SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 7 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 13 OVERDOSAGE 14 ACTION AND CLINICAL PHARMACOLOGY 14 STORAGE AND STABILITY 17 DOSAGE FORMS, COMPOSITION AND PACKAGING 17
PHARMACEUTICAL INFORMATION 18 CLINICAL TRIALS 19 DETAILED PHARMACOLOGY 33 TOXICOLOGY 34 REFERENCES 36
(tm)
fluticasone furoate nasal spray
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intranasal | Nasal Spray / 27.5 mcg | 0.015% w/w benzalkonium chloride For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING. |
AVAMYSTM (fluticasone furoate nasal spray) is indicated for: treatment of seasonal and perennial allergic rhinitis and its associated symptoms in patients 12 years of age and older
Pediatrics (2 years to < 12 years of age)
treatment of seasonal allergic rhinitis.
AVAMYSTM (fluticasone furoate nasal spray) is contraindicated in patients with a hypersensitivity to any of its ingredients. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
Systemic and/or local corticosteroid use has been associated with the following risks:
General
In patients previously on systemic steroids, either over prolonged periods or in high doses, the replacement with a topical corticosteroid can be accompanied by symptoms of withdrawal e.g. joint and/or muscular pain, lassitude and depression and, in severe cases, adrenal insufficiency may occur, necessitating the temporary resumption of systemic steroid therapy.
Ear/Nose/Throat
In clinical studies of 2 to 52 weeks' duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) than those who received placebo. These observations were more prevalent in a longer duration chronic use study (52 weeks in adults and adolescents) conducted in a perennial allergic rhinitis population and therefore may not be indicative of event rates incurred with short-term intermittent use. (see ADVERSE REACTIONS). In pediatric studies of up to 12 weeks' duration, epistaxis events occurred at a similar rate between the active and placebo groups (see ADVERSE REACTIONS). Candida albicans infection: Evidence of localized infections of the nose with Candida albicans was seen on nasal exams in 7 of 2,745 patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) during clinical trials and was reported as an adverse event in 3 patients. When such an infection develops, it may require treatment with appropriate local therapy and discontinuation of AVAMYS(tm) (fluticasone furoate nasal spray). Therefore, patients using AVAMYS(tm) (fluticasone furoate nasal spray) over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa. Impaired wound healing: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with recent nasal ulcers, nasal surgery, or nasal trauma, because of the inhibitory effect of corticosteroids on wound healing.
Endocrine and Metabolism
There is no evidence of HPA axis suppression following prolonged (12 months) treatment with AVAMYS(tm) (fluticasone furoate nasal spray). When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects may occur such as hypercorticism, suppression of HPA function, and/or reduction of growth velocity in children or teenagers. The results of a controlled, 2-week, cross-over study in children aged 6 to years with allergic rhinitis demonstrated that knemometric assessment of short-term lower-leg growth was similar after treatment with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg once daily compared with placebo. A phase IV clinical trial (one year linear growth study) is being carried out to evaluate the effect of AVAMYS(tm) (fluticasone furoate nasal spray) on long-term growth in pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids, by any route, and weigh the benefits of corticosteroid therapy against the possibility of growth suppression if growth appears slowed. If such changes occur, the dosage of all corticosteroids, including AVAMYS(tm) (fluticasone furoate nasal spray) should be discontinued slowly (see also ACTION AND CLINICAL PHARMACOLOGY; Pharmacodynamics).
Hepatic/Biliary/Pancreatic
Fluticasone furoate undergoes extensive first-pass metabolism by the liver enzyme CYP3A4, therefore the pharmacokinetics of AVAMYS(tm) (fluticasone furoate nasal spray) in patients with severe liver disease may be altered (see ACTION AND CLINICAL PHARMACOLOGY; Special Populations and Conditions). Based on data with another glucocorticoid metabolized by CYP3A4, co-administration with ritonavir is not recommended because of the risk of systemic effects secondary to increased exposure to fluticasone furoate. However, a study confirming the effects of ritonavir co-administration with AVAMYSTM (fluticasone furoate nasal spray) has not been conducted (see DRUG INTERACTIONS).
Immune
Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex may occur. Corticosteroids may mask some signs of infection and new infections may appear. A decreased resistance to localized infections has been observed during corticosteroid therapy; this may require treatment with appropriate therapy or stopping the administration of AVAMYS(tm) (fluticasone furoate) nasal spray. Patients who are on drugs that 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 globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
Ophthalmologic
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. Glaucoma and cataract formation was evaluated with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month study in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week study in 558 pediatric patients aged 2 to 11 years. The patients had perennial allergic rhinitis and were treated with either AVAMYS(tm) (fluticasone furoate nasal spray) (110 mcg once daily in adult and adolescent patients and 55 mcg or 110 mcg once daily in pediatric patients) or placebo. Intraocular pressure remained within the sponsor-defined threshold (< 21 mmHg) in >= 98% of the patients in both studies (see also ADVERSE REACTIONS, Ophthalmologic Safety). In the 52 week adult and adolescent study (FFR102123) intraocular pressure measurements increased above the sponsor-defined threshold (>= 21 mmHg) in < 2% of patients. These increases were not persistent or sustained at more than one timepoint. In the adult/adolescent study, 6 (1%) patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg once daily and 1 (0.5%) patient treated with placebo had cataracts identified during the study that were not present at baseline (note: subjects were randomized in a 3:1 ratio for fluticasone furoate nasal spray versus placebo). In the week pediatric study (FFR30008), intraocular pressure measurements increased above the sponsor-defined threshold (>= 21 mmHg) in < 2% of patients. One (< 1%) patient in the fluticasone furoate group reported a cataract at week 12 in both eyes that was not present at baseline. No visual disturbances or glaucoma was detected in either study (see also ADVERSE REACTIONS, Ophthalmologic Safety).
Special Populations
Pregnant Women: There are no adequate and well controlled studies in pregnant women. AVAMYSTM (fluticasone furoate nasal spray) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see TOXICOLOGY; Teratogenicity).
It is not known whether fluticasone furoate is excreted in human breast milk. However, other corticosteroids have been detected in human milk. Since there are no data from controlled trials on the use of AVAMYS(tm) (fluticasone furoate nasal spray) by nursing mothers, caution should be exercised when AVAMYS(tm) (fluticasone furoate nasal spray) is administered to a nursing woman. The use of fluticasone furoate in nursing mothers requires that the possible benefits of the drug be weighed against the potential hazards to the infant.
: The safety and effectiveness of AVAMYS(tm) (fluticasone furoate nasal spray) in children below 2 years of age have not been evaluated.
: A total of 344 subjects aged 12 to 17 years were randomized in clinical trials, with 198 of these subjects treated with AVAMYS(tm) (fluticasone furoate nasal spray). The proportion of subjects 12 - 17 years of age reporting adverse events in these clinical trials was generally lower than in the adult population (18 to < 65 year age group). In addition, other clinical trials of AVAMYS(tm) (fluticasone furoate nasal spray) have been conducted in 1,224 patients aged 2 to 11 years treated with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg or 55 mcg. Overall adverse events for subjects in this age group were reported with approximately the same frequency in patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) versus placebo (see ADVERSE REACTIONS).
: Clinical studies of AVAMYS(tm) (fluticasone furoate nasal spray) did not include sufficient numbers of subjects aged 65 and over 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Adverse Drug Reaction Overview
In general, in adults, adolescents and children, adverse reactions to AVAMYS(tm) (fluticasone furoate nasal spray) were similar to those seen with other intranasal corticosteroids and were primarily associated with irritation of the nasal mucous membranes. Overall adverse events were reported with approximately the same frequency by patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) and those receiving placebo. Less than 3% of patients in clinical trials discontinued treatment because of adverse events.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Systemic and local corticosteroid use may result in the following:
Epistaxis, ulcerations, Candida albicans infection, impaired wound healing [see WARNINGS AND PRECAUTIONS]
Cataracts and glaucoma [see WARNINGS AND PRECAUTIONS]
Immunosuppression [see WARNINGS AND PRECAUTIONS]
Hypothalamic-pituitary-adrenal (HPA) axis effects, including growth reduction [see WARNINGS AND PRECAUTIONS; Endocrine and Metabolism]
Adults and Adolescents (12 years of age and older)
The data described below reflect exposure to AVAMYS(tm) (fluticasone furoate nasal spray) in 768 adult and adolescent patients (473 females and 295 males aged 12 years and older) with seasonal or perennial allergic rhinitis in 6 controlled clinical trials. Patients were treated with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg once daily for 2 to 6 weeks. The rate of withdrawal among patients receiving AVAMYS(tm) (fluticasone furoate nasal spray) in these clinical trials was similar or lower than the rate among patients receiving placebo. Table 1 displays the common adverse events (>= 1%) that occurred in patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) compared with placebo treated patients. These represent the absolute number of reported adverse events, regardless of whether or not a causal association was established.
Table 1 Summary of adverse events with an incidence >= 1% during treatment (ITT population - studies FFR20001/ FFR20002/ FFR 30002/ FFR30003/ FFR103184/ FFR104861)
| Number of subjects (%) | ||
| Adverse Event | Placebo N=774 | FF 110 mcg QD N=768 |
| Any Event | 209 (27) | 225 (29) |
| Headache | 50 (6) | 64 (8) |
| Epistaxis | 32 (4) | 45 (6) |
| Pharyngolaryngeal pain | 8 (1) | 15 (2) |
| Nasal septum ulceration | 2 (<1) | 9 (1) |
| Nasopharyngitis | 11 (1) | 9 (1) |
| Back pain | 7 (<1) | 9 (1) |
In 1 controlled clinical trial, 605 patients (307 females and 298 males aged 12 years and older) were treated with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg once daily for 12 months. Adverse events were similar in type and rate between the treatment groups. However, epistaxis occurred more frequently in the group receiving AVAMYS(tm) (fluticasone furoate nasal spray) (123/605, 20%) than in the placebo group (17/201, 8%). The episodes of epistaxis were of mild intensity in the majority of patients (83/123 in the group receiving AVAMYS(tm) (fluticasone furoate nasal spray) and 17/17 in the placebo group). The episodes were of moderate intensity in 39 patients and of severe intensity in 1 patient receiving AVAMYS(tm) (fluticasone furoate nasal spray). This was a longer duration chronic use study conducted in a perennial allergic rhinitis population and therefore may not be indicative of event rates with short-term, intermittent use. Systemic corticosteroid side effects were not reported during this clinical study.
Less Common Clinical Trial Adverse Events (< 1%)
Table 2 displays the less common adverse events (<1%) that occurred in patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) compared with placebo treated patients. All incidences are included. These represent the absolute number of reported adverse events, regardless of whether or not a causal association was established.
Table 2 Summary of less common adverse events with an incidence <1% during treatment (ITT population-studies FFR20001/FFR20002/FFR30002/FFR30003/FFR103184/FFR104861)
| Body System | Less Common Adverse Events | Number of subjects (%) | |
| Placebo N=774 | FF 110 mcg QD N=768 | ||
| Nervous System | dizziness | 5 (<1%) | 5 (<1%) |
| Disorders | migraine | 3 (<1%) | 2 (<1%) |
| tremor | 0 | 1 (<1%) | |
| psychomotor | 0 | 1 (<1%) | |
| hyperactivity | |||
| Respiratory, Thoracic | cough | 4 (<1%) | 5 (<1%) |
| and Mediastinal | dry throat | 2 (<1%) | 5 (<1%) |
| Disorder | nasal discomfort | 3 (<1%) | 3 (<1%) |
| dysphonia | 1 (<1%) | 1 (<1%) | |
| dyspnoea | 2 (<1%) | 1 (<1%) | |
| sinus congestion | 0 | 1 (<1%) | |
| throat irritation | 0 | 1 (<1%) | |
| Infection | herpes simplex | 4 (<1%) | 2 (<1%) |
| upper respiratory | 7 (<1%) | 5 (<1%) | |
| infection | |||
| vaginal candidiasis | 0 | 1 (<1%) | |
| Metabolic | aspartate | 1 (<1%) | 2 (<1%) |
| aminotransferase | |||
| increased | |||
| alanine aminotransferase | 1 (<1%) | 1 (<1%) | |
| increased | |||
| blood pressure increased | 1 (<1%) | 2 (<1%) | |
| blood glucose increased | 4 (<1%) | 3 (<1%) | |
| Cardiovascular | palpitations | 0 | 2 (<1%) |
| atrioventricular block | 0 | 1 (<1%) | |
| second degree | |||
Pediatrics (2 to < 12 years of age)
The data from pediatric patients are based upon 3 clinical trials in which 795 children with seasonal or perennial rhinitis (352 females and 443 males 2 to < 12 years of age) were treated with AVAMYS(tm) (fluticasone furoate nasal spray) 55 or 110 mcg once daily for 2 to 12 weeks. Table 3 displays the common adverse events (>= 1%) that occurred in patients treated with AVAMYS(tm) (fluticasone furoate nasal spray) compared with placebo treated patients. These represent the absolute number of reported adverse events, regardless of whether or not a causal association was established. In children, the adverse event profile was similar to that seen for the adults and adolescents.
