Mometasone furoate, azelastine hydrochloride.
Mometasone Furoate: Mometasone Nasal Spray contains mometasone furoate, is an anti-inflammatory corticosteroid. It is chemically known as 9,21-Dichloro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 17-(2 furoate). It has the molecular formula of C27H30C12O6·H2O and a molecular weight of 539.45. Mometasone furoate is a white powder. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. Its partition coefficient between octanol and water is greater than 5000.
Azelastine Hydrochloride: Azelastine nasal spray is an antihistamine for the relief of the symptoms of seasonal and perennial allergic rhinitis. The drug is a phthalazinone derivative, differing in chemical structure from other antihistamines, adrenergic agents (epinephrine), theophylline, cromolyn, and beclomethasone. The chemical name for azelastine hydrochloride is (+/-)-1-(2H)-phthalazinone,4-((4-chlorophenyl) methyl)-2-(hexahydro-1-methyl-1H-azepin-4yl)-,monohydrochloride.
Each spray delivers: Mometasone Furoate BP 50 mcg, Azelastine Hydrochloride BP 140 mcg.
Excipients/Inactive ingredients: Preservative: Benzalkonium chloride BP 0.02% w/w.
Pharmacology: Mechanism of Action: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory properties. The precise mechanism of corticosteroid action on allergic rhinitis is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation.
In two clinical studies utilizing nasal antigen challenge, Mometasone furoate Nasal Spray, 50 mcg decreased some markers of the early- and late-phase allergic response. These observations included decreases (vs. placebo) in histamine and eosinophil cationic protein levels, and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known.
The effect of Mometasone furoate Nasal Spray, 50 mcg on nasal mucosa following 12 months of treatment was examined in patients with allergic rhinitis. There was no evidence of atrophy and there was a marked reduction in intraepithelial eosinophilia and inflammatory cell infiltration (e.g., eosinophils, lymphocytes, monocytes, neutrophils, and plasma cells).
Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H1-receptor antagonist activity in isolated tissues, animal models, and humans. Azelastine Nasal Spray is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in-vitro studies. The major metabolite, desmethylazelastine, also possesses H1-receptor antagonist activity.
Pharmacokinetics: Absorption: Mometasone furoate administered as a nasal spray suspension has very low bioavailability (<1%) in plasma using a sensitive assay with a lower quantitation limit (LOQ) of 0.25 pcg/mL.
After intranasal administration of 2 sprays per nostril (548 mcg total dose) of Azelastine Nasal Spray, the mean azelastine peak plasma concentration (Cmax) is 200 pg/mL, the mean extent of systemic exposure (AUC) is 5122 pghr/mL and the median time to reach Cmax (tmax) is 3 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration.
Distribution: The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.
Based on intravenous and oral administration, the steady-state volume of distribution of azelastine is 14.5 L/kg. In vitro studies with human plasma indicate that the plasma protein binding of azelastine and its metabolite, desmethylazelastine, are approximately 88% and 97%, respectively.
Metabolism: Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6β-hydroxymometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4 (CYP3A4).
Azelastine is oxidatively metabolized to the principal active metabolite, desmethylazelastine, by the cytochrome P450 enzyme system. The specific P450 isoforms responsible for the biotransformation of azelastine have not been identified. After a single-dose, intranasal administration of Azelastine Nasal Spray (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/mL, the AUC is 2131 pghr/mL and the median tmax is 24 hours. After intranasal dosing of azelastine to steady-state, plasma concentrations of desmethylazelastine range from 20-50% of azelastine concentrations.
Elimination: Following intravenous administration, the effective plasma elimination half-life of mometasone furoate is 5.8 hours. Any absorbed drug is excreted as metabolites mostly via the bile, and to a limited extent, into the urine.
Following intranasal administration of Azelastine Nasal Spray, the elimination half-life of azelastine is 22 hours while that of desmethylazelastine is 52 hours. Approximately 75% of an oral dose of radiolabeled azelastine hydrochloride was excreted in the feces with less than 10% as unchanged azelastine.
Special Populations: Hepatic impairment: Administration of a single inhaled dose of 400 mcg mometasone furoate to subjects with mild, moderate, and severe hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment, however, the numbers of detectable levels were few.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by hepatic impairment.
Renal impairment: The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated. Based on oral, single-dose studies of azelastine, renal insufficiency (creatinine clearance <50 mL/min) resulted in a 70-75% higher Cmax and AUC compared to healthy subjects. Time to maximum concentration was unchanged.
Age: Mometasone furoate pharmacokinetics has not been investigated in the pediatric population.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by age.
Gender: The effects of gender on mometasone furoate pharmacokinetics have not been adequately investigated.
Following oral administration of azelastine, pharmacokinetic parameters were not influenced by gender.
Race: The effects of race on mometasone furoate pharmacokinetics have not been adequately investigated.
The effect of race on azelastine has not been evaluated.
Rationale for the Combination: Antihistamines are recommended as the first line of therapy for mild AR, and intranasal corticosteroids are first line for moderate and severe AR according to the recent guidelines. In accordance with these recommendations in clinical practice, antihistamines and topical corticosteroids are the most commonly used pharmacological agents for the treatment of AR. Antihistamines block neural and vascular H1 receptors and have a clinical effect on symptoms such as nasal itching, sneezing and rhinorrhea. They are rapidly absorbed and begin to reduce nasal symptoms (itching and sneezing) within 1 hr. On the other hand, efficacy of steroids depends upon their long term anti-inflammatory effect rather than upon direct receptor antagonism. Understanding both the efficacy and the pharmacologic properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms clearly shows that the combination of the two drugs would be better than either drug alone in patients with moderate to severe allergic rhinitis.
Fixed dose combination of Mometasone and Azelastine nasal spray is indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older.
The recommended dose for treatment of the nasal symptoms of seasonal allergic rhinitis is 2 sprays in each nostril once daily or 1 spray in each nostril twice daily.
There are no data available on the effects of acute or chronic overdosage with Mometasone furoate Nasal Spray 50 mcg. Because of low systemic bioavailability, and an absence of acute drug-related systemic findings in clinical studies, overdose is unlikely to require any therapy other than observation. Intranasal administration of 1600 mcg (4 times the recommended dose of Mometasone furoate Nasal Spray 50 mcg for the treatment of nasal polyps in patients 18 years of age and older) daily for 29 days, to healthy human volunteers, showed no increased incidence of adverse events. Single intranasal doses up to 4000 mcg and oral inhalation doses up to 8000 mcg have been studied in human volunteers with no adverse effects reported. Chronic over dosage with any corticosteroid may result in signs or symptoms of hypercorticism. Acute overdosage with this dosage form is unlikely since one bottle of Mometasone furoate Nasal Spray 50 mcg contains approximately 8500 mcg of mometasone furoate.
There have been no reported overdosages with Azelastine Nasal Spray. Acute overdosage by adults with this dosage form is unlikely to result in clinically significant adverse events, other than increased somnolence. Clinical trials in adults with single doses of the oral formulation of azelastine hydrochloride (up to 16 mg) have not resulted in increased incidence of serious adverse events. General supportive measures should be employed if overdosage occurs. There is no known antidote to Azelastine Nasal Spray.
Fixed dose combination of Mometasone and Azelastine Nasal Spray is contraindicated in patients with known hypersensitivity to mometasone furoate or azelastine hydrochloride or any of its ingredients.
Nasal Spray should not be used in the presence of untreated localised infection involving the nasal mucosa.
Because of the inhibitory effect on wound healing, patients who have experienced recent nasal surgery or trauma should not use a nasal spray until healing has occurred.
Mometasone Furoate: Local Nasal Effects: Epistaxis: In clinical studies, epistaxis was observed more frequently in patients with allergic rhinitis with Mometasone furoate Nasal Spray than those who received placebo.
Candida Infection: In clinical studies with Mometasone furoate Nasal Spray 50 mcg, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, use of Mometasone furoate Nasal Spray 50 mcg should be discontinued and appropriate local or systemic therapy instituted, if needed.
Nasal Septum Perforation: Instances of nasal septum perforation have been reported following the intranasal application of corticosteroids. As with any long-term topical treatment of the nasal cavity, patients using Mometasone furoate Nasal Spray 50 mcg over several months or longer should be examined periodically for possible changes in the nasal mucosa.
Impaired Wound Healing: Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septum ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.
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.
Hypersensitivity Reactions: Hypersensitivity reactions including instances of wheezing may occur after the intranasal administration of Mometasone furoate. Discontinue Mometasone Nasal Spray if such reactions occur.
Immunosuppression: Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, 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 globin (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 infection of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections, or ocular herpes simplex because of the potential for worsening of these infections.
Hypothalamic-Pituitary-Adrenal Axis Effect: Hypercorticism and Adrenal Suppression: 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 Mometasone furoate Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.
Effect on Growth: Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving Mometasone furoate Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including Mometasone furoate Nasal Spray, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms.
