Source: Health Products and Food Branch (CA) Revision Year: 2019
Fluticasone propionate is a synthetic trifluorinated corticosteroid with anti-inflammatory activity. Fluticasone propionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor that is 18 times that of dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. The clinical significance of these findings is unknown.
Topical nasal steroids act by reducing late-phase allergic reactions and mucous secretion, inhibiting vascular permeability, preventing eicosanoid formation, inhibiting allergeninduced mediator release, and reducing eosinophil and basophil infiltration in nasal epithelium. Corticosteroids have been shown to have a wide range of effects 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. Fluticasone propionate controls multiple key inflammatory substances (histamine, chemokines, leukotrienes, cytokines, tryptases and prostaglandins) whereas most common non-prescription allergy pills act on histamine alone. These antiinflammatory actions of corticosteroids may contribute to their efficacy in rhinitis. In 7 trials in adults, Flonase Allergy Relief Nasal Spray has decreased nasal mucosal eosinophils in 66% of patients (35% for placebo) and basophils in 39% of patients (28% for placebo). The direct relationship of these findings to long-term symptom relief is not known.
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 0.017ng/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.
The potential systemic effects of Flonase Allergy Relief on the HPA axis were evaluated. Flonase Allergy Relief given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Flonase Allergy Relief at either dosage for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both dosages of oral prednisone significantly reduced the response to cosyntropin.
A study specifically designed to evaluate the effect of Flonase Allergy Relief on the QT interval has not been conducted.
Clinical studies in normal human subjects have shown that following intranasal administration of fluticasone propionate at the recommended daily dose of 200 mcg, 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 presystemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible.
Fluticasone propionate has a large volume of distribution at steady state (approximately 318 L). Plasma protein binding is moderately high (91%).
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.
Single intravenous doses of 1 mg in healthy volunteers revealed that the elimination rate is linear over the 250-1000 mcg dose range and are characterized by a high plasma clearance (CL=1.1 L/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8 hours terminal half-life. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% of the dose is excreted as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.
Clinical pharmacology in special populations has not been evaluated.
The results of the acute toxicity studies with fluticasone propionate administered by inhalation, orally, subcutaneously and intravenously, demonstrated a large margin of safety over the anticipated maximum daily exposure in humans of 400 mcg /day. The approximate LD50 values are shown in the following table:
Table 9. Acute Toxicity, Dosing Route and LD50:
| SPECIES | ROUTE | APPROXIMATE LD50 (mg/kg) |
|---|---|---|
| Mouse | Oral | >1000 |
| Rat | Oral | >1000 |
| Mouse | Subcutaneous | >1000 |
| Rat | Subcutaneous | >1000 |
| Rat | Intravenous | >2 |
| Rat | Inhalation | >1.66 |
| Dog | Inhalation | >0.82 |
High oral doses of 1 g/kg were well tolerated in both the mouse and rat. The only (reversible) changes observed were a slowing in growth rate and microscopically-evident cortical depletion of the thymus of animals killed 3 days after dosing.
Subcutaneous doses of fluticasone propionate at 1 g/kg were administered to mice and rats. Animals progressively lost condition and body weight and the effects seen were thymic depletion and various lesions associated with a compromised immune system. In addition, gastric steroid ulcers were seen. These observed changes are the expected response to glucocorticoid therapy. The lack of reversible thymic effects in subcutaneously-dosed animals is almost certainly due to the deposition and leaching of insoluble steroid from the injection site.
When given intravenously to rats at a dose of 2 mg/kg, the only changes seen were slightly subdued behaviour immediately after treatment and reversible thymic involution.
Subacute toxicity studies were conducted in adult and juvenile rats for periods up to 35 days and in Beagle dogs for periods up to 44 days. Fluticasone propionate was administered as follows:
Table 10. Fluticasone Propionate Dosing in Subacute Toxicity Studies:
| SPECIES | ROUTE | DOSES^*^ | DOSING PERIOD |
|---|---|---|---|
| Rat | Oral (gavage) | 1000 mcg/kg/day | 15 days |
| Dog | Oral (gavage) | 3000 mcg/kg/day | 7 days |
| Rat | Subcutaneous | 250/90 mcg/kg/day | 36 days |
| 10 mcg/kg/day | 35 days | ||
| Dog | Subcutaneous | 160 mcg/kg/day | 36 days |
| Rat | Inhalation | 60 mcg/L/day | 7 days |
| 18.2 mcg/L/day | 14 days | ||
| 475 mcg/kg/day | 30 days | ||
| Dog | Inhalation | 20 mg/animal/day | 10 days |
| 9 mg/animal/day | 44 days |
Key: ^*^Maximum dose of fluticasone propionate administered.
Clinical observations were similar for all routes of administration in both species. These consisted of reduced weight gain and general loss of condition. Inhalation studies in the dog resulted in clinical signs associated with the administration of a potent glucocorticoid and consistent with the symptoms of Canine Cushings' Syndrome.