Table 3 Adverse Events With >= 1% Incidence in Controlled Clinical Trials of 2 to 12 Weeks' Duration With AVAMYS(tm) in Pediatric Patients 2 to < 12 Years of Age With Seasonal or Perennial Allergic Rhinitis - Studies FFR100010, FFR30008, FFR100012
| Number (%) of Subjects | |||
| Adverse Event | Placebo (n= 429) | FF 55 mcg QD (n= 369) | FF 110 mcg QD (n= 426) |
| Any Event | 157 (37) | 158 (43) | 174 (41) |
| Headache | 30 (7) | 28 (8) | 32 (8) |
| Nasopharyngitis | 21 (5) | 20 (5) | 21 (5) |
| Epistaxis | 19 (4) | 17 (5) | 17 (4) |
| Pyrexia | 7 (2) | 17 (5) | 19 (4) |
| Pharyngolaryngeal pain | 14 (3) | 16 (4) | 12 (3) |
| Cough | 12 (3) | 12 (3) | 16 (4) |
| Bronchitis | 11 (3) | 11 (3) | 8 (2) |
Less Common Clinical Trial Adverse Drug Events (< 1%)
One of the less common clinical trial adverse events was nasal ulceration which occurred at a lower frequency in pediatric patients (2 to < 12 years of age) than in adult and adolescent patients. Drug-related nasal ulceration was reported in 1 patient receiving placebo (< 1%), 1 patient receiving 55 mcg AVAMYS (fluticasone furoate nasal spray) (< 1%) and 4 patients receiving 110 mcg AVAMYS (fluticasone furoate nasal spray) (< 1%) once daily. Another less common adverse event was increased intraocular pressure. Drug-related increased intraocular pressure was reported in 1 patient receiving placebo (< 1%), 2 patients receiving 55 mcg AVAMYS (tm) (fluticasone furoate nasal spray) once daily (< 1%) and 1 patient receiving 110 mcg AVAMYS(tm) (fluticasone furoate nasal spray) once daily (< 1%). One patient treated with 55 mcg AVAMYS (fluticasone furoate nasal spray) reported a cataract in both eyes at Week 12 that were not detected at baseline and was considered a drug-related adverse event (see also ADVERSE REACTIONS, Ophthalmologic Safety).
Ophthalmologic Safety
Glaucoma and cataract formation was evaluated in 1 controlled 12-month study in 806 adolescent and adult patients aged 12 years and older, and in 1 controlled 12-week study in 558 pediatric patients aged 2 to 11 years. Both studies were in the perennial allergic rhinitis patient population. Patients in the adult/adolescent study were randomized in a 3:1 ratio to treatment with either fluticasone furoate 110 mcg (n = 605) or placebo (n = 201), once daily. Ophthalmic evaluations were performed at Baseline and Weeks 12, 24 and 52. Intraocular pressure (IOP) remained within the sponsor-defined threshold (< 21 mmHg) in >= 98% of the patients. Nine patients, 5 in the fluticasone furoate group (< 1%) and 4 in the placebo group (2%), had IOP measurements >= 21 mmHg at baseline. Of these 5 patients in the fluticasone furoate group, 1 patient had no further IOP measurements, 1 patient had an IOP of 22 mmHg at a subsequent visit but values were lower than at baseline, and the remaining 3 patients had IOP measurements < 21 mmHg at all subsequent treatment assessments. During the study twelve patients in the fluticasone furoate group had IOP measurements that increased above the sponsor-defined threshold (>= 21 mmHg). However, no patient had an IOP > 21 mmHg at more than one treatment assessment. Therefore, these changes in IOP measurements would not be considered persistent/sustained at more than one timepoint during the study. In addition, funduscopic cup to disc percentage values remained below the sponsor-defined threshold (66%) in all of these patients at all assessments and no cataracts were reported for them. No visual disturbances or glaucoma were seen in the study. Further, 7 patients [6 (1%) in the fluticasone furoate group and 1 (0.5%) in the placebo group] had cataracts identified during the study that were not present at baseline. Posterior subcapsular cataracts were reported as adverse events in 2 patients (0.33%) receiving fluticasone furoate and 1 patient (0.5 %) receiving placebo. However, upon post-study