DYMISTA NASAL SPRAY 137 MICROGRAMS / 50 MICROGRAMS PER ACTUATION NASAL SPRAY SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dymista Nasal Spray

137 micrograms / 50 micrograms per actuation

Nasal Spray, Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each g of suspension contains 1000 micrograms azelastine hydrochloride and 365 micrograms fluticasone propionate.

One actuation (0.14 g) delivers 137 micrograms azelastine hydrochloride (= 125 micrograms azelastine) and 50 micrograms fluticasone propionate.

Excipient with known effect:

One actuation (0.14 g) delivers 0.014 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

Nasal spray, suspension.

White, homogeneous suspension.

4.1 Therapeutic indications

Relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis if monotherapy with either intranasal antihistamine or glucocorticoid is not considered sufficient.

4.2 Posology and method of administration

Posology

For full therapeutic benefit regular usage is essential.

Contact with the eyes should be avoided.

Adults and adolescents (12 years and older)

One actuation in each nostril twice daily (morning and evening).

Children below 12 years

Dymista Nasal Spray is not recommended for use in children below 12 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:

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.

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.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (see section 4.5).

Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing’s syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Dymista Nasal Spray undergoes extensive first-pass metabolism, therefore the systemic exposure of intranasal fluticasone propionate in patients with severe liver disease is likely to be increased. This may result in a higher frequency of systemic adverse events.

Caution is advised when treating these patients.

Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

In general the dose of intranasal fluticasone formulations should be reduced to the lowest dose at which effective control of the symptoms of rhinitis is maintained. Higher doses than the recommended one (see section 4.2) have not been tested for Dymista. As with all intranasal corticosteroids, the total systemic burden of corticosteroids should be considered whenever other forms of corticosteroid treatment are prescribed concurrently.

Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. Since growing up is also given in adolescents it is recommended that the growth of adolescents receiving prolonged treatment with nasal corticosteroids is regularly monitored, too. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid if possible, to the lowest dose at which effective control of symptoms is maintained.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Close monitoring is warranted in patients with a change in vision or with a history of increased ocular pressure, glaucoma and/or cataracts.

If there is any reason to believe that adrenal function is impaired, care must be taken when transferring patients from systemic steroid treatment to Dymista Nasal Spray.

In patients who have tuberculosis, any type of untreated infection, or have had a recent surgical operation or injury to the nose or mouth, the possible benefits of the treatment with Dymista Nasal Spray should be weighed against possible risk.

Infections of the nasal airways should be treated with antibacterial or antimycotical therapy, but do not constitute a specific contraindication to treatment with Dymista Nasal Spray.

Dymista contains benzalkonium chloride. Long term use may cause oedema of the nasal mucosa.

4.5 Interaction with other medicinal products and other forms of interaction

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.

A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly 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).

4.6 Fertility, pregnancy and lactation

Fertility

There are only limited data with regard to fertility (see section 5.3).

Pregnancy

There are no or limited amount of data from the use of azelastine hydrochloride and fluticasone propionate in pregnant women. Therefore, Dymista Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus (see section 5.3)

Lactation

It is unknown whether nasally administered azelastine hydrochloride/me­tabolites or fluticasone propionate/me­tabolites are excreted in human breast milk. Dymista Nasal Spray should be used during lactation only if the potential benefit justifies the potential risk to the newborns/infant.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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).

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:

Very common (>1/10)

Common    (>1/100 to <1/10)

Uncommon  (>1/1,000 to <1/100)

Rare         (>1/1­0,000 to <1/1,000)

Very rare     (<1/10,000)

Not known (cannot be estimated from the available data)_________­________

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4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids/ fluticasone, combinations, ATC code: R01AD58.

Mechanism of action and pharmacodynamic effects

Dymista Nasal Spray contains azelastine hydrochloride and fluticasone propionate, which have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis and rhino-conjunctivitis symptoms.

Fluticasone propionate

Fluticasone propionate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent antiinflammatory action, e.g. 3–5 fold more potent than dexamethasone in cloned human glucocorticoid receptor binding and gene expression assays.

Azelastine hydrochloride

Azelastine, a phthalazinone derivative is classified as a potent long-acting antiallergic compound with selective H1-antagonist, mast cell stabilizing and antiinflammatory properties. Data from in vivo (preclinical) and in vitro studies show that azelastine inhibits the synthesis or release of the chemical mediators known to be involved in early and late stage allergic reactions, e.g. leukotrienes, histamine, platelet-activating factor (PAF) and serotonin.

. A relief of nasal allergic symptoms is observed within 15 minutes after administration.

Dymista Nasal Spray

In 4 clinical studies in adults and adolescents with allergic rhinitis Dymista Nasal Spray one spray in each nostril twice daily significantly improved nasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) compared with placebo, azelastine hydrochloride alone and fluticasone propionate alone. It significantly improved ocular symptoms (comprising itching, tearing/watering and redness of the eyes) and the patients’ disease-related quality of life (Rhinoconjuncti­vitis Quality of Life Questionnaire -RQLQ) in all 4 studies.

In comparison to a marketed fluticasone propionate nasal spray substantial symptom improvement (50% reduction in nasal symptoms severity) was achieved significantly earlier (3 days and more) with Dymista Nasal Spray. The superior effect of Dymista Nasal Spray to fluticasone propionate nasal spray was maintained throughout one-year study in patients with chronic persistent allergic rhinitis and nonallergic/va­somotor rhinitis.

In a ragweed pollen allergen exposure chamber study, first statistically significant relief of nasal symptoms was observed at 5 minutes after administration of Dymista Nasal Spray (compared to placebo). At 15 minutes after administration of Dymista Nasal Spray 60% of patients reported a clinically relevant reduction in symptom scores of at least 30%.

5.2 Pharmacokinetic properties

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate

Glycerol

Microcrystalline cellulose

Carmellose sodium

Polysorbate 80

Benzalkonium chloride

Phenylethyl alcohol

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Bottle with 6.4 g suspension in 10 ml bottles: 18 months

Bottle with 23 g suspension in 25 ml bottles: 2 years

In-use shelf life (after first use): 6 months

6.4 Special precautions for storage

Do not refrigerate or freeze.

6.5 Nature and contents of container

Type I amber glass bottle fitted with a spray pump, a nasal polypropylene applicator (actuator) and a dust cap, containing 6.4 g (at least 28 actuations) and 23 g (at least 120 actuations) suspension.

Pack sizes:

1 bottle with 6.4 g suspension in 10 ml bottles (at least 28 actuations), 1 bottle with 23 g suspension in 25 ml bottles (at least 120 actuations)

Multipacks containing 64 g (10 bottles with 6.4 g) nasal spray, suspension Multipacks containing 69 g (3 bottles with 23 g) nasal spray, suspension

6.6 Special precautions for disposal

No special requirements for disposal.

Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom