AVAMYS Fluticasone Furoate 27.5mg / act. Suspension for Nasal Spray 30act.

Symptoms and Signs: In a bioavailability study, intranasal doses of up to 24 times the recommended daily adult dose were studied over three days with no adverse systemic effects observed. (See Pharmacology: Pharmacokinetics under Actions.)
Treatment: Acute overdose is unlikely to require any therapy other than observation.

Adequate data are not available regarding the use of Fluticasone furoate (Avamys) Nasal Spray during pregnancy and lactation in humans. Fluticasone furoate (Avamys) Nasal Spray should be used in pregnancy only if the benefits to the mother outweigh the potential risks to the foetus.
Fertility: There are no data in humans. (See Pharmacology: Toxicology: Pre-Clinical Safety Data: Reproductive Toxicology under Actions).
Pregnancy: Following intranasal administration of Fluticasone furoate (Avamys) Nasal Spray at the maximum recommended human dose (110 micrograms/day), plasma fluticasone furoate concentrations were typically non-quantifiable and therefore potential for reproductive toxicity is expected to be very low. (See Pharmacology: Toxicology: Pre-Clinical Safety Data: Reproductive Toxicology under Actions.)
Lactation: The excretion of fluticasone furoate into human breast milk has not been investigated.

Instructions for Use/Handling: Patients should be instructed that the device must be primed before first use and re-primed if the cap is left off or the device does not seem to be working. In order to prime the device, the nasal spray needs to be shaken vigorously for about 10 seconds with the cap on. This is important as Fluticasone furoate (Avamys) Nasal Spray is a thick suspension that becomes liquid when vigorously shaken. It will only spray when it becomes liquid. The patient must then press the button firmly all the way in, approximately 6 times until a fine mist is seen (to ensure a full-dose is delivered). Once primed, the patient must shake the nasal spray vigorously each time before use. The cap must be replaced after use to keep the nozzle clean and to prevent the need for re-priming.
This section includes the following information: The nasal spray; 6 important things to know about Fluticasone furoate (Avamys); preparing the nasal spray; using the nasal spray; cleaning the nasal spray.
The Nasal Spray: The medicine comes in a brown glass bottle inside a plastic casing. It will contain either 30, 60 or 120 sprays, depending on the pack size that has been prescribed for the patient.
A window in the plastic casing allows to see how much medicine is left. The patient will be able to see the liquid level for a new 30 or 60 spray bottle, but not for a new 120 spray bottle because the liquid level is above the window.
The medicine sprays out of the nozzle when the button on the side is pressed firmly all the way in.
A removable cap protects the nozzle from dust and prevents it from blocking up.
Six Important Things to Know About Fluticasone Furoate (Avamys): 1. The nasal spray comes in a brown glass bottle. To check how much is left, hold the nasal spray upright against a bright light. The patient will then be able to see the level through the window.
2. When the patient first use the nasal spray, shake it vigorously with the cap on for about 10 seconds. This is important as Fluticasone furoate (Avamys) Nasal Spray is very thick and becomes more liquid when the patient shakes it well. It will only spray when it becomes liquid.
3. The button on the side must be pressed firmly all the way in, to release a spray through the nozzle.
4. If the patient has difficulty pressing the button with the thumb, the patient can use two hands.
5. Always keep the cap on the nasal spray when not using it. The cap keeps the dust out, seals in the pressure and stops the nozzle from blocking up. When the cap is in place the button on the side can't be pressed accidentally.
6. Never use a pin or anything sharp to clear the nozzle. It will damage the nasal spray.
Preparing the Nasal Spray: The patient must prepare the nasal spray: Before using it for the first time; if the patient has left the cap off.
Preparing the nasal spray helps to make sure the patient always gets the full dose of medicine. Follow these steps: With the cap on, shake the nasal spray vigorously for about 10 seconds.
Remove the cap by gently squeezing the sides of the cap with the thumb and forefinger and pulling it straight off.
Hold the nasal spray upright and point the nozzle away from the patient.
Press the button firmly all the way in. Do this at least 6 times to release a fine spray into the air.
The nasal spray is now ready for use.
Using the Nasal Spray: 1. Shake the nasal spray vigorously.
2. Remove the cap.
3. Blow the nose to clear the nostrils, and then tilt the head forward a little bit.
4. Hold the nasal spray upright and carefully place the nozzle in one of the nostrils.
5. Point the end of the nozzle toward the outside of the nose, away from the centre ridge of the nose. This helps direct the medicine to the right part of the nose.
6. As the patient breathe in through the nose, press the button once firmly all the way in.
7. Be careful not to get any spray in the eyes. If the patient does, rinse the eyes with water.
8. Take the nozzle out and breathe out through the mouth.
9. If the physician has told the patient to take 2 sprays per nostril, repeat steps 4 to 6.
10. Repeat steps 4 to 6 for the other nostril.
11. Replace the cap on the nasal spray.
Cleaning the Nasal Spray: After each use: Wipe the nozzle and the inside of the cap. Don't use water to do this. Wipe with a clean, dry tissue.
Never use a pin or anything sharp on the nozzle.
Always replace the cap once the patient has finished to keep out dust, seal in the pressure and stop the nozzle from blocking up.
If the nasal spray does not seem to be working: Check if the patient still has medicine left. Look at the level through the window. If the level is very low there may not be enough left to work the nasal spray.
Check the nasal spray for damage.
If the patient thinks the nozzle may be blocked, don't use a pin or anything sharp to clear it.
Try to reset it by following the instructions as mentioned previously under Preparing the Nasal Spray for Use.
If it is still not working, or if it produces anything other than a fine mist (such as a jet of liquid), or if the patient feels any discomfort using the spray, return it to the pharmacist.

Store at temperatures not exceeding 30°C. Do not refrigerate or freeze.

Pharmacology: Pharmacodynamics: Mechanism of Action: Fluticasone furoate is a synthetic trifluorinated corticosteroid that possesses a very high affinity for the glucocorticoid receptor and has a potent anti-inflammatory action.
Clinical Studies: Adult and Adolescent Seasonal Allergic Rhinitis: Once daily 110 micrograms Fluticasone furoate (Avamys) Nasal Spray resulted in a significant improvement in daily reflective (how patient felt over the preceding 12 hours) and instantaneous (how patient felt at the time of assessment) pre-dose total nasal symptom scores (rTNSS and iTNSS, comprising rhinorrhea, nasal congestion, sneezing and nasal itching) and daily reflective and instantaneous total ocular symptom scores (rTOSS, comprising itching/burning, tearing/watering and redness of the eyes) versus placebo (see Table 1 as follows). The improvement in nasal and ocular symptoms was maintained over the full 24 hours after once daily administration. (See Table 1.)

The distribution of the patients' perception of overall response to therapy (using a 7-point scale ranging from significantly improved to significantly worse) favoured Fluticasone furoate (Avamys) Nasal Spray 110 micrograms over placebo, with a statistically significant treatment difference. Onset of action was experienced as early as eight hours after initial administration in two studies. Significant improvement in symptoms was observed in the first 24 hours in all four studies, and continued to improve over several days. The patients' quality of life (as assessed by the Rhinoconjunctivitis Quality of Life Questionnaire - RQLQ), was significantly improved from baseline with Fluticasone furoate (Avamys) Nasal Spray compared to placebo. (Minimum Important Difference in all studies = improvement of at least -0.5 over placebo; treatment difference -0.690, p<0.001, 95% CI -0.84, -0.54).
Adult and Adolescent Perennial Allergic Rhinitis: Fluticasone furoate (Avamys) Nasal Spray 110 micrograms once daily resulted in a significant improvement in daily rTNSS (LS mean difference = -0.706, P=0.005, 95% CI -1.20, -0.21). The improvement in nasal symptoms was maintained over the full 24 hours after once daily administration. The distribution of patients' perception of overall response to therapy was also significantly improved compared to placebo.
In a two-year study designed to assess the ocular safety of fluticasone furoate (110 micrograms once daily intranasal spray), adults and adolescents with perennial allergic rhinitis received either fluticasone furoate (n=367) or placebo (n=181). The primary outcomes [time to increase in posterior subcapsular opacity (≥0.3 from baseline in Lens Opacities Classification System, Version III (LOCS III grade)) and time to increase in intraocular pressure (IOP; ≥7 mmHg from baseline)] were not statistically significant between the two groups. Increases in posterior subscapsular opacity (≥0.3 from baseline) were more frequent in subjects treated with fluticasone furoate 110 micrograms [14 (4%)] versus placebo [4 (2%)] and were transient in nature for ten subjects in the fluticasone furoate group and two subjects in the placebo group. Increases in IOP (≥7 mmHg from baseline) were more frequent in subjects treated with fluticasone furoate 110 micrograms: 7 (2%) for fluticasone furoate 110 micrograms once daily and 1 (<1%) for placebo. These events were transient in nature for six subjects in the fluticasone furoate group and one placebo subject. At weeks 52 and 104, 95% of subjects in both treatment groups had posterior subcapsular opacity values within ±0.1 of baseline values for each eye and, at week 104, ≤1% of subjects in both treatment groups had ≥0.3 increase from baseline in posterior subcapsular opacity. At weeks 52 and 104, the majority of subjects (>95%) had IOP values of within ±5 mmHg of the baseline value. Increases in posterior subcapsular opacity or IOP were not accompanied by any adverse events of cataracts or glaucoma.
Children: The paediatric posology is based on assessment of the efficacy data across the allergic rhinitis population in children. In a seasonal allergic rhinitis study in children, Fluticasone furoate (Avamys) Nasal Spray 110 micrograms over two weeks was effective on primary (daily rTNSS LS mean difference = -0.616, P=0.025, 95% CI -1.15, -0.08) and all secondary nasal endpoints, except the individual reflective score for rhinorrhea. No significant differences were observed between 55 micrograms Fluticasone furoate (Avamys) Nasal Spray and placebo on any endpoint.
In a perennial allergic rhinitis study, Fluticasone furoate (Avamys) Nasal Spray 55 micrograms was effective on daily rTNSS (LS mean difference = -0.754, P=0.003, 95% CI -1.24, -0.27). Although there was a trend towards improvement in rTNSS in 100 micrograms, this did not reach statistical significance (LS mean difference = -0.452, P=0.073, 95% CI -1.24, -0.04). Post-hoc analysis of efficacy data over 6 and 12 weeks from this study, and a 6-week HPA-axis safety study, each showed that the improvement in rTNSS for Fluticasone furoate (Avamys) Nasal Spray 110 micrograms nasal spray over placebo was statistically significant.
A randomised, double-blind, parallel-group, multicenter, one-year placebo-controlled clinical growth study evaluated the effect of fluticasone furoate nasal spray 110 micrograms daily on growth velocity in 474 prepubescent children (5 to 7.5 years of age for girls and 5 to 8.5 years of age for boys) with stadiometry. Mean growth velocity over the 52-week treatment period was lower in the patients receiving fluticasone furoate (5.19 cm/year) compared to placebo (5.46 cm/year). The mean treatment difference was -0.27 cm per year [95% CI -0.48 to -0.06].
Pharmacokinetics: Absorption: Fluticasone furoate undergoes extensive first-pass metabolism and incomplete absorption in the liver and gut resulting in negligible systemic exposure. The intranasal dosing of 110 micrograms once daily does not typically result in measurable plasma concentrations (less than 10 picograms/mL). The absolute bioavailability for fluticasone furoate administered as 880 micrograms three times per day (2640 micrograms total daily dose) is 0.50%.
Distribution: 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.
Metabolism: Fluticasone furoate is rapidly cleared (total plasma clearance of 58.7 L/h) from systemic circulation principally by hepatic metabolism to an inactive 17 beta-carboxylic metabolite (GW694301X), by the cytochrome P450 enzyme CYP3A4. The principal route of metabolism was hydrolysis of the S-fluoromethyl carbothioate function to form the 17 beta-carboxylic acid metabolite. In vivo studies have revealed no evidence of cleavage of the furoate moiety to form fluticasone.
Elimination: Elimination was primarily via the faecal 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 Patient Populations: Elderly: Only a small number of elderly subjects (n=23/872; 2.6%) provided pharmacokinetic data. There was no evidence for a higher incidence of subjects with quantifiable fluticasone furoate concentrations in the elderly, when compared to the younger subjects.
Children: Fluticasone furoate is typically not quantifiable (less than 10 picograms/mL) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were observed in less than 16% of paediatric patients following intranasal dosing of 110 micrograms once daily and only less than 7% of paediatric patients following 55 micrograms once daily. There was no evidence for a higher incidence of quantifiable levels of fluticasone furoate in younger children (less than 6 years of age).
Renal Impairment: Fluticasone furoate is not detectable in urine from healthy volunteers after intranasal dosing. Less than 1% of dose-related material is excreted in urine and therefore renal impairment would not be expected to affect the pharmacokinetics of fluticasone furoate.
Hepatic Impairment: There are no data on intranasal fluticasone furoate in subjects with hepatic impairment. Data are available following inhaled administration of fluticasone furoate (as fluticasone furoate or fluticasone furoate/vilanterol) to subjects with hepatic impairment that are also applicable for intranasal dosing.
A study of a single 400 microgram dose of orally inhaled fluticasone furoate in patients with moderate hepatic impairment (Child-Pugh B) resulted in increased C_max (42%) and AUC_(0-∞) (172%) compared to healthy subjects. Following repeat dosing of orally inhaled fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure [on average two-fold as measured by AUC_(0–24)] in subjects with moderate or severe hepatic impairment (Child-Pugh B or C) compared with healthy subjects. The increase in fluticasone furoate systemic exposure in subjects with moderate hepatic impairment (fluticasone furoate/vilanterol 200/25 micrograms) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. There was no effect on serum cortisol in subjects with severe hepatic impairment (fluticasone furoate/vilanterol 100/12.5 micrograms). Based on these findings, the average predicted exposure for 110 micrograms of intranasal fluticasone furoate in this patient population would not be expected to result in suppression of cortisol.
Other Pharmacokinetic: Fluticasone furoate is typically not quantifiable (less than 10 picograms/mL) following intranasal dosing of 110 micrograms once daily. Quantifiable levels were only observed in less than 31% of patients aged 12 years and above and in less than 16% of paediatric patients following intranasal dosing of 110 micrograms once daily. There was no evidence for gender, age (including paediatrics), or race to be related to those subjects with quantifiable levels, when compared to those without.
Toxicology: Pre-clinical Safety Data: Carcinogenesis, Mutagenesis: There were no treatment-related increases in the incidence of tumours in 2 year inhalation studies in rats and mice.
Fluticasone furoate (Avamys) Nasal Spray was not genotoxic in vitro or in vivo.
Reproductive Toxicology: The potential for reproductive toxicity was assessed in animals by inhalation administration to ensure high systemic exposure to fluticasone furoate. There were no effects on mating performance or fertility of male or female rats. In rats, developmental toxicity was confined to an increased incidence of incompletely ossified sternabrae in association with lower foetal weight. High doses in rabbits induced abortion. These findings are typical following systemic exposure to potent corticosteroids. There were no major skeletal or visceral abnormalities in either rats or rabbits, and no effect on pre- or post-natal development in rats.
Animal Toxicology and/or Pharmacology: Findings in general toxicology studies were similar to those observed with other glucocorticoids and are not considered to be clinically relevant to intranasal use of Fluticasone furoate (Avamys) Nasal Spray.