evaluation in a patient in the fluticasone furoate group, the posterior subcapsular cataract was no longer detected. Patients in the pediatric study were randomized to treatment with either fluticasone furoate 110 mcg (n=185), fluticasone furoate 55 mcg (n=185) or placebo (n=188) once daily for 12 weeks. Ophthalmic evaluations were performed at baseline and Week 12. Intraocular pressure (IOP) remained within the sponsor-defined threshold (< 21 mmHg) in >= 98% of the patients. Two patients [1 in the fluticasone furoate 55 mcg group (< 1%) and 1 in the fluticasone furoate 110 mcg group (< 1%)] had IOP measurements >= 21 mmHg at baseline. However, these IOP measurements had decreased to below < 21 mmHg at Week 12. Four adverse events of increased intraocular pressure were considered drug-related (see Pediatrics, Less Common Clinical Trial Adverse Drug Events). However, funduscopic cup to disc percentage values remained below the sponsor-defined threshold (66%) in all of these subjects at all assessments and none of these patients reported a cataract. In the same study, 4 patients in the fluticasone furoate 55 mcg group (2%) reported a cataract in at least one eye compared with 2 patients in the placebo group (1%). However, these were not considered as drug related adverse events. One patient in fluticasone furoate 55 mcg reported a cataract in both eyes at Week 12 that were not detected at baseline and was considered as a drug-related adverse event. No patient in the 110 mcg fluticasone furoate group reported a cataract. No visual disturbances or glaucoma were seen in the study.
Overview
Fluticasone furoate is cleared by extensive first-pass metabolism mediated by the cytochrome P450 isozyme CYP3A4. In a drug interaction study of intranasal fluticasone furoate and the CYP3A4 inhibitor ketoconazole given as a 200-mg once-daily dose for 7 days, 6 of 20 subjects receiving fluticasone furoate and ketoconazole had measurable but low levels of fluticasone furoate compared with 1 of 20 receiving fluticasone furoate and placebo. Based on this study and the low systemic exposure, there was a 5% reduction in 24-hour serum cortisol levels with ketoconazole compared to placebo. The data from this study should be carefully interpreted because the study was conducted with ketoconazole 200 mg once daily rather than 400 mg, which is the maximum recommended dosage. Therefore, caution is required with the co-administration of AVAMYS(tm) (fluticasone furoate nasal spray) and ketoconazole or other potent CYP3A4 inhibitors. Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, co-administration of AVAMYS(tm) (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.
Drug-Drug Interactions
Table 4 Established or Potential Drug-Drug Interactions
| Proper name | Ref | Effect | Clinical comment |
| Ritonavir | CS | Systemic effects including Cushing's syndrome and adrenal suppression. | Concomitant use of fluticasone furoate and ritonavir should be avoided. (See DRUG INTERACTIONS; Overview) |
| Other inhibitors of cytochrome P450 3A4 | CT | Potential increased systemic exposure to fluticasone furoate. | Care is advised when co-administering potent cytochrome P450 3A4 inhibitors. (See DRUG INTERACTIONS; Overview) |
CS - Class Statement
CT - Clinical Trial
Dosing Considerations
For full therapeutic benefit, regular scheduled usage is recommended. Onset of action has been observed as early as 8 hours after initial administration in SAR and as early as 24 hours after initial administration in PAR. It may take several days of treatment to achieve maximum benefit. An absence of an immediate effect should be explained to the patient. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.
Recommended Dose and Dosage Adjustment
The recommended dosage is two sprays (27.5 mcg of fluticasone furoate per spray) in each nostril once daily (total daily dose, 110 mcg).
The recommended dosage for pediatric patients (2 to < 12 years old) with season allergic rhinitis (SAR) is two sprays (27.5 mcg of fluticasone furoate per spray) in each nostril once daily (total daily dose, 110 mcg). If adequate control of symptoms is achieved, dose reduction to one spray in each nostril (total daily dose, 55 mcg) may be an effective maintenance dose in certain patients.
Missed Dose
If a single dose is missed, instruct the patient to take the next dose when it is due. Do not instruct the patient to take an extra dose.
Administration
AVAMYS(tm) (fluticasone furoate nasal spray) should be administered only by the intranasal route. It is necessary to prime the pump with 6 actuations before first use or after 30 days of non-use or if the cap has been left off for more than 5 days. AVAMYS(tm) (fluticasone furoate nasal spray) may be administered at any time of day. Illustrated instructions for proper use appear in PART III: CONSUMER INFORMATION.
Chronic overdosage may result in signs/symptoms of hypercorticism (see WARNINGS AND PRECAUTIONS; Endocrine and Metabolism). There are no data on the effects of acute or chronic overdosage with AVAMYS(tm) (fluticasone furoate nasal spray). Because of low systemic bioavailability and an absence of acute drug related systemic findings in clinical studies (with dosages of up to 440 mcg/day for 2 weeks [4 times the maximum recommended daily dose]), 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 AVAMYS(tm) (fluticasone furoate nasal spray) to healthy human volunteers for 3 days was well tolerated. The oral median lethal dose in mice and rats was > 2,000 mg/kg compared with the maximum recommended clinical dose of 2.2 mcg/kg based on a 50 kg bodyweight. Acute overdosage with the intranasal dosage form is unlikely since 1 bottle of AVAMYS(tm) (fluticasone furoate nasal spray) contains approximately 3 mg of fluticasone furoate, and the bioavailability of fluticasone furoate is < 1% for 2.6 mg/day given intranasally and 1.26% for a single 2-mg dose 2 mg/day given as an oral solution. For management of a suspected drug overdose, contact your regional Poison Control Centre.
Mechanism of Action
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 to have a wide range of actions 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. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in rhinitis. Specific effects of fluticasone furoate demonstrated in in vitro and in vivo models included activation of the glucocorticoid response element and inhibition of pro inflammatory transcription factors such as NFkB, potent protection of respiratory cells against physical and chemical damage and inhibition of antigen induced lung eosinophilia in sensitized rats. Human glucocorticoid receptor binding studies demonstrated that fluticasone furoate binds with significantly greater affinity than fluticasone propionate and other intranasal corticosteroids. 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. In addition, it has been shown that fluticasone furoate binds more avidly to respiratory tissue than other corticosteroids. The clinical significance of these findings is unknown. AVAMYS(tm) (fluticasone furoate nasal spray), like other corticosteroids, does not have an immediate effect on rhinitis symptoms. Onset of action has been observed as early as 8 hours after initial administration in SAR and as early as 24 hours after initial administration in PAR. It may take several days of treatment to achieve maximum benefit. An absence of an immediate effect should be explained to the patient. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.
Pharmacodynamics
The effects of AVAMYS(tm) (fluticasone furoate nasal spray) on adrenal function have been evaluated in 2 controlled clinical trials with domiciled visits at the beginning and end of treatment. The first study was a randomized, double blind, parallel group clinical trial conducted in adult and adolescent patients aged 12 years and older with perennial allergic rhinitis. Patients were treated once daily with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg (n = 48), prednisone 10 mg (n = 13), or placebo (n = 51) for 6 weeks. The 24 hour serum cortisol weighted mean was similar after treatment with AVAMYS(tm) (fluticasone furoate nasal spray) compared with placebo (AVAMYS(tm) (fluticasone furoate nasal spray):placebo ratio 0.98 [95% CI 0.89, 1.07]). In contrast, the 24 hour serum cortisol weighted mean was reduced by treatment with prednisone (prednisone:placebo ratio 0.49 [95% CI 0.43, 0.57]). The second study was of a similar design, but with no prednisone comparison, in pediatric patients aged 2 to 11 years with perennial allergic rhinitis. Patients were treated once daily with AVAMYS(tm) (fluticasone furoate nasal spray) 110 mcg (n = 57) or placebo (n = 55) for 6 weeks. The 24 hour serum cortisol weighted mean was similar for the 2 treatment groups (AVAMYS(tm) (fluticasone furoate nasal spray): placebo ratio 0.97 [95% CI 0.88, 1.07]). Both studies also assessed 24-hour urinary cortisol excretion during the domiciled visits. There were no differences between the groups receiving AVAMYS(tm) (fluticasone furoate nasal spray) or placebo in 24-hour urinary cortisol. No evidence of a decrease in 24 hour urinary free cortisol excretion was observed in 2 placebo-controlled non domiciled (outpatient) clinical studies that included a 12 week study in patients 2 to 11 years and a 1 year study in patients 12 years and older.
