FURAMIST AZ Nasal Spray (Fluticasone furoate + Azelastine hydrochloride)

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1 Published on: 27 Jan 2016 FURAMIST AZ Nasal Spray (Fluticasone furoate + Azelastine hydrochloride) Composition Each spray delivers: Azelastine Hydrochloride BP 140 mcg Fluticasone Furoate 27.5 mcg Dosage Form Intranasal spray Description FURAMIST AZ nasal spray is an antihistamine-corticosteroid combination available as a metered spray formulation for intranasal administration. It contains azelastine hydrochloride, which is a second generation H 1 receptor-antagonist with potent topical activity, and fluticasone furoate, a synthetic corticosteroid with anti-inflammatory properties. Pharmacology As FURAMIST AZ nasal spray is a combination of azelastine hydrochloride and fluticasone furoate, the pharmacological properties of both the molecules are given separately. Pharmacodynamics Azelastine Hydrochloride Azelastine hydrochloride, a phthalazinone derivative, exhibits histamine H 1 receptor-antagonist activity in isolated tissues, animal models, and humans. The major metabolite, desmethylazelastine, also possesses H 1 receptor-antagonist activity. There was no evidence of cardiac repolarization (represented as corrected QT interval) after administration of azelastine hydrochloride nasal spray (2 sprays per nostril) in 56-day placebo-controlled trial with 95 patients with allergic rhinitis. Following multiple dose oral administration of azelastine 4 mg or 8 mg twice daily, the mean change in QTc was 7.2 msec and 3.6 msec, respectively. Interaction studies investigating the cardiac repolarization effects of concomitantly administered oral azelastine hydrochloride and erythromycin or ketoconazole were conducted. These drugs had no effect on QTc based on analysis of serial electrocardiograms. Fluticasone furoate Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects rhinitis symptoms is not known. Corticosteroids have been shown

2 to have a wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in inflammation. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element, inhibition of pro-inflammatory transcription factors such as nuclear factor-kappa B (NFkB), and inhibition of antigen-induced lung eosinophilia in sensitized rats. Fluticasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is approximately 29.9 times that of dexamethasone and 1.7 times that of fluticasone propionate. Pharmacokinetics Azelastine Hydrochloride Absorption After intranasal administration of 2 sprays per nostril (548 mcg total dose) of 137 mcg azelastine hydrochloride, the mean azelastine peak plasma concentration (C max ) is 200 pg/ml, the mean extent of systemic exposure (AUC) is 5122 pg hr/ml and the median time to reach Cmax (t max ) is 3 hours. The systemic bioavailability of azelastine hydrochloride is approximately 40% after intranasal administration. Distribution 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 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 137 mcg azelastine hydrochloride (548 mcg total dose), the mean desmethylazelastine Cmax is 23 pg/ml, the AUC is 2131 pg hr/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 intranasal administration of 137 mcg azelastine hydrochloride, 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 Following oral administration, pharmacokinetic parameters were not influenced by age, gender, or hepatic impairment. Based on oral, single-dose studies, renal impairment (creatinine clearance <50 ml/min) resulted in a 70 75% higher C max and AUC compared to normal subjects. Time to maximum concentration was unchanged. Fluticasone furoate Absorption Following intranasal administration of fluticasone furoate, most of the dose is eventually swallowed and undergoes incomplete absorption and extensive first-pass metabolism in the liver and gut, resulting in negligible systemic exposure. At the highest recommended intranasal dosage of 110 mcg once daily for up to 12 months in adults and up to 12 weeks in children, plasma concentrations of fluticasone furoate are typically not quantifiable despite the use of a sensitive HPLC-MS/MS assay with a lower limit of quantification (LOQ) of 10 pg/ml. However, in a few isolated cases (<0.3%) fluticasone furoate was detected in high concentrations above 500 pg/ml, and in a single case, the concentration was as high as 1,430 pg/ml in the 52-week study. There was no relationship between these concentrations and cortisol levels in these subjects. The reasons for these high concentrations are unknown.

3 Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral solution and intravenous dosing of radiolabelled drug have demonstrated that at least 30% of fluticasone furoate is absorbed and then rapidly cleared from plasma. Oral bioavailability is on average 1.26%, and the majority of the circulating radioactivity is due to inactive metabolites. Distribution Following intravenous administration, the mean volume of distribution at steady state is 608 L. Binding of fluticasone furoate to human plasma proteins is greater than 99%. Metabolism In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone. Fluticasone furoate is cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism via the cytochrome P450 isozyme, CYP3A4. The principal route of metabolism is hydrolysis of the S-fluoromethyl carbothioate function to form the inactive 17beta-carboxylic acid metabolite. Elimination Fluticasone furoate and its metabolites are eliminated primarily in the faeces, accounting for approximately 101% and 90% of the orally and intravenously administered dose, respectively. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively. The elimination phase half-life averaged 15.1 hours following intravenous administration. Special Populations Hepatic impairment Since fluticasone furoate undergoes extensive first-pass metabolism by the hepatic cytochrome P450 isozyme, CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. The systemic exposure would be expected to be higher than that observed had the study been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use fluticasone furoate nasal spray with caution in patients with severe hepatic impairment. Renal Impairment Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of doserelated material is excreted in the urine. No dosage adjustment is required in patients with renal impairment. Indications FURAMIST AZ nasal spray is indicated for the management of symptoms of allergic rhinitis, once the need for an antihistamine and corticosteroid has been established. It is recommended for the treatment of persistent, moderate to severe symptoms in adults and adolescents above 12 years of age. Dosage And Administration FURAMIST AZ nasal spray should be administered by the intranasal route only. Adults and Adolescents (12 years of age and older) One spray per nostril twice daily. The recommended dosage should not be exceeded. Contraindications FURAMIST AZ nasal spray is contraindicated in patients with known hypersensitivity to azelastine hydrochloride or

4 fluticasone furoate or any of the components of this preparation. Warnings And Precautions General Concurrent use of this drug combination with alcohol or other central nervous system (CNS) depressants or other antihistamines should be avoided as additional reductions in alertness and additional impairment of CNS performance may occur due to azelastine hydrochloride. In clinical trials, the occurrence of somnolence has been reported in some patients taking intranasal azelastine hydrochloride. 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 this drug combination. 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 fluticasone furoate nasal spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy. The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. Some patients may experience symptoms of withdrawal, e.g., joint and/or muscular pain, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms. The concomitant use of an intranasal corticosteroid with other corticosteroids could increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis. Therefore, such a combination should be used cautiously in patients with other pathological conditions requiring steroids. Intranasal corticosteroids may cause a reduction in growth velocity when administered to paediatric patients. The recommended dosage of FURAMIST AZ nasal spray should not be exceeded. To minimize the systemic effects of intranasal corticosteroids, including fluticasone furoate nasal spray, titrate each patient s dose to the lowest dosage that effectively controls his/her symptoms. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections. Persons who are on immunosuppressant drugs are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can take a more serious or even a fatal course in children or adults on immunosuppressant corticosteroids. In children or adults who have not had these diseases or have not been properly immunized, 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 a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox or measles develops, treatment with antiviral agents may be considered. During long-term therapy, monitoring of haematological and adrenal functions is advisable. In clinical studies with intranasal fluticasone furoate, the development of localized infections of the nose and the

5 pharynx, caused by Candida albicans, has been seen infrequently. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of treatment with Furamist AZ is advised. In clinical studies of 2 52 weeks duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with fluticasone furoate nasal spray than those who received placebo. Instances of nasal septal perforation have been reported in patients following the intranasal application of corticosteroids. There were no instances of nasal septal perforation observed in clinical studies with fluticasone furoate nasal spray. Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use fluticasone furoate nasal spray until healing has occurred. 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, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of FURAMIST AZ Nasal Spray. Discontinue FURAMIST AZ Nasal Spray if such reactions occur. Drug Interactions The use of FURAMIST AZ nasal spray in patients taking concurrent drugs that are potent inhibitors of the cytochrome P450 3A4 (CYP450) system, such as ketoconazole and protease inhibitors such as ritonavir, may be associated with increased systemic exposure of fluticasone furoate. Therefore, caution is required with the co-administration of fluticasone furoate nasal spray and ketoconazole or other potent CYP3A4 inhibitors. Co-administration of fluticasone furoate nasal spray with the potent CYP3A4 inhibitor, ritonavir, is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. High exposure to corticosteroids increases the potential for systemic side effects, such as cortisol suppression. Enzyme induction and inhibition data suggest that fluticasone furoate is unlikely to significantly alter the cytochrome P450-mediated metabolism of other compounds at clinically relevant intranasal dosages. 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 effectson QTc were observed. Cimetidine (400 mg twice daily) increased the mean Cmax and AUC of orally administered azelastine hydrochloride (4 mg twice daily) by approximately 65%. Hepatic Impairment Reduced liver function may affect the elimination of corticosteroids. Since fluticasone furoate undergoes extensive firstpass metabolism by the hepatic cytochrome P450 isozyme, CYP3A4, the pharmacokinetics of fluticasone furoate may be altered in patients with hepatic impairment. The systemic exposure would be expected to be higher than that observed had the study been conducted after multiple doses and/or in patients with severe hepatic impairment. Therefore, use fluticasone furoate nasal spray with caution in patients with severe hepatic impairment. Renal Impairment Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of doserelated material is excreted in the urine. No dosage adjustment is required in patients with renal impairment.

