Flix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLIX (FLIX)

Composition:

Active substance: mometasone furoate;

One dose contains 51.8 mcg of mometasone furoate monohydrate, equivalent to 50 mcg of mometasone furoate;

Excipients: glycerol, sodium carboxymethylcellulose-microcrystalline cellulose (Avicel RC-591), sodium citrate dihydrate, citric acid monohydrate, benzalkonium chloride solution, polysorbate 80, purified water.

Pharmaceutical form. Nasal spray, suspension.

Main physicochemical properties: viscous, homogeneous, white, odorless suspension.

Pharmacotherapeutic group. Anti-inflammatory and other locally acting drugs for nasal cavity disorders. Corticosteroids. ATC code R01AD09.

Pharmacological Properties

Pharmacodynamics

Mometasone furoate is a synthetic corticosteroid for topical use that exerts a pronounced anti-inflammatory effect. Local anti-inflammatory activity of mometasone furoate is observed at doses that do not cause systemic effects.

The primary mechanism of the anti-inflammatory and antiallergic action of mometasone furoate is related to its ability to suppress the release of mediators of allergic reactions. Mometasone furoate significantly reduces the synthesis/release of leukotrienes from leukocytes of patients suffering from allergic diseases. In cell culture studies, mometasone furoate demonstrated 10-fold greater activity than other steroids, including beclomethasone dipropionate, betamethasone, hydrocortisone, and dexamethasone, in inhibiting the synthesis/release of IL-1, IL-5, IL-6, and TNFα. It is also a potent inhibitor of Th2 cytokine production, specifically IL-4 and IL-5, from human CD4+ T-cells. Mometasone furoate is also 6 times more effective than beclomethasone dipropionate and betamethasone in suppressing IL-5 production.

In challenge studies involving antigen application to the nasal mucosa, high anti-inflammatory activity of mometasone furoate in the form of a nasal spray was demonstrated both in the early and late phases of the allergic reaction. This was confirmed by a reduction (compared to placebo) in histamine levels and eosinophil activity, as well as a decrease (compared to baseline) in the number of eosinophils, neutrophils, and epithelial cell adhesion proteins.

A pronounced clinical effect within the first 12 hours of treatment with mometasone furoate nasal spray was achieved in 28% of patients with seasonal allergic rhinitis. On average (50%), symptom relief occurred within 35.9 hours. In addition, mometasone furoate in the form of a nasal spray demonstrated significant efficacy in reducing ocular symptoms (redness, tearing, itching) in patients with seasonal allergic rhinitis.

In clinical studies involving patients with nasal polyps, mometasone furoate in the form of a nasal spray demonstrated significant clinical efficacy in relieving nasal congestion, reducing polyp size, and restoring the sense of smell compared to placebo.

In clinical studies involving patients aged 12 years and older, mometasone furoate in the form of a nasal spray at a dose of 200 mcg twice daily demonstrated high efficacy in alleviating symptoms of rhinosinusitis compared to placebo. Over 15 days of treatment, rhinosinusitis symptoms were assessed using the Major Symptom Score (MSS) scale (facial pain, pressure in the nasal sinuses, tenderness upon palpation, pain in the sinus area, rhinorrhea, postnasal drip, and nasal congestion). The efficacy of amoxicillin 500 mg three times daily did not significantly differ from placebo in reducing rhinosinusitis symptoms on the MSS scale. During the post-treatment follow-up period, the number of relapses in the group receiving mometasone furoate was low and comparable to the relapse rates in the amoxicillin and placebo groups. Treatment duration for acute rhinosinusitis beyond 15 days was not evaluated.

Pharmacokinetics

The bioavailability of mometasone furoate when administered as a nasal spray is < 1% in plasma (based on data obtained using a sensitive method with a lower limit of quantification of 0.25 pg/mL). Mometasone furoate suspension is very poorly absorbed from the gastrointestinal tract, and any small amount that may be swallowed and absorbed undergoes extensive first-pass metabolism before excretion, primarily in the form of metabolites via bile and to a lesser extent via urine.

Distribution

In vitro studies have reported that the binding of mometasone furoate to plasma proteins is 98–99% within the concentration range of 5–500 ng/mL.

Metabolism

Studies on the metabolism of mometasone furoate have shown no major metabolites in plasma. In vitro, one of the minor metabolites, 6β-hydroxymometasone furoate, was identified, which is metabolized via CYP3A4 (P-450 3A4).

