Instruction for use: Dymista

Active substance Azelastine+Fluticasone

ATX code R01AD58 Fluticasone in combination with other drugs

Pharmacological group

Corticosteroids

Composition

One dose of the spray contains:

Active substances:

Azelastine hydrochloride 0.137 mg

Fluticasone propionate 0.050 mg

Excipients:

Glycerol 3.151 mg; Avicel CL-611 [microcrystalline cellulose, carmellose sodium] 2,740 mg; Polysorbate - 80 0,007 mg; Disodium edetate dihydrate 0.014 mg; Benzalkonium chloride 0.014 mg; Phenylethanol 0.343 mg; Purified water 130.545 mg

Description of dosage form

White homogeneous redispersible suspension.

Pharmacological group

Anti-allergic drug combined (H1-histamine receptor blocker + glucocorticosteroid for topical application).

Pharmacodynamics

Dimista contains azelastine hydrochloride and fluticasone propionate, which have a different mechanism of action and show synergy with regard to alleviating the symptoms of allergic rhinitis and rhinoconjunctivitis.

Fluticasone propionate is a synthetic trifluorinated glucocorticosteroid, which has a high affinity for glucocorticoid receptors, exhibits a powerful anti-inflammatory effect that is 3-5 times greater than that of dexamethasone.

Azelastine hydrochloride, a derivative of phthalazinone, is known as a long-acting antiallergic compound that is an selective blocker of H1-histamine receptors, stabilizes mast cells and possesses

Anti-inflammatory properties. In vivo and in vitro studies show that azelastine inhibits the synthesis and / or release of chemical mediators that participate in the early and late stages of allergic reactions, such as leukotrienes, histamine, platelet activating factor (FAT), and serotonin. Azelastine in the form of a nasal spray is characterized by a rapid onset of action compared with oral administration of antihistamines and glucocorticosteroids. Relief of nasal allergic symptoms is observed as early as 15 minutes after administration.

The drug Dimist

In comparison with placebo and separately applied azelastine hydrochloride and fluticasone propionate, the use of Dimista in a single dose in each nasal twice daily significantly alleviates nasal symptoms (including rhinorrhea, nasal congestion, sneezing and itching in the nose). There was also a significant relief of eye symptoms, such as itching, lacrimation and redness of the eyes.

In comparison with the preparation of fluticasone propionate, significant relief of the main symptoms (a 50% reduction in the severity of the symptoms) was achieved much faster (by 3 days or more) with the use of Dimist.

Pharmacokinetics

Suction

After intranasal administration of fluticasone propionate (200 μg per day), the maximum concentration (C max) was 0.017 ng / ml. Absorption from the mucosa of the nasal cavity is negligible due to the low solubility of the drug in the water, and most of the dose is probably swallowed. When administered orally, less than 1% of the administered dose is absorbed, which is due to slow absorption and active metabolism immediately after ingestion. Thus, the total systemic absorption, which represents the aggregate of absorption from the nasal mucosa and absorption when ingested, is insignificant.

After repeated administration of a daily dose of 0.56 mg of azelastine hydrochloride (corresponding to the administration of a single dose in each nasal passage twice a day), the C max in plasma was 0.027 ng / ml in healthy volunteers. The active metabolite level of N-desmethylazelastine was at or below the lower detection threshold (0.12 ng / ml).

In patients with allergic rhinitis after the administration of a daily dose of 0.56 mg of azelastine hydrochloride (two doses to the nasal passage once a day), the azelastin concentration in the plasma 2 hours after the administration was about 0.65 ng / ml. Doubling the daily dose to 0.12 mg of azelastine hydrochloride (two injections in each nasal passage twice a day)

Resulted in an increase in the plasma azelastine concentration up to 1.09 ng / ml, which indicates a proportional increase in concentration depending on the dose.

Distribution

Fluticasone propionate has a large volume of distribution in a stable state (approximately 318 liters). Binding to plasma proteins is 91%. The volume of distribution of azelastine indicates a preferential distribution in peripheral tissues. The level of binding to plasma proteins is 80-90%. Both substances have a wide therapeutic window.

Metabolism

Fluticasone propionate is rapidly excreted from the systemic blood stream, mainly through metabolism in the liver with the formation of an inactive metabolite - carboxylic acid via the cytochrome P450 isoenzyme CYP3A4. Metabolism of the swallowed fraction of fluticasone propionate during the first passage through the liver occurs in the same way. Caution should be exercised when concurrently administering potent inhibitors of CYP3A4 such as ketoconazole and ritonavir. Since it is possible to increase the concentration of fluticasone propionate in the blood.

Azelastine is metabolized to A-desmethylazelastine using various CYP isoenzymes, mainly CYP3A4, CYP2D6 and CYP2C19.

