Dymista Nasal Spray 1,0 mg and 0,365 mg Suspension

Dymista Nasal Spray is indicated for the treatment of seasonal and perennial allergic rhinitis (including hay fever) and rhino-conjunctivitis in adults if the use of either intranasal antihistamine or corticosteroid alone is not sufficient. Dymista Nasal Spray is also indicated for short term treatment of seasonal allergic rhinitis in children above the age of 6 years if the use of either intranasal antihistamine or corticosteroid alone is not sufficient.

Posology
For full therapeutic benefit regular usage is essential. Contact with the eyes should be avoided.
Adults and children (6 years and older)
One actuation in each nostril twice daily (morning and evening).
Children below 6 years
Dymista Nasal Spray is not recommended for use in children below 6 years of age as safety and efficacy has not been established in this age group.
Elderly
No dose adjustment is required in this population.
Renal and hepatic impairment
There are no data in patients with renal and hepatic impairment.
Duration of treatment
Dymista Nasal Spray is suitable for long-term use. The duration of treatment should correspond to the period of allergenic exposure.
Method of administration
Dymista Nasal Spray is for nasal use only.
Instruction for use
Preparing the spray: The bottle should be shaken gently before use for about 5 seconds by tilting it upwards and downwards and the protective cap be removed afterwards. Prior to first use Dymista Nasal Spray must be primed by pressing down and releasing the pump 6 times. If Dymista Nasal Spray has not been used for more than 7 days it must be reprimed once by pressing down and releasing the pump.
Using the spray: After blowing the nose the suspension is to be sprayed once into each nostril keeping the head tilted downward (see figure). After use the spray tip is to be wiped and the protective cap to be replaced.

Known hypersensitivity to azelastine hydrochloride, fluticasone propionate, or any of the excipients of Dymista Nasal Spray (listed in section 6.1).

Somnolence
Somnolence has been reported in some patients using Dymista Nasal Spray in trials (see section 4.8). 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 Nasal Spray. Concurrent use of Dymista Nasal Spray with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur (see section 4.5 and 4.7).
Local Nasal Effects
In clinical trials, epistaxis was observed more frequently in patients treated with Dymista Nasal Spray than those who received placebo (see section 4.8). Instances of nasal ulceration and nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. There were no instances of nasal ulceration or nasal septal perforation observed in clinical trials with Dymista Nasal Spray. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should avoid use of Dymista Nasal Spray until healing has occurred. In clinical trials with fluticasone propionate administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with Dymista Nasal Spray. Patients using Dymista Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.
Glaucoma and Cataracts
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 clinical study in adolescent and adult patients aged 12 years and older with perennial allergic or vasomotor rhinitis (VMR). In the Dymista Nasal Spray group, one patient had increased intraocular pressure at month 6. In addition, three patients had evidence of posterior subcapsular cataract at month 6 and one at month 12 (end of treatment). In the fluticasone propionate group, three patients had evidence of posterior subcapsular cataract at month 12 (end of treatment).
Immunosuppression
Persons who are using medicines, such as corticosteroids, that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles 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. 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
When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of Dymista Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The concomitant use of intranasal corticosteroids with other inhaled corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.
Use of Cytochrome P450 3A4 Inhibitors
Ritonavir and other strong cytochrome P450 3A4 (CYP3A4) inhibitors can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations (see sections 4.5 and 5.2). During postmarketing use, there have been reports of clinically significant medicine interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of Dymista Nasal Spray and ritonavir is not recommended. Use caution with the coadministration of Dymista Nasal Spray and other potent CYP3A4 inhibitors, such as ketoconazole (see sections 4.5 and 5.2).
Effect on Growth
Corticosteroids may cause growth retardation when administered to paediatric patients. Growth should be routinely monitored in paediatric patients receiving Dymista Nasal Spray (see section 4.8). Dymista contains benzalkonium chloride. Benzalkonium chloride may cause irritation or swelling of the nasal mucosa and bronchospasm especially if used for a long time.

Fluticasone propionate
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely. An interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can significantly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects. Co-treatment with other CYP 3A4 inhibitors, including cobicistat-containing products is also expected to increase the risk of systemic side effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole), as there is potential for increased systemic exposure to fluticasone propionate.
Azelastine hydrochloride
No specific interaction studies with azelastine hydrochloride nasal spray have been performed. Interaction studies at high oral doses have been performed. However, they bear no relevance to azelastine nasal spray as given recommended nasal doses result in much lower systemic exposure. Nevertheless, care should be taken when administering azelastine hydrochloride in patients taking concurrent sedative or central nervous medications because sedative effect may be enhanced. Alcohol may also enhance this effect (see section 4.7).

Pregnancy
There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. There are no adequate and well-controlled clinical trials of Dymista Nasal Spray, azelastine hydrochloride only, or fluticasone propionate only in pregnant women. Animal reproductive studies of azelastine hydrochloride and fluticasone propionate in mice, rats, and/or rabbits revealed evidence of teratogenicity as well as other developmental toxic effects.
Azelastine hydrochloride: Azelastine hydrochloride has shown teratogenic effects in experimental animals, such as mice, rats and rabbits. Effects such as embryo-foetal death, malformations (cleft palate; short or absent tail; fused, absent or branched ribs), delayed ossification, and decreased fetal weight and maternal toxicity occurred in mice. In rats, azelastine hydrochloride caused malformations (oligo- and brachydactylia), delayed ossification and skeletal variations, in the absence of maternal toxicity. Azelastine hydrochloride also caused embryo-fetal death and decreased fetal weight at higher doses. This also caused severe maternal toxicity. In rabbits, azelastine hydrochloride caused abortion, delayed ossification, and decreased foetal weight and also resulted in severe maternal toxicity.
Fluticasone propionate: Fluticasone propionate has also shown teratogenic effects. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. In the rabbit, foetal weight reduction, skeletal variations, omphalocele and cleft palate were observed.
Nonteratogenic Effects: Fluticasone propionate crossed the placenta following oral administration of approximately 4 and 25 times the MRHDID (Maximum Recommended Human Daily Inhalation Dose) in adult rats and rabbits.
Lactation
It is not known whether Dymista Nasal Spray is excreted in human breast milk. Caution should be exercised when Dymista Nasal Spray is administered to breastfeeding women (see section 5.3).
Fertility
There are only limited data with regard to fertility (see section 5.3).

Dymista Nasal Spray has minor influence on the ability to drive and use machines. In isolated cases fatigue, weariness, exhaustion, dizziness or weakness that may also be caused by the disease itself, may occur when using Dymista Nasal Spray. In these cases, the ability to drive and use machines may be impaired. Alcohol may enhance this effect.

a. Summary of the safety profile
Commonly, dysgeusia, a substance-specific unpleasant taste, may be experienced after administration (often due to incorrect method of application, namely tilting the head too far backwards during administration).
b. Tabulated summary of adverse reactions
The following undesirable effects have been observed and reported during treatment with Dymista Nasal Spray with the following frequencies:
Very common (u2265 1/10)
Common (u2265 1/100 to <1/10)
Uncommon (u2265 1/1 000 to <1/100)
Rare (u2265 1/10 000 to <1/1 000)
Very rare (< 1/10 000)
Not known (cannot be estimated from the available data)
MedDRA system organ class Frequency Adverse reactions
Immune system disorders Very rare Hypersensitivity including anaphylactic reactions, angioedema (oedema of the face or tongue and skin rash), bronchospasm
Nervous system disorders Common Headache, Dysgeusia (unpleasant taste), unpleasant smell Very rare Dizziness, somnolence (drowsiness, sleepiness)
Eye disorders Very rare Glaucoma, increased intraocular pressure, cataract Frequency unknown Vision, blurred (see also section 4.4)
Respiratory, thoracic and mediastinal disorders Very common Epistaxis Uncommon Nasal discomfort (including nasal irritation, stinging, itching), sneezing, nasal dryness, cough, dry throat, throat irritation, Very rare Nasal septal perforation**, mucosal erosion
Gastrointestinal disorders Rare Dry mouth Very rare Nausea
Skin and subcutaneous tissue disorders Very rare Rash, pruritus, urticaria
General disorders and administration site conditions Very rare Fatigue (weariness, exhaustion), weakness (see section 4.7) Fatigue (weariness, exhaustion), weakness (see section 4.7)
* A very small number of spontaneous reports have been identified following prolonged treatment with intranasal fluticasone propionate.
** Nasal septal perforation has been reported following the use of intranasal corticosteroids.
c. Description of selected adverse reactions
Common adverse reactions include the following:
u2022 Dysgeusia which is a substance-specific unpleasant taste that may be experienced after administration.
u2022 Epistaxis which involves bleeding from the inside of the nose.
d. Paediatric population
Use of Dymista Nasal Spray in short term trials for seasonal allergic rhinitis have reported dysgeusia and epistaxis in children 6-11 years of age (see section 5.1). Growth retardation has been reported in children receiving nasal corticosteroids. Growth retardation may be possible in adolescents, too (see section 4.4).
e. Other special populations
Dymista Nasal Spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained. Systemic effects of some nasal corticosteroids may occur, particularly when administered at high doses for prolonged periods (see section 4.4). In rare cases osteoporosis was observed when nasal glucocorticoids were administered long-term.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

With the nasal route of administration overdose reactions are not anticipated. There are no data from patients available on the effects of acute or chronic overdosage with intranasal fluticasone propionate. Intranasal administration of 2 milligrams fluticasone propionate (10 times the recommended daily dose) twice daily for seven days to healthy human volunteers has no effect on hypothalamo-pituitary-adrenal (HPA) axis function. Administration of doses higher than those recommended over a long period of time may lead to temporary suppression of adrenal function. In these patients, treatment with Dymista Nasal Spray should be continued at a dose sufficient to control symptoms; the adrenal function will recover in a few days and can be verified by measuring plasma cortisol. In the event of overdose after incidental oral uptake, disturbances of the central nervous system (including drowsiness, confusion, coma, tachycardia and hypotension) caused by azelastine hydrochloride are to be expected based on the results of animal experiments. Treatment of these disorders must be symptomatic. Depending on the amount swallowed, gastric lavage is recommended. There is no known antidote.