Table of Contents
SUMMARY OF PRODUCT INFORMATION..................................................... 3 INDICATIONS AND CLINICAL USE ................................................................ 3 CONTRAINDICATIONS ...................................................................................... 3 WARNINGS AND PRECAUTIONS .................................................................... 3 ADVERSE REACTIONS ...................................................................................... 6 DRUG INTERACTIONS....................................................................................... 8 DOSAGE AND ADMINISTRATION................................................................... 9 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 STORAGE AND STABILITY 11 DOSAGE FORMS, COMPOSITION AND PACKAGING 11
PHARMACEUTICAL INFORMATION 12 CLINICAL TRIALS 12 DETAILED PHARMACOLOGY 14 TOXICOLOGY 18 REFERENCES 22
Fluticasone Propionate Aqueous Nasal Spray Apotex Standard | ||
|---|---|---|
| Route of Administration | Dosage Form/Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intranasal | Suspension/ 50 mcg per metered dose | None For a complete listing see Dosage Forms, Composition and Packaging Section. |
APO-FLUTICASONE (fluticasone propionate aqueous nasal spray) is indicated for the treatment of seasonal allergic rhinitis including hay fever, and perennial rhinitis poorly responsive to conventional treatment. In patients with allergic rhinitis, fluticasone propionate aqueous nasal spray is also indicated for the management of associated sinus pain and pressure. Regular usage is essential for full therapeutic benefit since maximum relief may not be obtained until after 2 to 3 days of treatment.
APO-FLUTICASONE (fluticasone propionate aqueous nasal spray) is contraindicated in patients with a history of hypersensitivity to any of its ingredients, and in patients with untreated fungal, bacterial, or tuberculosis infections of the respiratory tract.
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. Careful attention must be given to patients with asthma or other clinical conditions in whom a rapid decrease in systemic steroids may cause a severe exacerbation of their symptoms. A drug interaction study of intranasal fluticasone propionate 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 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.
General
Patients should be informed that the full effect of APO-FLUTICASONE (fluticasone propionate aqueous nasal spray) therapy is not achieved until 2 to 3 days of treatment have been completed. Treatment of seasonal rhinitis should, if possible, start before the exposure to allergens. Although fluticasone propionate 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. Under most circumstances, treatment with corticosteroids should not be stopped abruptly but tapered off gradually. Patients should be advised to inform subsequent physicians of prior use of corticosteroids.
The replacement of a systemic steroid with fluticasone propionate must be gradual and carefully supervised by the physician. The guidelines under "DOSAGE AND ADMINISTRATION" should be followed in all such cases.
To ensure proper dosage and administration of the drug, the patient should be instructed by a physician or other health professional in the use of fluticasone propionate (see PART III CONSUMER INFORMATION).
During long-term therapy, HPA axis function and haematological status should be assessed. The long-term effects of fluticasone propionate in humans are still unknown, in particular, its local effects; the possibility of atrophic rhinitis and/or pharyngeal candidiasis should be kept in mind.
Ear Nose and Throat
In patients who have had recent nasal surgery or trauma, a nasal corticosteroid should be used with caution until healing has occurred, because of the inhibitory effect of corticosteroids on wound healing.
Endocrine and Metabolism
Systemic Effects
Use of excessive doses of corticosteroids may lead to signs or symptoms of hypercorticism, suppression of HPA function, and/or reduction of growth velocity in children or teenagers. 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. Although systemic effects have been minimal with recommended doses of fluticasone propionate aqueous nasal spray, potential risk increases with larger doses. Therefore, larger than recommended doses of fluticasone propionate aqueous nasal spray should be avoided.
There is an enhanced effect of corticosteroids on patients with hypothyroidism.
Hepatic/Biliary/Pancreatic
Cirrhosis
There is an enhanced effect of corticosteroids on patients with cirrhosis.
Immune
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 fluticasone propionate. 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 nonimmune 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 affects 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.
Special Populations
Pregnant Women
The safety of fluticasone propionate in pregnancy has not been established. If used, the expected benefits should be weighed against the potential hazard to the foetus, particularly during the first trimester of pregnancy. Like other glucocorticosteroids fluticasone propionate is teratogenic to rodent species (see TOXICOLOGY). Adverse effects typical of potent corticosteroids are only seen at high systemic exposure levels; direct intranasal application ensures minimal systemic exposure. The relevance of these findings to humans has not yet been established. Infants born of mothers who have received substantial doses of glucocorticosteroids during pregnancy should be carefully observed for hypoadrenalism.
Glucocorticosteroids are excreted in human milk. It is not known whether fluticasone propionate is excreted in human milk. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the breast milk. However, following intranasal administration to primates, no drug was detected in the plasma, and it is therefore unlikely that the drug would be detectable in milk. The use of fluticasone propionate in nursing mothers, requires that the possible benefits of the drug be weighed against the potential hazards to the infant.
