Avamys

Avamys

fluticasone

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GlaxoSmithKline
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Contents
Fluticasone furoate.
Description
AVAMYS Nasal Spray is a white, uniform suspension contained in an amber glass bottle, fitted with a metering (50 microlitres) atomising spray pump. This inner pack is incorporated within a predominantly off-white plastic device with a blue side-actuated lever and a lid which contains a stopper. Each spray of the suspension delivers approximately 27.5 micrograms of micronised fluticasone furoate as an ex-device dose.
Excipients/Inactive Ingredients: Glucose Anhydrous (also known as Dextrose Anhydrous), Microcrystalline Cellulose and Carboxymethylcellulose Sodium (also known as Dispersible Cellulose), Polysorbate 80, Benzalkonium Chloride Solution, Disodium Edetate (also known as Edetate Disodium), Purified Water.
Action
Pharmacology: 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 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.)


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The distribution of the patients' perception of overall response to therapy (using a 7-point scale ranging from significantly improved to significantly worse) favoured 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 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: 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, 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 AVAMYS Nasal Spray and placebo on any endpoint.
In a perennial allergic rhinitis study, 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 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 Cmax (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 two year inhalation studies in rats and mice.
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 AVAMYS Nasal Spray.
Indications/Uses
Adults and Adolescents (12 years and older): Treatment of the nasal symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing) and ocular symptoms (itching/burning, tearing/watering, and redness of the eye) of seasonal allergic rhinitis.
Treatment of the nasal symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing) of perennial allergic rhinitis.
Children (2 to 11 years): Treatment of the nasal symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing) of seasonal and perennial allergic rhinitis.
Dosage/Direction for Use
AVAMYS Nasal Spray is for administration by the intranasal route only. For full therapeutic benefit, regular scheduled usage is recommended. Onset of action has been observed as early as 8 hours after initial administration. It may take several days of treatment to achieve maximum benefit. An absence of an immediate effect should be explained to the patient (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Populations: For the treatment of seasonal allergic rhinitis and perennial allergic rhinitis: Adults and Adolescents (12 years and older): The recommended starting dosage is 2 sprays (27.5 micrograms per spray) in each nostril once daily (total daily dose, 110 micrograms).
Once adequate control of symptoms is achieved, dose reduction to 1 spray in each nostril once daily (total daily dose, 55 micrograms) may be effective for maintenance.
Children (2 to 11 years): The recommended starting dosage is 1 spray (27.5 micrograms per spray) in each nostril once daily (total daily dose, 55 micrograms).
Patients not adequately responding to 1 spray in each nostril once daily (total daily dose, 55 micrograms) may use 2 sprays in each nostril once daily (total daily dose, 110 micrograms). Once adequate control of symptoms is achieved, dose reduction to 1 spray in each nostril once daily (total daily dose, 55 micrograms) is recommended.
Children (under 2 years of age): There are no data to recommend use of AVAMYS Nasal Spray for the treatment of seasonal or perennial allergic rhinitis in children under 2 years of age.
Elderly: No dosage adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dosage adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dosage adjustment is required in patients with hepatic impairment. (see Precautions, and Pharmacology: Pharmacokinetics under Actions).
Overdosage
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.
Contraindications
AVAMYS Nasal Spray is contra-indicated in patients with hypersensitivity to any of the ingredients.
Special Precautions
Based on data with another glucocorticoid metabolised by CYP3A4, co-administration with ritonavir is not recommended because of the potential risk of increased systemic exposure to fluticasone furoate (see Interactions and Pharmacology: Pharmacokinetics under Actions).
Systemic effects with nasal corticosteroids have been reported, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. A reduction in growth velocity has been observed in children treated with fluticasone furoate 110 micrograms daily for one year (see Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions). Therefore, children should be maintained on the lowest dose which delivers adequate symptom control (see Dosage & Administration). As with other intranasal corticosteroids, physicians should be alert to potential systemic steroid effects including ocular changes (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Nasal: Nasal side effects: in clinical trial data, the common side effects reported were epistaxis and nasal ulceration. Post-marketing cases of nasal septal perforation have been reported in patients following the intranasal application of fluticasone furoate nasal spray (see Adverse Reactions).
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 (IOP), glaucoma, and/or cataracts.
Glaucoma and cataract formation was evaluated with intraocular pressure measurements and slit lamp examinations in 1 controlled 12-month trial in 806 adolescent and adult patients aged 12 years and older and in 1 controlled 12-week trial in 558 children aged 2 to 11 years. The patients had perennial allergic rhinitis and were treated with either fluticasone furoate nasal spray (110 mcg once daily in adult and adolescent patients and 55 or 110 mcg once daily in pediatric patients) or placebo. Intraocular pressure remained within the normal range (less than 21 mmHg) in greater than or equal to 98% of the patients in any treatment group in both trials. However, in the 12-month trial in adolescents and adults, 12 patients, all treated with fluticasone furoate nasal spray 110 mcg once daily, had intraocular pressure measurements that increased above normal levels (greater than or equal to 21 mmHg). In the same trial, 7 patients (6 treated with fluticasone furoate nasal spray 110 mcg once daily and 1 patient treated with placebo) had cataracts identified during the trial that were not present at baseline.
Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria, may occur after administration of fluticasone furoate nasal spray. Discontinue fluticasone furoate nasal spray if such reactions occur (see Contraindications).
Hypothalamic-Pituitary-Adrenal Axis Effects: 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 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. In addition, some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, 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.
Effects on Ability to Drive and Use Machines: Based on the pharmacology of fluticasone furoate and other intranasally administered steroids, there is no reason to expect an effect on ability to drive or to operate machinery with AVAMYS Nasal Spray.
Use In Pregnancy & Lactation
Adequate data are not available regarding the use of AVAMYS Nasal Spray during pregnancy and lactation in humans. 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 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.
It is unknown whether nasal administered fluticasone furoate is excreted in human breast milk.
Administration of fluticasone furoate to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
Adverse Reactions
Systemic and local corticosteroid use may result in the following: Cataracts and glaucoma (see Precautions).
Data from large clinical trials were used to determine the frequency of adverse reactions. The following convention has been used for the classification of frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 2.)