Pharmacokinetics
The activity of AVAMYS(tm) (fluticasone furoate nasal spray) is due to the parent drug, fluticasone furoate. 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 dose of 110 mcg once daily for up to 12 months in adults, 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.
The absolute bioavailability was evaluated in 16 male and female subjects following supratherapeutic dosages of fluticasone furoate (880 mcg given intranasally at 8-hour intervals for 10 doses, or 2,640 mcg/day). The average absolute bioavailability was 0.50% (90% CI 0.34%, 0.74%).
The plasma protein binding of fluticasone furoate is greater than 99%. Fluticasone furoate is widely distributed with volume of distribution at steady-state of, on average, 608 L.
studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone. Fluticasone furoate is rapidly 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 17b-carboxylic acid metabolite.
Elimination was primarily via the fecal route following oral and intravenous administration indicative of excretion of fluticasone furoate and its metabolites via the bile. Following intravenous administration, the elimination phase
half-life averaged 15.1 hours. Urinary excretion accounted for approximately 1% and 2% of the orally and intravenously administered dose, respectively.
Special Populations and Conditions
Reduced liver function may affect the elimination of corticosteroids. 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. A study of a single 400-mcg dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh Class B) resulted in increased Cmax (42%) and AUC(0-4) (172%), resulting in an approximately 20% reduction in serum cortisol level in patients with hepatic impairment compared to healthy subjects. 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 AVAMYS(tm) (fluticasone furoate
nasal spray) with caution in patients with severe hepatic impairment. No dosage adjustment is needed for patients with mild or moderate hepatic impairment.
Fluticasone furoate is not detectable in urine from healthy subjects following intranasal dosing. Less than 1% of dose-related material is excreted in urine. No dosage adjustment is required in patients with renal impairment.
A placebo-controlled clinical study was carried out in 382 patients with seasonal allergic rhinitis, of which 80% were African American, to
determine the onset of action of fluticasone furoate using an allergen challenge chamber (ACC). Patients with a confirmed diagnosis of ragweed allergy were exposed to controlled pollen concentration in an Allergen Challenge Chamber (ACC) and then treated with a single dose of either fluticasone furoate 110 mcg aqueous nasal spray or vehicle placebo nasal spray following which the iTNSS was determined hourly for 12 hours. A statistically significant difference versus placebo was not shown during the entire 12-hour study duration; therefore no efficacy was demonstrated with fluticasone furoate by which an onset of action could be determined based on the results of this study.
Store the device between 4degC and 30degC, in the upright position with the cap in place. Do not refrigerate or freeze.
AVAMYS(tm) (fluticasone furoate nasal spray), 27.5 mcg is supplied in an amber glass bottle enclosed in a nasal device with a small, short nozzle and a side-actuated mist- release button to actuate the spray. Each bottle contains a net fill weight of 4.5 g, 6.5 g or 10 g and will provide 30, 60 or 120 metered sprays, respectively, after the initial priming. Each spray delivers a fine mist containing 27.5 mcg of fluticasone furoate in 50 mcL of formulation through the nozzle. The contents of the bottle can be viewed through an indicator window. The nasal device should be discarded after the labelled amount of sprays has been used. Beyond this, the correct amount of medication in each spray cannot be assured, even though the bottle is not completely empty. AVAMYS(tm) (fluticasone furoate nasal spray) is an unscented, taste free, alcohol free, preserved aqueous suspension of micronized fluticasone furoate for topical administration to the nasal mucosa by means of a metering (50 mcL), atomizing spray pump. AVAMYS(tm) (fluticasone furoate nasal spray) also contains 0.015% w/w benzalkonium chloride, dextrose anhydrous, edetate disodium, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, and purified water.