonal allergic rhinitis in adult and pediatric patients 6 years of age and older.

Recommended Dosage

The recommended dosage of DYMISTA is 1 spray (137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate) in each nostril twice daily.

Important Administration Instructions • Administer DYMISTA by the nasal route only. • Shake the bottle gently before each use. • Avoid spraying DYMISTA into the eyes. If sprayed in the eyes, flush eyes with water for at least 10 minutes. Priming Prime DYMISTA before initial use by releasing 6 sprays or until a fine mist appears.

Repriming (as needed) When DYMISTA has not been used for 14 or more days, reprime with 1 spray or until a fine mist appears.

Clinical Trials Experience

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. 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, 1% of patients in both the DYMISTA and placebo groups discontinued due to adverse reactions. Table 1 contains adverse reactions reported with frequencies greater than or equal to 2% and more frequently than placebo in patients treated with DYMISTA in the seasonal allergic rhinitis controlled clinical trials. Table 1.

Overall, adverse reactions were 16% in the DYMISTA treatment group, and 12% in the placebo group. 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 In the above trial, somnolence was not reported.

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 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. 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 fluticasone propionate nasal spray treatment group 8 patients (9%) had mild epistaxis. There were two reports of somnolence, one severe, among children taking DYMISTA.

Postmarketing Experience

The following spontaneous adverse reactions have been reported with DYMISTA or one of the components (azelastine and fluticasone). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: atrial fibrillation, increased heart rate, palpitations Eye Disorder: blurred vision, cataracts, conjunctivitis, dryness and irritation, eye swelling, glaucoma, increased intraocular pressure, vision abnormal, xerophthalmia Gastrointestinal Disorders: nausea, vomiting General Disorders and Administration Site Condition: aches and pain, application site irritation, chest pain, edema of face and tongue, fatigue, tolerance Immune System Disorders: anaphylaxis Musculoskeletal and Connective Tissue Disorders: growth suppression 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

Central Nervous System Depressants

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.

Cytochrome P450 3A4 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. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone propionate and ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Ketoconazole (also a strong CYP3A4 inhibitor), administered in multiple 200 mg doses to steady-state, increased plasma exposure of fluticasone propionate, reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol, following administration of a single 1000 mcg dose of fluticasone propionate by oral inhalation route. Caution should be exercised when DYMISTA is coadministered with ketoconazole and other known strong CYP3A4 inhibitors.

Pregnancy Risk Summary Limited data from postmarketing experience with DYMISTA in pregnant women have not identified any drug associated risks of miscarriage, birth defects, or other adverse maternal or fetal outcomes. The individual components of DYMISTA have been marketed for decades. While the data regarding the use of nasal preparations of fluticasone propionate in pregnancy are limited, data from clinical studies of inhaled fluticasone propionate do not indicate an increased risk of adverse maternal or fetal outcomes.

Animal reproduction studies with DYMISTA are not available; however, studies are available with its individual components, azelastine hydrochloride and fluticasone propionate. In animal reproduction studies, there was no evidence of fetal harm in animals at oral doses of azelastine hydrochloride approximately 10 times the clinical daily dose. Oral administration of azelastine hydrochloride to pregnant mice, rats, and rabbits, during the period of organogenesis, produced developmental toxicity that included structural abnormalities, decreased embryo-fetal survival, and decreased fetal body weights at doses 530 times and higher than the maximum recommended human daily nasal dose (MRHDID) of 0.548 mg.

However, the relevance of these findings in animals to pregnant women was considered questionable based upon the high animal to human dose multiple. In animal reproduction studies, fluticasone propionate administered via nose-only inhalation to rats decreased fetal body weight, but did not induce teratogenicity at a maternal toxic dose less than the MRHDID on a mcg/m 2 basis. Teratogenicity, characteristic of corticosteroids, decreased fetal body weight and/or skeletal variations, in rats, mice, and rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than the MRHDID of 200 mcg on a mcg/m 2 basis (see Data ).

Experience with corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Azelastine Hydrochloride: In an embryo-fetal development study in mice dosed during the period of organogenesis, azelastine hydrochloride caused embryo-fetal death, structural abnormalities (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight at approximately 610 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 68.6 mg/kg/day), which also caused maternal toxicity as evidenced by decreased maternal body weight. Neither fetal nor maternal effects occurred in mice at approximately 25 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 3 mg/kg/day).

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities (oligo- and brachydactylia), delayed ossification, and skeletal variations, in the absence of maternal toxicity, at approximately 530 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, azelastine hydrochloride caused abortion, delayed ossification and decreased fetal weight and severe maternal toxicity at approximately 1100 times the MRHDID in adults (on a mg/m 2 basis at a maternal oral dose of 30 mg/kg/day). In a prenatal and postnatal development study in pregnant rats dosed from late in the gestation period and through the lactation period from gestation day 17 through lactation day 21, azelastine hydrochloride produced no adverse developmental effects on pups at maternal doses up to approximately 530 times the MRHDID (on mg/m 2 basis at a maternal dose of 30 mg/kg/day).

Fluticasone Propionate: In embryofetal development studies with pregnant rats and mice dosed by the subcutaneous route throughout the period of organogenesis, fluticasone propionate was teratogenic in both species. Omphalocele, decreased body weight, and skeletal variations were observed in rat fetuses, in the presence of maternal toxicity, at a dose approximately 5 times the MRHDID (on a mg/m 2 basis with a maternal subcutaneous dose of 100 mcg/kg/day). Neither fetal nor maternal effects occurred in rats at approximately 1 times the MRHDID (on a mg/m 2 basis with a maternal subcutaneous dose of 30 mcg/kg/day).

Cleft palate and fetal skeletal variations were observed in mouse fetuses at a dose approximately 1 times the MRHDID (on a mg/m 2 basis with a maternal subcutaneous dose of 45 mcg/kg/day). Neither fetal nor maternal effects occurred in mice with a dose approximately 0.4 times the MRHDID (on a mg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg/day). In an embryofetal development study with pregnant rats dosed by the nose-only inhalation route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations, in the presence of maternal toxicity, at a dose approximately 1 times the MRHDID (on a mg/m 2 basis with a maternal nose-only inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.

Neither fetal nor maternal effects occurred in rats with a dose approximately 0.25 times the MRHDID (on a mg/m 2 basis with a maternal nose-only inhalation dose of 5.5 mcg/kg/day). In an embryofetal development study in pregnant rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate produced reductions of fetal body weights, in the presence of maternal toxicity, at doses approximately 0.06 times the MRHDID and higher (on a mg/m 2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits.

In a pre- and post-natal development study in pregnant rats dosed from late gestation through delivery and lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 2 times the MRHDID (on a mg/m 2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).

Pediatric Use The safety and effectiveness of DYMISTA for seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. 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 effectiveness has not been established.

Safety and effectiveness of DYMISTA have not been established in pediatric patients below the age of 4 years. Controlled clinical studies have shown that nasal 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 nasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch-up” growth following discontinuation of treatment with nasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving nasal 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.

DYMISTA is contraindicated in patients with hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any other ingredients of DYMISTA. Reactions have included anaphylaxis. Reactions have included anaphylaxis.

• DYMISTA: DYMISTA contains both azelastine hydrochloride and fluticasone propionate; therefore, the risks associated with overdosage for the individual components described below apply to DYMISTA.
• 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 reactions, other than increased somnolence, since one 23 g bottle of DYMISTA contains approximately 23 mg of azelastine hydrochloride. General supportive measures should be employed if overdosage occurs. There is no known antidote to DYMISTA. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, DYMISTA should be kept out of the reach of children.
• Fluticasone Propionate: Chronic fluticasone propionate overdosage may result in signs/symptoms of hypercorticism.