Fluticasone propionate is not presently recommended for children younger than 4 years of age due to limited clinical data in this age group. Until greater clinical experience has been gained, the continuous, long-term treatment of children under age 12 is not recommended.
Clinical Trials Adverse Drug Reactions
Adverse reactions in controlled clinical studies with fluticasone propionate aqueous nasal spray have been primarily associated with irritation of the nasal mucous membranes, and are consistent with those expected from application of a topical medication to an already inflamed membrane. The adverse reactions reported by patients treated with fluticasone propionate aqueous nasal spray were similar to those reported by patients receiving placebo. The most frequently reported adverse reactions (>= 1% in any treatment group) considered by the investigator to be potentially related to fluticasone propionate aqueous nasal spray or placebo in trials of seasonal allergic rhinitis are listed below. These studies conducted in 948 adults and in 499 children evaluated 14-28 days of treatment with recommended doses of fluticasone propionate compared with placebo.
| Adverse Reactions Reported Most Frequently in Clinical Trials of Seasonal Allergic Rhinitis | ||||||
| Adults (age >= 12 years) | Children (age 4-11 years) | |||||
| Fluticasone | Fluticasone | Placebo | Fluticasone | Futicasone * | Placebo | |
| * | * | * | 200 mcg od | |||
| 100 mcg bid | 200 mcg od | (n=314) | 100 mcg od | (n=164) | (n=168) | |
| (n=312) | (n=322) | % | (n=167) | % | % | |
| % | % | % | ||||
| Nasal burning | 2.2 | 3.4 | 2.5 | 1.8 | 2.4 | 1.2 |
| Pharyngitis | 1.3 | 1.6 | <1 | <1 | 0 | 0 |
| Runny nose | <1 | 1.6 | <1 | <1 | <1 | <1 |
| Blood in nasal mucus | 0 | 1.6 | <1 | 0 | <1 | 0 |
| Epistaxis | 1.6 | 2.8 | 2.2 | 3.0 | 3.7 | 3.6 |
| Sneezing | <1 | 1.2 | 2.2 | 0 | <1 | 0 |
| Crusting in nostrils | 0 | 0 | 0 | 1.2 | 0 | 0 |
| Nasal congestion | 0 | 0 | 0 | 0 | 1.2 | 0 |
| Nasal ulcer | <1 | 0 | 0 | 1.2 | 1.2 | 1.2 |
| Headache | 1.3 | 2.5 | 1.9 | 1.2 | 1.2 | 1.2 |
*Fluticasone propionate aqueous nasal spray.
In two 6 month trials involving 831 patients aged 12-75 years with perennial allergic rhinitis, the adverse reactions reported by patients treated with fluticasone propionate aqueous nasal spray were similar in type and incidence to those reported in seasonal trials, with the exception of epistaxis (<=13.3%) and blood in nasal mucous (<=8.3%). In addition to the events reported most frequently in the seasonal trials, patients receiving fluticasone propionate aqueous nasal spray in the 6 month trials reported nasal soreness (<=2.5%), nasal excoriation (<= 2.0%), sinusitis (<=1.6%), and nasal dryness (<= 1.3%).
Less Common Clinical Trial Adverse Drug Reactions
Infrequent adverse reactions (incidence of 0.1%-1% and greater than placebo) reported by patients receiving fluticasone propionate aqueous nasal spray at the recommended daily dose of 200 mcg (or 100 mcg per day for children 4-11 years of age) in the aforementioned clinical trials included pharyngeal irritation, nasal stinging, nausea and vomiting, unpleasant smell and taste, and sinus headache (0.3%); lacrimation, eye irritation, xerostomia, cough, urticaria, and rash (0.2%); and nasal septum perforation (0.1%).
Post-Market Adverse Drug Reactions:
The following events have been identified during post-approval use of fluticasone propionate in clinical practice.
General: Headache and hypersensitivity reactions including angioedema, skin rash, edema of the face or tongue, pruritis, urticaria, bronchospasm, wheezing, dyspnea, and anaphylaxis/anaphylactoid reactions have been reported.
Ear, Nose and Throat: Alteration or loss in sense of taste and/or smell and, rarely, nasal septal perforation, nasal ulcer, sore throat, throat irritation and dryness, cough, hoarseness, and voice changes.
Eye:
Dryness and irritation of the eyes, conjunctivitis, blurred vision, and very rarely, glaucoma, increased intraocular pressure, and cataracts.
