Instruction for use: Azelastine+Fluticasone (Azelastineum+Fluticasonum)

Pharmacological group

H1-antihistamines in combination

Glucocorticosteroids in combinations

Nosological classification (ICD-10)

H10.1 Acute atopic conjunctivitis

Allergic conjunctivitis, Allergic eye disease, Allergic conjunctivitis, Allergic conjunctivitis is caused by chemical and physical factors, Allergic rhinoconjunctivitis,Allergic inflammation of the eye, Spring catarrh, Spring keratitis, Spring conjunctivitis, allergic Conjunctivitis, Perennial allergic conjunctivitis,Exacerbation of pollen allergy in the form of Syndrome rinokonyunktivalnogo, Acute allergic keratoconjunctivitis, Acute allergic conjunctivitis,Superficial bacterial eye infections,rhinoconjunctivitis, Seasonal allergic conjunctivitis, Seasonal conjunctivitis, Sennoz, Chronic allergic keratoconjunctivitis, Chronic allergic conjunctivitis

J30 Vasomotor and allergic rhinitis

Allergic rinopatiya, Allergic rhinosinusopathy, Allergic respiratory diseases, Allergic rhinitis, nasal allergy, Seasonal Allergic Rhinitis, Vasomotor rhinitis, Long-allergic rhinitis, Perennial allergic rhinitis, Perennial allergic rhinitis, Year-round or seasonal allergic rhinitis, Year-round allergic rhinitis nature, Rhinitis allergic vasomotor, Exacerbation of pollen allergy in the form of Syndrome rinokonyunktivalnogo, Acute allergic rhinitis, Edema of the nasal mucosa, Edema of the nasal mucosa, Swelling of the mucosa of the nasal cavity, Swelling of the nasal mucosa, Swelling of the nasal mucosa, pollen disease, Permanent allergic rhinitis, rhinoconjunctivitis, rhinosinusitis,rhinosinusopathy, Seasonal allergic rhinitis, Seasonal Allergic Rhinitis, Haymarket rhinitis, Chronic allergic rhinitis, Allergic respiratory diseases

Pharmacology

Pharmacological action - anti-inflammatory, antiallergic, glucocorticoid, H1-antihistamine.

Pharmacodynamics

The combination of Azelastine + fluticasone contains Azelastine (in the form of hydrochloride) and fluticasone (in the form of 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 GCS (glucocorticosteroids), 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 an antiallergic long-acting compound that is an selective blocker of H1-histamine receptors, stabilizes mast cells and has anti-inflammatory properties. In vivo and in vitro studies show that Azelastine inhibits the synthesis and / or release of chemical mediators that are involved in the early and late stages of allergic reactions, such as LT (leukotrienes), histamine, FAT (platelet activating factor), and serotonin. Azelastine with intranasal application is characterized by a rapid onset of action compared with oral administration of antihistamine drugs (drug) and GCS (glucocorticosteroids). Relief of nasal allergic symptoms is observed as early as 15 minutes after administration.

In comparison with placebo and separately applied Azelastine hydrochloride and fluticasone propionate, the combination of Azelastine + fluticasone 2 times a day significantly alleviates nasal symptoms (including rhinorrhea, nasal congestion, sneezing and itching in the nose). There is also a significant relief of eye symptoms, such as itching, lacrimation and redness of the eyes.

In comparison with fluticasone propionate in the form of monotherapy, relief of the main symptoms (a 50% reduction in the severity of symptoms) was achieved with Azelastine + fluticasone combination significantly faster (for 3 days or more).

Pharmacokinetics

Suction. After intranasal administration of fluticasone propionate (200 μg / day), C max was 0.017 ng / ml. Absorption from the mucous membrane of the nasal cavity is negligible due to the low solubility of fluticasone in 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 a set of absorption from the nasal mucosa and when swallowed, is insignificant.

After repeated administration of a daily dose of 0.56 mg of Azelastine hydrochloride (corresponding to the administration of one dose in each nasal passage 2 times a day), Cmax in plasma was 0.027 ng / ml in healthy volunteers. The level of the active metabolite 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, the Azelastine concentration in the plasma 2 hours after the administration was about 0.65 ng / ml. Doubling the daily dose to 0.12 mg led to an increase in the concentration of Azelastine in the blood plasma to 1.09 ng / ml, which indicates a proportional increase in concentration depending on the dose.

Distribution. Fluticasone propionate has a large Vss (approximately 318 L). Binding to plasma proteins is 91%. Vd 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 - through the isoenzyme CYP3A4 (cytochrome P450 isoenzyme) cytochrome P450. 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 concomitant administration of strong CYP3A4 inhibitors, such as ketoconazole and ritonavir, is recommended. There is the possibility of increasing the concentration of fluticasone propionate in the blood.

Azelastine is metabolized to N-desmethylAzelastine by various isoenzymes of the liver, mainly CYP3A4 (cytochrome P450 isoenzyme), CYP2D6 (cytochrome P450 isoenzyme), and CYP2C19 (cytochrome P450 isoenzyme).

