Dymista
(azelastine hydrochloride)Dosage & Administration
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Dymista Prescribing 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
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- Administer DYMISTA by the nasal route only.
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- Shake the bottle gently before each use.
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- 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.
Nasal spray: 137 mcg of azelastine hydrochloride and 50 mcg of fluticasone propionate per spray.
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/m2 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/m2 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/m2 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/m2 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/m2 basis at a maternal oral dose of 30 mg/kg/day). Azelastine hydrochloride caused embryo-fetal death and decreased fetal weight and severe maternal toxicity at approximately 1200 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 68.6 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 55 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 3 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/m2 basis at a maternal oral dose of 30 mg/kg/day). Neither fetal nor maternal effects occurred at approximately 10 times the MRHDID (on a mg/m2 basis at a maternal oral dose of 0.3 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis with a maternal subcutaneous dose of 0.57 mcg/kg/day). Teratogenicity was evident based upon a finding of cleft palate for 1 fetus at dose approximately 0.4 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 4 mcg/kg/day). Neither fetal nor maternal effects occurred in rabbits with a dose approximately 0.01 times the MRHDID (on a mg/m2 basis with a maternal subcutaneous dose of 0.08 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/m2 basis with maternal subcutaneous doses up to 50 mcg/kg/day).
Lactation
Risk Summary
There are no available data on the presence of azelastine hydrochloride or fluticasone propionate in human milk, the effects on the breastfed infant, or the effects on milk production. Breastfed infants should be monitored for signs of milk rejection during DYMISTA use by lactating women (see Clinical Considerations). Fluticasone propionate is present in rat milk (see Data). Other corticosteroids have been detected in human milk. However, fluticasone propionate concentrations in plasma after nasal therapeutic doses are low and therefore concentrations in human breast milk are likely to be correspondingly low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DYMISTA and any potential adverse effects on the breastfed infant from DYMISTA or from the underlying maternal condition.
Clinical Considerations
Monitoring for Adverse Reactions
Breastfed infants of lactating women treated with DYMISTA should be monitored for possible signs of milk rejection related to the bitter taste of azelastine hydrochloride.
Data
Subcutaneous administration of 10 mcg/kg of tritiated fluticasone propionate to lactating rats resulted in measurable radioactivity in the milk.
Pediatric Use
The safety and effectiveness of DYMISTA for seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. Use of DYMISTA for this indication in pediatric patients 6 to 11 years of age is supported by evidence from controlled clinical trials (416 patients 6 to 11 years of age with allergic rhinitis were treated with DYMISTA) [see Adverse Reactions (6.1) and Clinical Studies (14)].
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.
Geriatric Use
Clinical trials of DYMISTA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other 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.
DYMISTA is contraindicated in patients with hypersensitivity to azelastine hydrochloride, fluticasone propionate, or to any other ingredients of DYMISTA. Reactions have included anaphylaxis [see Adverse Reactions (6.2)].
Somnolence
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 placebo 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 reductions in alertness and additional impairment of central nervous system performance may occur [see Drug Interactions (7.1)].
Local Nasal Effects
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 nasal 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 nasally, 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
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 and Risk of Infections
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 (IG) may be indicated. (See the respective Prescribing Information for VZIG and IG.) 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.
Hypercorticism and Adrenal Suppression
When nasal 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 nasal 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
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
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)].