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 involving fluticasone propionate are unlikely. A drug interaction study of intranasal fluticasone propionate 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 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. This study has 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. However, there have been a few case reports during world-wide post-market use of adrenal cortisol suppression associated with concomitant use of azole anti-fungals and inhaled fluticasone propionate. Therefore, care is advised when co-administering potent cytochrome P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
Acetylsalicylic acid should be used cautiously in conjunction with corticosteroids in hypothrombinemia.
.
The therapeutic effects of corticosteroids, unlike those of decongestants, are not immediate. Since the effect of APO-FLUTICASONE (fluticasone propionate aqueous nasal spray) depends on its regular use, patients must be instructed to take the nasal inhalation at regular intervals and not, as with other nasal sprays, as they feel necessary.
The usual dosage is two sprays (50 micrograms/each metered dose) in each nostril once a day, (total daily dosage, 200 micrograms). Some patients with severe rhinitis may benefit from two sprays in each nostril every 12 hours. The recommended maximum daily dose is 400 micrograms (four sprays in each nostril).
The usual dosage is one or two sprays (50 micrograms/each metered dose) in each nostril in the morning (100 or 200 micrograms per day). The recommended maximum daily dose is 200 micrograms (two sprays in each nostril). The safety and efficacy of fluticasone propionate aqueous nasal spray in children below 4 years of age have not been established and therefore, APO-FLUTICASONE Nasal Spray is not recommended in this patient population. Until greater clinical experience has been gained, the continuous, long-term treatment of children under age 12 is not recommended. An improvement of symptoms usually becomes apparent within a few days after the start of therapy. However, symptomatic relief may not occur in some patients for as long as two weeks. APO-FLUTICASONE should not be continued beyond three weeks in the absence of significant symptomatic improvement. In the presence of excessive nasal mucous secretion or oedema of the nasal mucosa, the drug may fail to reach the site of action. In such cases it is advisable to use a nasal vasoconstrictor for two to three days prior to starting treatment with APO-FLUTICASONE. Patients should be instructed on the correct method of use, which is to blow the nose, then insert the nozzle carefully into the nostril, compress the opposite nostril and actuate the spray while inspiring through the nose, with the mouth closed (see PART III CONSUMER INFORMATION). Careful attention must be given to patients previously treated for prolonged periods with systemic corticosteroids when transferred to APO-FLUTICASONE. Initially, APO-FLUTICASONE and the systemic corticosteroid must be given concomitantly, while the dose of the latter is gradually decreased. The usual rate of withdrawal of the systemic steroid is the equivalent of 1.0 mg of prednisone every four days if the patient is under close supervision. If continuous supervision is not feasible, the withdrawal of the systemic steroid should be slower, approximately 1.0 mg of prednisone (or equivalent) every ten days. If withdrawal symptoms appear, the previous dose of the systemic steroid should be resumed for a week before further decrease is attempted.
Like any other nasally administered corticosteroid, acute overdosing is unlikely in view of the total amount of active ingredient present. However, when used chronically in excessive doses or in conjunction with other corticosteroid formulations, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of fluticasone propionate should be discontinued slowly, consistent with accepted procedures for discontinuation of chronic steroid therapy (see DOSAGE AND ADMINISTRATION). The restoration of HPA axis function may be slow. During periods of pronounced physical stress (i.e. severe infections, trauma, surgery) a supplement with systemic steroids may be advisable.
Fluticasone propionate is a potent anti-inflammatory steroid. When administered intranasally in therapeutic doses, it has a direct anti-inflammatory action on the nasal mucosa, the mechanism of which is not yet completely defined. The onset of action is not immediate, and two to three days treatment may be required before maximum relief is obtained. This is because the anti-inflammatory activities of glucocorticoids are related to specific steroid effects, which involve several biochemical events, including protein synthesis. Following intranasal dosing of fluticasone propionate, (200 mcg/day) steady-state maximum plasma concentrations were not quantifiable in most subjects (<0.01 ng/mL). The highest Cmax observed was 0.017 ng/mL. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. When administered orally the systemic exposure is <1 % due to poor absorption and pre-systemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible. In clinical trials, no hypothalamic-pituitary-adrenal (HPA) axis effects have been observed. Following intranasal dosing of fluticasone propionate, (200 mcg/day) no significant change in 24- hour serum cortisol AUC was found compared to placebo (ratio 1.01, 90% CI 0.9- 1.14).
Store at room temperature 15-30 degC (59-86degF). Shake gently before use.
APO-FLUTICASONE 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. Each metered dose of APO-FLUTICASONE Nasal Spray contains 50 mcg of fluticasone propionate. Inactive Ingredients: benzalkonium chloride (as a preservative), dextrose monohydrate, microcrystalline cellulose and carboxymethylcellulose sodium, phenylethyl alcohol, polysorbate 80 and purified water. APO-FLUTICASONE Nasal Spray is available in amber glass bottles of 16 g net weight (120 metered sprays).