Excretion

The elimination of fluticasone propionate is linear in the dose range from 250 to 1000 μg and is characterized by a high plasma clearance (1.1 l / min). The maximum plasma concentration is reduced by approximately 98% within 3-4 hours, and only at very low plasma concentrations a final half-life of 7.8 hours is observed. The renal clearance of fluticasone propionate is negligible (less than 0.2%), and the inactive metabolite - carboxylic acid - is less than 5%. Fluticasone propionate and its metabolites are mainly excreted with bile through the intestine.

After a single administration, the azelastin half-life of plasma is approximately 20-25 hours and about 45 hours for its therapeutically active metabolite N- dimemelazelastine. Excretion occurs mainly through the intestine. Prolonged excretion of small amounts through the intestine testifies to the possibility of the existence of intestinal-hepatic circulation.

Indications

Symptomatic treatment of allergic rhinitis / rhinoconjunctivitis of moderate and severe severity.

Contraindications

Hypersensitivity to the active ingredients or to any of the auxiliary components of the drug. Children under 12 years.

pregnancy and lactation

Pregnancy

Data on the use of azelastine hydrochloride and fluticasone propionate in pregnant women are absent or limited. Thus, the drug Dimist can be used during pregnancy only if the expected benefit exceeds the possible risk.

Breastfeeding period

It is not known whether nasal administration of azelastine hydrochloride or its metabolites and fluticasone propionate or its metabolites into breast milk penetrates, therefore, Dimist should be prescribed to lactating women only if the expected benefit exceeds the possible risk to the child.

Impact on fertility

Studies of the effect of Dimist on fertility have not been conducted.

There was no evidence of the effect of azelastine hydrochloride on the fertility of male and female rats when administered orally at doses up to 30 mg / kg (approximately 530 times the maximum recommended daily dose for an adult). When a drug was administered at a dose of 68.6 mg / kg, an increase in the duration of the estrous cycle was noted with a decrease in the copulative activity of animals and a decrease in the number of pregnancies. The number of yellow bodies in the ovaries and implantations decreased, but without raising the level of pre-implantation losses.

In studies on the reproductive toxicity of fluticasone propionate, conducted in male and female rats with subcutaneous administration of the drug at doses up to 50 μg / kg (approximately 2 times the recommended daily dose for an adult), no effect on the fertility of the animals was recorded. When subcutaneous administration of the drug at a dose of 50 mcg / kg, a significant reduction in the weight of the prostate gland was recorded.

Dosing and Administration

Intranasally.

Adults and adolescents (12 years and older) - one dose in each nasal passage twice a day (morning and evening).

Patients of advanced age

This age group does not require dose adjustment.

Preparation and use of the spray

1. Shake the bottle several times.

2. Remove the protective cap.

3. Before the first use, the nasal spray Dimist must be activated, i.e. Press and release the activator of the dispenser 6 times until the appearance of small sprays. If the spray has not been used for 7 days, it must be re-activated.

4. Clean the nose, tilt the head down.

Introduce the nebulizer into one nasal passage, covering the second with the finger. Press and inhale. Repeat the same with the second nasal passage.

5. Wipe the activator tip and wear the protective cap.

Side effects

The incidence of side effects is determined as follows:

Very often (≥1 / 10)

Often (≥1 / 100 to <1/10)

Infrequently (≥1 / 1000 to <1/100)

Rarely (≥1 / 10000 to <1/1000)

Very rarely (<1/10000)

From the immune system: very rarely - hypersensitivity reactions, including anaphylactic reactions, angioedema, bronchospasm.

From the nervous system: often - headache, very rarely - dizziness, drowsiness, lethargy.

From the senses: often - dysgeusia (perversion of taste), usually due to improper application, namely excessive tilt of the head back during the intake; Very rarely - glaucoma, increased intraocular pressure, cataract.

From the respiratory system, chest and mediastinum: infrequently - nosebleeds, nasal discomfort (burning, itching), sneezing, dryness of the nasal mucosa, cough, dryness in the throat, irritation of the throat; Very rarely - perforation of the nasal septum, erosion of the mucous membrane of the nasal cavity; Unpleasant odor.

From the gastrointestinal tract: rarely - dry mouth; Very rarely - nausea.

From the skin and subcutaneous tissue: very rarely - rash, itching, urticaria.

General disorders and disorders at the injection site: very rarely - fatigue, weakness.

With the use of intranasal glucocorticosteroids, it is possible to develop systemic side effects, especially with prolonged use in high doses (see section "Special instructions"). These effects are much less pronounced than with the oral administration of glucocorticosteroids. Possible systemic side effects may include: Itenko-Cushing syndrome, suppression of adrenal function, growth retardation in children, development of osteoporosis with prolonged use.

Overdose

With a nasal route of administration, an overdose is unlikely.

There is no evidence of an acute and chronic overdose of fluticasone propionate.

Nasal administration of 2 mg of fluticasone propionate (10 recommended daily doses) twice daily for 7 days in healthy volunteers had no effect on the hypothalamic-pituitary-adrenal system. The use of the drug in doses exceeding the recommended for a long period of time, can lead to a temporary suppression of the function of the adrenal glands. In this case, treatment should continue with the use of minimal doses sufficient to control the symptoms.