6 Pregnancy There are no adequate and well-controlled studies in pregnant women. This combination should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Azelastine hydrochloride has been shown to cause developmental toxicity in mice, rats, and rabbits. Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored. Lactation It is not known whether azelastine hydrochloride or fluticasone furoate is excreted in human milk. Hence, caution should be exercised while prescribing this combination to nursing mothers. Pediatric Use The safety and effectiveness of this combination in children below 12 years of age have not been established. Geriatric Use Clinical studies of fluticasone furoate and azelastine hydrochloride nasal spray did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Undesirable Effects Fluticasone furoate Clinical Trials Adults and Adolescents 12 Years of Age and Older The most common adverse events (>1% incidence) reported with fluticasone furoate use are: Headache, epistaxis, pharyngolaryngeal pain, nasal ulceration, back pain, pyrexia, and cough. The most common adverse events (>3% incidence) with fluticasone furoate in paediatric patients 2 to 11 years of age reported in clinical trials are: headache, nasopharyngitis, epistaxis, pyrexia, pharyngolaryngeal pain and cough. There were no differences in the incidence of adverse reactions based on gender or race. Pyrexia occurred more frequently in children 2 to <6 years of age compared with children 6 to <12 years. In a long term (52-week) safety trial, epistaxis occurred more frequently in patients who received fluticasone furoate nasal spray than in patients who received placebo. Epitaxis tended to be more severe in patients treated with fluticasone furoate nasal spray. Systemic and local corticosteroid use may result in the following: Epistaxis, ulcerations, Candida albicans infection, impaired wound healing, and nasal septal perforation Cataracts and glaucoma Immunosuppression Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of fluticasone furoate nasal spray. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone furoate or a combination of these factors.

7 Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Respiratory, Thoracic, and Mediastinal Disorders Rhinalgia, nasal discomfort (including nasal burning, nasal irritation, and nasal soreness), nasal dryness, and nasal septal perforation, Epistaxis, nasal ulceration. Nervous system disorders Headache Eye disorders Transient ocular changes Musculoskeletal and connective tissue disorders (Children) Growth retardation Azelastine Hydrochloride In placebo-controlled 2-week clinical trials with adults and adolescents 12 years of age and older having seasonal allergic rhinitis treated with azelastine hydrochloride nasal spray the common adverse events ( 2% incidence) were: Bitter taste, epistaxis, headache, nasal discomfort, fatigue, and somnolence. In long term (12 month) safety trials with azelastine hydrochloride nasal spray in adults and adolescents the most frequently reported adverse events were: headache, bitter taste, epistaxis, and nasopharyngitis, nasal mucosal ulceration. Twenty-two patients (5%) treated with azelastine hydrochloride nasal spray (137mcg) discontinued from the trial due to adverse events. During the post approval use of azelastine nasal spray, the following adverse reactions have been identified: Abdominal pain, nasal burning, nausea, sweet taste, and throat irritation. 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. Additionally, the following adverse reactions have been identified during the post approval use of the original azelastine hydrochloride 0.1% nasal spray (total daily dose 0.55 mg to 1.1 mg). 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. Adverse reactions reported include the following: anaphylactoid reaction, application site irritation, atrial fibrillation, increased heart rate, blurred vision, chest pain, anxiety, 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. Overdosage Azelastine Hydrochloride 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 hydrochloride nasal spray. Oral ingestion of antihistamines has the potential to cause serious adverse effects in children. Accordingly, this nasal spray should be kept out of the reach of children. The results of animal studies show that toxic doses can produce CNS symptoms, e.g., excitation, tremor, and convulsions. Should these occur in humans, symptomatic and supportive treatment should be initiated, as there is no specific antidote. Gastric lavage is recommended if the overdose is recent.

8 With the nasal route of administration, overdosage reactions are not anticipated. Fluticasone furoate There are no data on the effects of acute or chronic overdosage with fluticasone furoate nasal spray. 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 up to 2,640 mcg/day (24 times the recommended adult dose) of fluticasone furoate was administered to healthy human volunteers for 3 days. Single- and repeat-dose studies with orally inhaled fluticasone furoate doses of 50 4,000 mcg have shown decreased mean serum cortisol at doses of 500 mcg or higher. Chronic overdosage with any corticosteroid may result in signs or symptoms of hypercorticism. Packaging Information FURAMIST AZ Nasal Spray: Each sales pack contains 70 metered doses Last Updated: Dec 2015 Last Reviewed: Dec 2015 FURAMIST AZ Nasal Spray Source URL: