Apo-Fluticasone

Fluticasone propionate.

Each metered dose of APO-FLUTICASONE Aqueous Nasal Spray contains 50 mcg of fluticasone propionate (micronized).
APO-FLUTICASONE Aqueous Nasal Spray is a white to off-white, milky suspension for topical administration to the nasal mucosa by means of a metering atomizing spray pump.
Excipients/Inactive Ingredients: Each metered dose of APO-FLUTICASONE Aqueous Nasal Spray contains 40 mcg of Benzalkonium Chloride and 250 mcg of Phenylethyl Alcohol as preservatives.

Therapeutic Classification: Corticosteroid for nasal use.
Pharmacology: Pharmacodynamics: Mode of Action: Fluticasone propionate has potent anti-inflammatory activity but when used topically on the nasal mucosa has no detectable systemic activity.
Fluticasone propionate causes little or no hypothalamic-pituitary-adrenal axis suppression following intranasal administration.
Following intranasal dosing of fluticasone propionate, (200 micrograms/day) no significant change in 24 h serum cortisol AUC was found compared to placebo (ratio: 1.01, 90% CI 0.9 to 1.14).
Clinical Trials: Rhinitis: Clinical trials aimed to establish the efficacy of fluticasone propionate aqueous nasal spray (FPANS) 200 micrograms once daily (od) in adults and 100 micrograms od in children with seasonal or perennial rhinitis. To determine that these dosages were optimal for treating adults and children respectively, and to compare the efficacy of FPANS 200 micrograms od and 100 micrograms od with that of the standard therapy, beclomethasone dipropionate aqueous nasal spray (BDPANS) 200 micrograms was used twice daily (bd). Clinical trial data is available from over 4000 patients. Efficacy determination included daily symptom assessments.
Dose-ranging studies showed FPANS to be significantly superior to placebo in the relief of symptoms of rhinitis, even at very low doses (25 micrograms twice daily), although higher doses (eg 200 micrograms daily) provided significant improvements more rapidly.
Once daily doses of 200 micrograms FPANS have been shown to be efficacious in patients with seasonal rhinitis. For the relief of adult perennial rhinitis, 200 micrograms once daily was as effective as 100 micrograms twice daily.
Paediatric studies showed that FPANS 100 micrograms od was as effective as 200 micrograms od for the treatment of both seasonal and perennial rhinitis. The maximum treatment duration in children was 12 weeks.
Sinus pain and pressure: In patients with allergic rhinitis, fluticasone propionate aqueous nasal spray has also been shown to be of benefit for the management of associated sinus pain and pressure.
Two 14 days, randomized, double blind, parallel group clinical studies were performed in 401 adult and adolescent patients aged ≥ 12 years. Both studies compared fluticasone propionate nasal spray 200 micrograms once daily, administered as two 50 micrograms sprays per nostril, with placebo. The primary endpoint for both studies was the mean change from baseline in the patient-rated sinus pain and pressure score at week 2. In both studies, fluticasone propionate nasal spray provided significantly greater improvement compared with placebo for the primary endpoint (p<0.05). The magnitude of the improvement was 10 points compared to placebo and approximately 35 points from baseline (baseline score for this symptom was 75 on a 0-100 scale). The sinus pain and pressure score was also significantly decreased in the fluticasone propionate nasal spray treated group over the entire 2 week study period (p<0.05).
Treatment with fluticasone propionate nasal spray provided significantly greater improvement in symptoms of nasal congestion during week 1, 2 and overall during the 2 week study period (p<0.05). The overall improvement in congestion compared to placebo was 10 points and approximately 37 points from baseline (baseline score for this symptom was 78 on a 0-100 scale).
Pharmacokinetics: Absorption: Following intranasal dosing of fluticasone propionate (200 micrograms/day), steady-state maximum plasma concentrations were not quantifiable in most subjects (less than 0.01 nanograms/ml). The highest C_max observed was 0.017 nanograms/ml. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. Absolute oral bioavailability is negligible (less than absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible).
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 L). Plasma protein binding is moderately high (91%).
Metabolism: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate.
Elimination: The elimination rate of i.v. administered fluticasone propionate is linear over the 250 to 1000 micrograms dose range and is characterized by a high plasma clearance (CL=1.1 L/min). Peak plasma concentrations are reduced by approximately 98% within 3 to 4 h and only low plasma concentrations were associated with the 7.8 h terminal half-life. The renal clearance of fluticasone propionate is negligible (less than 0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.

APO-FLUTICASONE Aqueous Nasal Spray is indicated for the prophylaxis and treatment of seasonal allergic rhinitis including hay fever, and perennial rhinitis. Fluticasone propionate has potent anti-inflammatory activity but when used topically on the nasal mucosa has no detectable systemic activity.

For full therapeutic benefit regular usage is essential. The absence of an immediate effect should be explained to the patient as maximum relief may not be obtained until after three to four days of treatment.
APO-FLUTICASONE Aqueous Nasal Spray is for administration by the intranasal route only.
Adults and children over 12 years of age: For the prophylaxis and treatment of seasonal allergic rhinitis and perennial rhinitis: Two sprays into each nostril once a day, preferably in the morning. In some cases two sprays into each nostril twice daily may be required. The maximum daily dose should not exceed four sprays into each nostril.
Elderly: The normal adult dosage is applicable.
Children under 12 years of age: For the prophylaxis and treatment of seasonal allergic rhinitis and perennial rhinitis in children aged 4-11 years: One spray into each nostril once a day, preferably in the morning. In some cases one spray into each nostril twice daily may be required. The maximum daily dose should not exceed two sprays into each nostril.

Symptoms and Treatment of Overdosage: There are no data from patients available on the effects of acute or chronic overdosage with intranasal fluticasone propionate. In healthy volunteers, intranasal administration of 2 mg fluticasone propionate twice daily for seven days had no effect on hypothalamic-pituitary-adrenal (HPA) axis function. Administration of doses higher than those recommended over a long period of time may lead to temporary suppression of adrenal function. In these patients, treatment with fluticasone propionate should be continued at a dose sufficient to control symptoms; adrenal function will recover in a few days and can be monitored by measuring plasma cortisol.

APO-FLUTICASONE (fluticasone propionate aqueous nasal spray) is contraindicated in patients with a history of hypersensitivity to any of its ingredients.

Local infection: Infections of the nasal airways should be appropriately treated but do not constitute a specific contraindication to the treatment with intranasal fluticasone propionate.
The full benefit of APO-FLUTICASONE Aqueous Nasal Spray may not be achieved until treatment has been administered for several days.
Care must be taken when withdrawing patients from systemic steroid treatment, and commencing therapy with intranasal fluticasone propionate, particularly if there is any reason to suspect that their adrenal function is impaired.
Although APO-FLUTICASONE Aqueous Nasal Spray will control seasonal allergic rhinitis in most cases, an abnormally heavy challenge of summer allergens may in certain instances necessitate appropriate additional therapy.
Systemic effects of nasal corticosteroids may occur particularly at high doses prescribed for prolonged periods. These effects vary between patients and different corticosteroids.
Growth retardation has been reported in children receiving some nasal corticosteroids at licensed doses. It is recommended that the height of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid, if possible, to the lowest dose at which effective control of symptoms is maintained. In addition, consideration should be given to referring the patient to a paediatric specialist.
Treatment with higher than recommended doses of nasal corticosteroids may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used then additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
Visual disturbance: Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects (see Interactions).
Effects on Ability to Drive and Use Machines: Fluticasone propionate is unlikely to produce an effect.

As with other drugs, the use of intranasal fluticasone propionate during pregnancy and lactation requires that the benefits be weighed against possible risks associated with the product or with any alternative therapy.
There is inadequate evidence of safety in human pregnancy. In animal reproduction studies, adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; direct intranasal application ensures minimal systemic exposure.
The excretion of fluticasone propionate in human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration, there was evidence of fluticasone propionate in the breast milk. However, plasma levels in patients following intranasal application of fluticasone propionate at recommended doses are likely to be low.

Adverse events are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000) and very rare (< 1/10,000) including isolated reports. Very uncommon, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data. In assigning adverse event frequencies, the background rates in placebo groups were not taken into account, since these rates were generally comparable to those in the active treatment group.
Immune system disorders: Very rare: Hypersensitivity reactions, anaphylaxis/anaphylactic reactions, bronchospasm, skin rash, oedema of the face or tongue.
Nervous system disorders: Common: Headache, unpleasant taste, unpleasant smell.
As with other nasal sprays, unpleasant taste and smell and headache have been reported.
Eye disorders: Very rare: Glaucoma, raised intraocular pressure, cataract.
A very small number of spontaneous reports have been identified following prolonged treatment. However, clinical trials of up to one year duration have shown that intranasal fluticasone propionate is not associated with an increased incidence of ocular events including cataract, increased intraocular pressure or glaucoma.
Unknown: Vision, blurred.
Respiratory, thoracic and mediastinal disorders: Very common: Epistaxis.
Common: Nasal dryness, nasal irritation, throat dryness, throat irritation.
As with other intranasal products, dryness and irritation of the nose and throat, and epistaxis have been reported.
Very rare: Nasal septal perforation.
Nasal septal perforation has been reported following the use of intranasal corticosteroid.

Under normal circumstances, very low plasma concentrations of fluticasone propionate are achieved after intranasal dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in system in corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Studies have shown that other inhibitors of cytochrome P450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when coadministering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole), as there is potential for increased systemic exposure to fluticasone propionate.

Instructions for Use of Apo-Fluticasone Aqueous Nasal Spray: Before Using: A. Shake the bottle gently, then remove the dust cover by gently squeezing the ribs between the finger and thumb and lifting off.
B. Hold the spray with the forefinger and middle finger on either side of the nozzle and the thumb underneath the bottle.
C. If using APO-FLUTICASONE Aqueous Nasal Spray for the first time or if the patient has not used it for a week or more test the spray as follows: with the nozzle pointing away from the patient, press down several times until a fine mist comes out of the nozzle.
Using the Spray: D. Blow the nose gently.
E. Close one nostril and put the nozzle in the other nostril. Tilt the head forward slightly and keep the spray upright.
F. Start to breathe in through the nose and WHILE BREATHING IN press down with the fingers ONCE to release one spray.
G. Breathe out through the mouth. If a second spray in that nostril is required repeat steps F and G.
H. Repeat E, F, and G for the other nostril.
After Use: I. Wipe the nozzle with a tissue or handkerchief and replace the cover.
Cleaning: J. Gently pull off the nozzle. Wash it in warm water.
K. Shake off excess water and allow to dry in a warm place but avoid excessive heat.
L. Gently push the nozzle back on top of the brown bottle. Replace the dust cover.
M. If the nozzle becomes blocked it can be removed and left to soak in warm water. Rinse under a cold tap, allow to dry and refit. Do not try to unblock the nozzle by inserting a pin or other sharp objects.

Store below 30°C. Shake gently before use.

Nasal Decongestants & Other Nasal Preparations

R01AD08 - fluticasone ; Belongs to the class of topical corticosteroids used for prophylaxis and treatment of allergic rhinitis.

POM