In case of an overdose due to accidental ingestion, there may be disorders of the nervous system (including drowsiness, confusion, coma, tachycardia or hypotension) caused by azelastine hydrochloride.

Treatment is symptomatic. Depending on the amount ingested, gastric lavage is recommended. There is no known antidote.

Interaction

Fluticasone propionate

The effects of other drugs on fluticasone propionate

Caution should be given to fluticasone propionate in patients who simultaneously take medications that are inhibitors of the cytochrome P450 isoenzyme ZA4 (for example, protease inhibitors such as ritonavir). When investigating the interaction in healthy volunteers against the background of intranasal administration of fluticasone propionate, the administration of 100 mg of ritonavir twice a day led to an increase in the concentration of fluticasone propionate in the blood plasma several hundred fold, which significantly reduced serum hydrocortisone levels. Post-registration use reported cases of clinically significant interactions in patients receiving fluticasone propionate and ritonavir, leading to systemic effects, including Itenko-Cushing syndrome and suppression of adrenal function. Simultaneous reception of these drugs should be avoided, unless the potential benefit to the patient exceeds the possible risk of systemic side effects of glucocorticosteroids (see section "Special instructions").

Inhibitors of the cytochrome P450 ZA4 isoenzyme cause a negligible (erythromycin) or insignificant (ketoconazole) increase in the concentration of fluticasone propionate in the blood plasma, which does not entail any noticeable decrease in serum cortisol concentrations. Nevertheless, caution should be exercised when combined with cytochrome P450 ZA4 isoenzyme inhibitors (eg, ketoconazole) and fluticasone propionate because of the possible increase in plasma concentration of the latter.

Azelastine hydrochloride

Special studies to study the interaction with other drugs with intranasal use of azelastine hydrochloride were not carried out. Studies have been conducted on the interaction of azelastine when ingested at high doses with other drugs, but the results of these studies can not be transferred to the intranasal use of the drug.

In some cases, alcohol and sedatives can increase fatigue, dizziness, or weakness when taking Dimist.

special instructions

Possible manifestations of systemic action of nasal glucocorticosteroids, especially when assigning high doses and long-term treatment. The possibility of these phenomena is much lower than with oral administration of glucocorticosteroids, and they can vary in individual patients and between different glucocorticosteroid preparations. Possible manifestations of systemic action may include Itenko-Cushing syndrome, characteristic signs of cushingoid, oppression of adrenal function, growth retardation in children and adolescents, cataracts, glaucoma, and, significantly less often, changes in mental state and behavior, which is manifested by psychomotor hyperactivity, sleep disorders, anxiety , Depression or aggression (especially in children).

It is necessary to monitor patients receiving the drug for a long time. When detecting cases of growth retardation, it is necessary to reduce the dose of nasal glucocorticosteroid to the lowest, which allows to effectively control the symptoms. In addition, you should refer the patient to a consultation with the pediatrician. Patients with visual impairment or increased intraocular pressure, glaucoma and / or cataract in the anamnesis should be under constant supervision.

If there is any suspicion of adrenal insufficiency, transfer of patients from systemic treatment with glucocorticosteroids to treatment with Dimist nasal spray should be done with caution.

Treatment with glucocorticosteroids at doses higher than recommended may lead to clinically significant suppression of adrenal function and if it is known that high doses of glucocorticosteroids have been used, consideration should be given to the possibility of additional use of systemic glucocorticosteroids during periods of stress or planned surgical intervention.

In patients with tuberculosis, any untreated infection, or a recent surgery or injury to the nose and mouth, the expected benefit of using Dimist should be compared with the possible risks.

Infections of the nasal cavity or paranasal sinuses require appropriate treatment, but are not a contraindication to the use of Dimist.

Ritonavir

Post-registration use reported cases of clinically significant interactions in patients receiving fluticasone propionate and ritonavir leading to systemic effects, including Itenko-Cushing syndrome and suppression of adrenal function. Simultaneous intake of these drugs should be avoided, unless the potential benefit to the patient exceeds the possible risk of systemic side effects of glucocorticosteroids.

Influence on the ability to drive vehicles, mechanisms In some cases, when using the drug Dimist, there may be violations from the nervous system: headache, dizziness, drowsiness, lethargy.

When these undesirable phenomena appear, one should refrain from driving and working with machinery.

Form of issue

Spray nasal dosed 137 mcg / dose + 50 mcg / dose

For 4 ml (28 doses) or 17 ml (120 doses) of a spray in a vial of dark glass with a dispenser - a dispenser in a crimping lid.

1 bottle together with the instruction for use is placed in a cardboard box.

Storage conditions

Store at 8 - 25 ° C Keep out of the reach of children.

Shelf life

2 years

Opened vials - 6 months

Do not use after the expiry date printed on the package.

Conditions of leave from pharmacies

on prescription