Changes typical of glucocorticoid overdosage were seen in both hematological and clinical chemistry parameters. Effects were seen on the red cell parameters and a characteristic leukopenia resulting from a lymphopenia accompanied by a neutrophilia. Endogenous cortisol and corticosterone were depressed in dogs and rats respectively.
Microscopic pathology was again consistent with the administration of a potent glucocorticoid showing thymic and adrenal atrophy, lymphoid depletion in rats and dogs and glycogenic vacuolation of the liver in dogs. There was no change or evidence of irritancy attributable to fluticasone propionate in the respiratory tract in any of the inhalation studies.
There were no specific effects on the maturation of juvenile rats after subcutaneous dosing.
Chronic inhalation toxicity studies using fluticasone propionate were conducted for up to 18 months in rats, using snout-only exposure. In two 6 month studies rats received doses of up to 80 mcg/kg/day; the maximum daily dose administered during the 18 month study was 57 mcg/kg. Changes seen in hematological, biochemical and urinalysis parameters were those typical of glucocorticoid overdosage. Histological findings included lymphoid depletion and thymic and adrenal atrophy. There was at least partial regression of all clinical changes either during the treatment period or within the recovery period.
At all dose levels the observed changes were considered to have arisen directly or indirectly from the immunomodulatory or physiological actions of a corticosteroid. None of these changes was of pathological significance.
Inhalation studies with fluticasone propionate of up to 12 months duration were also conducted in dogs. In one 6 month study, doses of fluticasone propionate administered were 60, 150 or 450 mcg/animal/day, while in the second study, groups received 68, 170 or 510 mcg/animal/day. In a third study, dogs received 7.5, 18 or 50.7 mcg/animal/day for 12 months.
The most commonly observed dose related clinical signs were characteristic corticosteroid effects consisting of poor coat and/or skin condition, increased hair loss, loose feces, distended abdomen and obesity.
Hematological and biochemical parameters were typical of glucocorticoid overdosage and consisted of a moderate to marked leukopenia and lymphopenia and increased erythrocytes, serum enzymes, protein and cholesterol.
Dose related histopathological changes consisted of thymic involution, adrenal atrophy, lymphoid depletion in lymph nodes and spleen, and glycogenic infiltration of the liver. No histopathological changes were seen in the respiratory tract after inhalation of fluticasone propionate.
Most of the fluticasone propionate-induced changes showed a rapid regression after cessation of treatment by inhalation. Some symptoms persisted throughout the recovery period after subcutaneous administration probably due to prolonged release of fluticasone propionate from subcutaneous depots.
Two dogs (510 mcg/day group, 26 weeks) died of opportunistic infections as a result of reduced immunocompetence arising from excess corticosteroid administration.
Fluticasone propionate did not induce gene mutation in prokaryotic microbial cells, and there was no evidence of toxicity or gene mutational activity in eukaryotic Chinese hamster cells in vitro. The compound did not induce point mutation in the Fluctuation assay, and did not demonstrate gene convertogenic activity in yeast cells. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro, and fluticasone propionate was not demonstrably clastogenic in the mouse micronucleus test when administered at high doses by oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.
Subcutaneous studies in the mouse and rat at 150 and 100 mcg/kg/day respectively, revealed maternal and fetal toxicity characteristic of potent glucocorticoid compounds, including reduction in maternal weight gain, embryonic growth retardation, increased incidences of retarded cranial ossification, and of omphalocele and cleft palate in rats and mice, respectively.
In the rabbit, subcutaneous doses of 30 mcg/kg/day and above were incompatible with sustained pregnancy. This is not unexpected since rabbits are known to be particularly sensitive to glucocorticoid treatment.
These parenteral doses are approximately 10-100 times the recommended human intranasal dose (200 mcg/day).
Following oral administration of fluticasone propionate up to 300 mcg/kg to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal fetal defects. A very small fraction (<0.005%) of the dose crossed the placenta following oral administration to rats (100 mcg/kg/day) and rabbits (300 mcg/kg/day).
No treatment related effects were observed on the type or incidence of neoplasia in an 18 month oral (gavage) study in mice administered fluticasone propionate at dose levels of up to 1 mg/kg/day. In a lifetime (2 years) snout-only inhalation study in rats, at dose levels of up to 57 mcg/kg/day, there was an increase in the incidence of tumours in the mammary gland, liver and pancreas. These were not considered as evidence of tumorigenic effect of fluticasone propionate based on the absence of statistical support of an increase in incidence and the historical tumour incidence data.
Intranasal administration of fluticasone propionate aqueous nasal spray to cynomolgus monkeys for 28 days at 400 mcg/day did not cause local irritancy to the nasal cavity or respiratory tract, or systemic toxicity.
Micronised fluticasone propionate was considered to be non-irritating in the rabbit eye when assessed using a modified Draize test and, in the guinea pig split adjuvant test for evaluating contact sensitivity, results were completely negative.
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