Excretion

The elimination half-life is 5.8 hours. The majority of metabolites are excreted via bile, with the remainder excreted in urine.

Clinical characteristics.

Indications.

Treatment of seasonal or perennial allergic rhinitis in adults and children aged 3 years and older. Prophylactic treatment of moderate to severe allergic rhinitis should be initiated 4 weeks before the anticipated start of the pollen season.

As an adjunctive therapeutic agent in antibiotic treatment of acute episodes of sinusitis in adults (including elderly) and children aged 12 years and older.

Treatment of symptoms of acute rhinosinusitis without signs of severe bacterial infection in adults and children aged 12 years and older.

Treatment of nasal polyps and associated symptoms, including nasal congestion and loss of smell, in patients aged 18 years and older.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

The medicinal product should not be used in the presence of untreated localized infection of the nasal mucosa, such as herpes simplex.

Due to the inhibitory effect of corticosteroids on wound healing, nasal corticosteroids should not be administered to patients who have recently undergone nasal surgery or nasal trauma until healing has occurred.

Interaction with other medicinal products and other forms of interaction.

Concomitant therapy with CYP3A inhibitors, including drugs containing cobicistat, is expected to increase the risk of systemic adverse effects. Concomitant use should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse effects; in such cases, patients should be monitored for the occurrence of systemic corticosteroid adverse effects.

In a clinical study, mometasone furoate was administered concomitantly with a non-sedating oral antihistamine (loratadine). The pharmacokinetic parameters and safety profile remained unchanged for both drugs.

Special precautions for use.

Immunosuppression.

The medicinal product Flix should be used with caution or not used at all in patients with active or inactive respiratory tuberculosis or untreated fungal, bacterial, or systemic viral infections. Patients receiving corticosteroids who potentially have suppressed immunity should be warned about the risk of contracting certain infections (e.g., varicella, measles) and the importance of seeking medical advice if such infections occur.

Candida infection.

Localized infections of the nose and pharynx caused by Candida albicans have occurred following intranasal administration of mometasone furoate. If such an infection develops, treatment with mometasone furoate should be discontinued and, if necessary, appropriate local or systemic therapy should be initiated.

Nasal septum perforation.

Cases of nasal septum perforation have been observed in patients following intranasal use of corticosteroids, including mometasone furoate. As with any prolonged local treatment of the nasal cavity, patients using mometasone furoate for several months or longer should be periodically examined for possible changes in the nasal mucosa.

Local nasal effects.

After 12 months of treatment with mometasone furoate in a study of patients with perennial rhinitis, no signs of atrophy of the nasal mucosa were observed; in fact, mometasone furoate tended to restore the nasal mucosa toward a normal histological phenotype. Nevertheless, patients using mometasone furoate for several months or longer should be periodically examined for possible changes in the nasal mucosa. If a localized fungal infection of the nose or pharynx develops, discontinuation of Flix and appropriate treatment may be required. Persistent irritation of the nasopharynx may be an indication for discontinuing mometasone furoate.

Flix is not recommended in cases of nasal septum perforation (see section "Special precautions for use").

Nasal bleeding.

Nasal bleeding was observed more frequently in patients with allergic rhinitis and in patients with chronic rhinosinusitis with nasal polyps receiving mometasone furoate than in those receiving placebo (see section "Adverse reactions").

Systemic effects of corticosteroids.

Hypercorticism and adrenal suppression may occur if intranasal corticosteroids, including mometasone furoate, are used at doses higher than recommended (see section "Dosage and administration") or in patients at risk of developing such effects. If such changes occur, the dose of mometasone furoate should be gradually reduced/withdrawn according to established procedures for discontinuing oral corticosteroid therapy. These effects are much less likely than with oral corticosteroids and may vary between individual patients and depending on the type of corticosteroid. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma, and, less frequently, various psychological or behavioral effects, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (particularly in children).

Cases of increased intraocular pressure have been reported after the use of intranasal corticosteroids (see section "Special precautions for use"). Visual disturbances may occur with systemic and topical (including intranasal, inhaled, and intraocular) use of corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, referral to an ophthalmologist should be considered to evaluate possible causes of visual disturbances, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and topical corticosteroid use.

Patients who are transitioning from long-term systemic corticosteroid therapy to the intranasal spray Flix require special attention. Systemic withdrawal of corticosteroids in such patients may lead to adrenal insufficiency over several months until hypothalamic-pituitary-adrenal (HPA) axis function recovers. If these patients experience signs and symptoms of adrenal insufficiency or withdrawal symptoms (e.g., joint and/or muscle pain, fatigue, and depression at the beginning), systemic corticosteroid therapy should be reinstated, and other therapeutic approaches and appropriate treatment measures should be implemented. Such a transition may also unmask pre-existing allergic conditions, such as allergic conjunctivitis and eczema, previously suppressed by systemic corticosteroid therapy. Treatment with doses higher than recommended may lead to clinically significant suppression of adrenal function. If there is evidence of use of doses higher than recommended, additional systemic corticosteroid therapy should be considered during periods of stress or elective surgery.

Impaired wound healing.

Due to the inhibitory effect of corticosteroids on wound healing, intranasal corticosteroids should not be used in patients who have recently experienced nasal septum ulceration, nasal surgery, or nasal trauma until complete healing has occurred.

Nasal polyps.

The safety and efficacy of the intranasal spray Flix for the treatment of unilateral polyps, polyps associated with cystic fibrosis, or polyps completely obstructing the nasal cavity have not been studied. Unilateral polyps of unusual or irregular appearance, especially if ulcerated or bleeding, should be further investigated.

Use in the pediatric population.

The safety and efficacy of mometasone furoate for the prevention of nasal symptoms of seasonal allergic rhinitis have been established in pediatric patients aged 12 years and older. The use of mometasone furoate for this indication is supported by evidence from controlled studies involving adults and children aged 12 years and older. The safety and efficacy of mometasone furoate for the treatment of chronic rhinosinusitis with nasal polyps in pediatric patients under 18 years of age have not been established. Efficacy was not demonstrated in one 4-month study evaluating the safety and efficacy of mometasone furoate in the treatment of chronic rhinosinusitis with nasal polyps in children aged 6 to 17 years. The primary objective of the study was to assess safety. In total, 127 patients with chronic rhinosinusitis and nasal polyps were randomized to receive placebo or mometasone furoate 100 mcg once or twice daily (patients aged 6 to 11 years) or 200 mcg once or twice daily (patients aged 12 to 17 years). The results of this study do not support the efficacy of mometasone furoate in the treatment of chronic rhinosinusitis with nasal polyps in children. Adverse reactions reported in this study were similar to those reported in patients aged 18 years and older with chronic rhinosinusitis with nasal polyps.

Effect on children's growth.

Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction in growth velocity in children. This effect has been observed in the absence of laboratory evidence of suppression of the hypothalamic-pituitary-adrenal (HPA) axis, indicating that growth velocity is a more sensitive indicator of systemic corticosteroid effects in pediatric patients than some of the standard HPA axis function tests. The long-term consequences of this reduced growth velocity associated with intranasal corticosteroids, including the effect on final adult height, are unknown. The potential for "catch-up" growth after discontinuation of intranasal corticosteroid therapy has not been adequately studied. Growth in children receiving intranasal corticosteroids, including mometasone furoate, should be monitored regularly (e.g., using stadiometry). The potential impact of long-term treatment on growth should be weighed against the clinical benefits achieved and the availability of safe and effective non-corticosteroid treatment alternatives. To minimize systemic effects of intranasal corticosteroids, including mometasone furoate, the lowest effective dose should be used for each patient.

Symptoms not related to the nose.

Although the intranasal spray Flix controls nasal symptoms in most patients, concomitant use of appropriate additional therapy may provide additional relief of other symptoms, particularly ocular symptoms.

Important information about excipients.

The intranasal spray Flix contains benzalkonium chloride. Benzalkonium chloride may cause irritation or swelling inside the nose, especially with prolonged use.

Use during pregnancy or breastfeeding.

Systemic (subcutaneously administered) corticosteroids have been shown to have teratogenic effects in animals. Clinical studies in pregnant women or women who are breastfeeding have not been conducted.

Corticosteroid preparations should not be used during pregnancy or breastfeeding unless absolutely necessary.

Ability to affect reaction speed when driving or operating machinery.

Unknown.

Method of Administration and Dosage

Before each use, the nose should be thoroughly cleared of mucus.

Treatment and prevention of seasonal or perennial allergic rhinitis in adults and children aged 12 years and older. The recommended prophylactic and therapeutic dose of the medicinal product for adults (including elderly patients) and children aged 12 years and older is 2 sprays (50 mcg each) in each nostril once daily (total daily dose – 200 mcg). After achieving the therapeutic effect, maintenance therapy should be continued with a reduced dose of 1 spray in each nostril once daily (total daily dose – 100 mcg).

If symptoms cannot be adequately controlled with the recommended therapeutic dose, the daily dose may be increased to the maximum: 4 sprays in each nostril once daily (total daily dose – 400 mcg). After symptom relief, dose reduction is recommended.

Mometasone furoate has demonstrated a clinically significant onset of action within 12 hours after the first dose in some patients with seasonal allergic rhinitis. However, full therapeutic benefit may not be achieved within the first 48 hours; therefore, patients should continue regular use to achieve optimal therapeutic effect.

The recommended therapeutic dose for children aged 3–11 years is 1 spray (50 mcg) in each nostril once daily (total daily dose – 100 mcg).

Treatment of patients with seasonal allergic rhinitis should begin with prophylactic use of the drug 2–4 weeks prior to the pollen season.

Adjunctive treatment of acute sinusitis episodes. The recommended therapeutic dose for adults (including elderly patients) and children aged 12 years and older is 2 sprays (50 mcg each) in each nostril twice daily (total daily dose – 400 mcg).

If symptoms cannot be controlled with the recommended therapeutic dose, the daily dose may be increased to 4 sprays in each nostril twice daily (total daily dose – 800 mcg). After symptom relief, dose reduction is recommended.

Acute rhinosinusitis. The recommended therapeutic dose for adults and children aged 12 years and older is 2 sprays (50 mcg each) in each nostril twice daily (total daily dose – 400 mcg).

Nasal polyps. The recommended dose for patients aged 18 years and older (including elderly patients) is 2 sprays (50 mcg each) in each nostril twice daily (total daily dose – 400 mcg). After achieving clinical response, the dose should be reduced to 2 sprays in each nostril once daily (total daily dose – 200 mcg).

Children.

Seasonal and perennial allergic rhinitis. The safety and efficacy of mometasone furoate nasal spray in children under 3 years of age have not been established.

Nasal polyposis. The safety and efficacy of mometasone furoate nasal spray in children and adolescents under 18 years of age have not been established.

Overdose.

Overdose is unlikely to require any therapy other than observation.

Inhalation or oral ingestion of excessive doses of corticosteroids may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis function.

Adverse Reactions

Short description of the safety profile.

Nasal bleeding was generally self-limiting and mild in severity, occurred more frequently compared to placebo (5%), but at a comparable or lower frequency than observed with the studied active control intranasal corticosteroids (up to 15%), as reported in clinical trials of allergic rhinitis. The incidence of all other adverse effects was comparable to that of placebo. In patients receiving treatment for nasal polyps, the overall incidence of adverse effects was similar to that observed in patients with allergic rhinitis.

Systemic effects of intranasal corticosteroids may occur, particularly with high doses administered over prolonged periods.

Tabulated list of adverse reactions.

Treatment-related adverse reactions (≥ 1%) reported in clinical trials in patients with allergic rhinitis or nasal polyps, as well as post-marketing reports, regardless of indication, are presented in the table below. All adverse reactions are listed by system organ class and frequency: 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), and frequency not known (cannot be estimated from the available data).

Treatment-related adverse reactions are listed by system organ class and frequency.

* for twice-daily dosing in nasal polyposis.

† reported with atypical frequency for twice-daily dosing in the treatment of nasal polyposis.

Pediatric patients.

In the pediatric population, the incidence of adverse effects observed in clinical studies, such as epistaxis (6%), headache (3%), nasal irritation (2%), and sneezing (2%), was comparable to placebo.

The following clinically significant adverse reactions are described in other sections

• Epistaxis, nasal ulcers, Candida albicans infection, impaired wound healing (see section "Special precautions");
• Glaucoma and cataract (see section "Special precautions");
• Immunosuppression and increased risk of infections (see section "Special precautions");
• Hypercorticism and adrenal suppression, including growth suppression (see sections "Special precautions").

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Do not freeze.

Packaging.

9 g or 18 g in a polyethylene bottle with a pump dispenser; 1 bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ABDI IBRAHIM Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and location of operations.

Orhan Gazi Mahallesi, Tunc Jadde No. 3, Esenyurt, Istanbul, Turkey.

Marketing authorization holder.

Delta Medical Promotions AG.

Address of the marketing authorization holder.

Ottenbachstrasse 26, Zurich CH – 8001, Switzerland.