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). Cmax in blood plasma is reduced by approximately 98% within 3-4 hours, and only at very low concentrations in the plasma there is a final T1 / 2 - 7.8 hours. Renal clearance of fluticasone propionate is negligible (less than 0.2%), and inactive Metabolite - carboxylic acid - less than 5%. Fluticasone propionate and its metabolites are mainly excreted with bile through the intestine.

After a single application of T1 / 2, Azelastine from the blood plasma is approximately 20-25 hours and about 45 hours for its therapeutically active metabolite N-desmethylAzelastine. 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.

Application of Azelastine + Fluticasone

Allergic rhinitis / rhinoconjunctivitis of moderate and severe degree (symptomatic treatment).

Contraindications

Hypersensitivity to the active ingredients of the combination; Children under 12 years.

pregnancy and lactation

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

It is not known whether the intranasal administration of Azelastine hydrochloride or its metabolites and fluticasone propionate or its metabolites into breast milk penetrates, therefore a combination of Azelastine + fluticasone should be given to lactating women only if the expected benefit exceeds the possible risk to the child.

Fertility. Studies of the effect of Azelastine + fluticasone 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). With the administration of drugs 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 SC administration 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. With n / k introduction at a dose of 50 mcg / kg, a significant reduction in the mass of the prostate gland was recorded.

Side effects

The incidence of side effects is determined as follows: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <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 (distortion of taste), usually due to improper application, namely excessive tilt of the head back; Very rarely - glaucoma, an increase in IOP, cataracts.

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

From the digestive 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, fatigue.

Intranasal application of GCS may lead to the development of systemic side effects, especially with prolonged use in high doses (see "Precautions"). These effects are much less pronounced than with oral administration of GCS. Possible systemic side effects may include Itenko-Cushing syndrome, suppression of adrenal function, growth retardation in children, development of osteoporosis with prolonged use.

Interaction

Fluticasone

The effect of other drugs (drug) on fluticasone propionate. Caution should be given to fluticasone propionate in patients who simultaneously take drugs that are potent inhibitors of the CYP3A4 isoenzyme (eg, protease inhibitors such as ritonavir). When studying the interaction in healthy volunteers against the background of intranasal administration of fluticasone propionate, the administration of 100 mg of ritonavir 2 times a day resulted in an increase in the concentration of fluticasone propionate in blood plasma several hundred times, 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 drug data should be avoided, unless the potential benefit to the patient exceeds the possible risk of systemic side effects of GCS (see "Precautions").

Erythromycin causes negligible, and ketoconazole - a slight increase in the concentration of fluticasone propionate in the blood plasma, which does not entail any significant decrease in the concentration of serum cortisol. Nevertheless, care should be taken when combining the use of cytochrome CYP3A4 isoenzyme inhibitors (eg ketoconazole) and fluticasone propionate in view of a possible increase in plasma concentration of the latter.

Azelastine

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 intranasal application.

In some cases, alcohol and sedative drugs may increase fatigue, dizziness, or weakness when combined with Azelastine plus fluticasone.

Overdose

With an intranasal route of administration, an overdose is unlikely.

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

Symptoms: Intranasal administration of 2 mg fluticasone propionate (10 recommended daily doses) 2 times a day for 7 days in healthy volunteers did not have an effect on the hypothalamic-pituitary-adrenal system. The use of combination Azelastine + fluticasone in doses exceeding 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: symptomatic. Depending on the amount swallowed, gastric lavage is recommended. There is no known antidote.

Routes of administration

Intranasally.

Precautions

Possible manifestations of systemic action of nasal SCS, especially when assigning high doses and long-term treatment. The possibility of these phenomena is much lower than with oral administration of GCS, and they can vary in individual patients and between different SCSs. Possible manifestations of systemic action may include the Itzenko-Cushing syndrome, characteristic signs of cushingoid, oppression of adrenal function, growth retardation in children and adolescents, cataracts, glaucoma, and much 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 a combination of Azelastine + fluticasone for a long time. In case of detection of growth retardation, the intranasal SCS dose should be reduced 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 IOP, glaucoma and / or cataract in a history should be under constant supervision.

If there is any suspicion of adrenal insufficiency, the transfer of patients from systemic treatment of GCS to the intranasal use of the Azelastine + fluticasone combination should be carried out with caution.

The use of GCS in doses higher than the recommended ones can lead to clinically significant suppression of adrenal function, and if it is known that high doses of GCS were used, consideration should be given to the possibility of additional use of systemic SCS 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 from the appointment of a combination of Azelastine + fluticasone with possible risks should be compared.

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

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 reception of drug data should be avoided, unless the potential benefit to the patient exceeds the possible risk of systemic side effects of GCS.

Influence on the ability to drive vehicles, work with mechanisms. In some cases, when using a combination of Azelastine + fluticasone, there may be disorders from the nervous system - headache, dizziness, drowsiness, lethargy. When such undesirable phenomena appear, one should refrain from driving and working with machinery.