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Inform the doctor or pharmacist immediately if the patient has any undesired effects from using this drug.
Drug Interactions
Fluticasone furoate is rapidly cleared by extensive first pass metabolism mediated by the cytochrome P450 3A4. In a drug interaction study of intranasal fluticasone furoate with the potent CYP3A4 inhibitor ketoconazole, there were more subjects with measurable fluticasone furoate plasma concentrations in the ketoconazole group (6 of the 20 subjects) compared to placebo (1 of the 20 subjects). This small increase in exposure did not result in a statistically significant difference in 24 hour serum cortisol levels between the two groups.
The enzyme induction and inhibition data suggest that there is no theoretical basis for anticipating metabolic interactions between fluticasone furoate and the cytochrome P450 mediated metabolism of other compounds at clinically relevant intranasal doses. Therefore, no clinical studies have been conducted to investigate interactions of fluticasone furoate on other drugs (see Precautions, and Pharmacology: Pharmacokinetics under Actions).
Based on data with another glucocorticoid, fluticasone propionate, metabolized by CYP3A4, 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.
Caution For Usage
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 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 the patient needs to know about AVAMYS Nasal Spray; 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 the patient 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 the patient needs to know about AYAMYS Nasal Spray: 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 using first the nasal spray it must be shaken vigorously with the cap on for about 10 seconds. This is important as 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, he/she 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.
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 breathes 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 doctor 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 there's still 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 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.
Incompatibilities: None.
Storage
Store below 30°C.
Do not refrigerate or freeze.
Shelf-Life: 36 months.
ATC Classification
R01AD12 - fluticasone furoate ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.
Presentation/Packing
Nasal spray 27.5 mcg/spray (white, uniform suspension) x 30's, 60's, 120's.
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