Azelastine Hydrochloride: Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has been reported in some patients taking Azelastine Nasal Spray. 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 Azelastine Nasal Spray. Concurrent use of Azelastine 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.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation section for further information.
Use in Children: The safety and effectiveness of Mometasone furoate Nasal Spray 50 mcg for allergic rhinitis in children 12 years of age and older have been established. Controlled clinical studies have shown intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. The potential of Mometasone furoate Nasal Spray 50 mcg to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out.
Safety and effectiveness of Azelastine Nasal Spray in pediatric patients below the age of 12 years have not been established.
Use in the Elderly: The adverse reactions reported in geriatric population were similar in type and incidence to those reported by younger patients.
Clinical trials of Azelastine Nasal Spray did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Pregnancy Teratogenic Effects: There are no adequate and well-controlled studies in pregnant women. Mometasone furoate Nasal Spray 50 mcg, like other corticosteroids, should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy. There are no adequate and well-controlled clinical trials in pregnant women. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Azelastine Nasal Spray should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known if mometasone furoate is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be used when Mometasone furoate monohydrate Nasal Spray, 50 mcg is administered to nursing women.
It is not known whether azelastine hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Azelastine Nasal Spray is administered to a nursing woman.
Treatment-related adverse events reported in clinical studies for allergic rhinitis in adult and adolescent patients are shown as follows: (see table).
Click on icon to see table/diagram/image
Epistaxis was generally self-limiting and mild in severity, and occurred at a higher incidence compared to placebo (5%), but at a comparable or lower incidence when compared to the active control nasal corticosteroids studied (up to 15%). The incidence of all other effects was comparable with that of placebo.
In the paediatric population, the incidence of adverse events, e.g., epistaxis (6%), headache (3%), nasal irritation (2%) and sneezing (2%) was comparable to placebo.
Systemic effects of nasal corticosteroids may occur, particularly when prescribed at high doses for prolonged periods.
The most frequently adverse reactions reported in several clinical trials with Azelastine Nasal Spray in adult and adolescent patients with seasonal and perennial allergic rhinitis were bitter taste, epistaxis, headache, nasal discomfort, fatigue, somnolence, nasopharyngitis, sinusitis and sneezing.
Post-Marketing Experience: The following adverse reactions have been identified during the post-marketing period for Mometasone furoate Nasal Spray 50 mcg: nasal burning and irritation, anaphylaxis and angioedema, disturbances in taste and smell and nasal septal perforation.
The following adverse reactions have been identified during the post-marketing period for Azelastine Nasal Spray: abdominal pain, nasal burning, nausea, sweet taste, throat irritation, anaphylactoid reaction, application site irritation, atrial fibrillation, blurred vision, chest pain, confusion, dizziness, dyspnea, facial edema, hypertension, involuntary muscle contractions, nervousness, palpitations, paresthesia, parosmia, paroxysmal sneezing, pruritus, rash, disturbance or loss of sense of smell and/or taste, tachycardia, tolerance, urinary retention, and xerophthalmia.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Mometasone furoate: No formal drug-drug interaction studies have been conducted with Mometasone furoate Nasal Spray 50 mcg.
Inhibitors of Cytochrome P450 3A4: Ketoconazole: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In vitro studies have confirmed the primary role of cytochrome CYP 3A4 in the metabolism of this compound. Coadministration with ketoconazole, a potent CYP 3A4 inhibitor, may increase the plasma concentrations of mometasone furoate.
Loratadine: A clinical interaction study was conducted with loratadine. No interactions were observed.
Azelastine Hydrochloride: Central Nervous System Depressants: Concurrent use of Azelastine Nasal Spray with alcohol or other central nervous system depressants should be avoided because reductions in alertness and impairment of central nervous system performance may occur.
Erythromycin and Ketoconazole: Interaction studies investigating the cardiac effects, as measured by the corrected QT interval (QTc), of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. Oral erythromycin (500 mg three times daily for 7 days) had no effect on azelastine pharmacokinetics or QTc based on analyses of serial electrocardiograms. Ketoconazole (200 mg twice daily for 7 days) interfered with the measurement of azelastine plasma concentrations on the analytic HPLC; however, no effects on QTc were observed.
Cimetidine: Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65%.
Incompatibilities: Not applicable.
Store at temperatures not exceeding 30°C.
Protect from freezing & light.
Do not exceed the recommended dose.
Shelf-Life: 24 months.
R01AD59 - mometasone, combinations ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.
Momate Az 50 mcg/140 mcg nasal spray
(150 actuations) 1's (P819/bottle)
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