Nasal Allergy and Congestion Relief Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS

NASAL ALLERGY AND CONGESTION RELIEF (mometasone furoate aqueous nasal spray) is indicated for use in adults and children of 12 years and older to treat the symptoms of seasonal or perennial allergic rhinitis.

Full effect depends on continued use. Therefore, regular usage is essential since symptoms relief may be obtained only after 12 to 48 hours of treatment.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

NASAL ALLERGY AND CONGESTION RELIEF should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections or ocular herpes simplex.

WARNINGS AND PRECAUTIONS

General

During transfer from systemic corticosteroid to NASAL ALLERGY AND CONGESTION RELIEF, some patients may experience symptoms of withdrawal from systemically active corticosteroids (e.g., joint and/or muscular pain, lassitude, and depression initially) despite relief from nasal symptoms and will require encouragement to continue NASAL ALLERGY AND CONGESTION RELIEF therapy.

Such transfer may also unmask pre-existing allergic conditions such as allergic conjunctivitis and eczema, previously suppressed by systemic corticosteroid therapy.

Ear/Nose/Throat

NASAL ALLERGY AND CONGESTION RELIEF should not be used in the presence of untreated localized infection involving the nasal mucosa.

Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal surgery or trauma should not use a nasal corticosteroid until healing has occurred.

Following 12 months of treatment with mometasone furoate aqueous nasal spray, there was no evidence of atrophy of the nasal mucosa; also, mometasone furoate tended to reverse the nasal mucosa closer to a normal histologic phenotype. As with any long-term treatment, patients using NASAL ALLERGY AND CONGESTION RELIEF over several months or longer should be examined periodically for possible changes in the nasal mucosa. If localized fungal infection of the nose or pharynx develops, discontinuance of NASAL ALLERGY AND CONGESTION RELIEF therapy or appropriate treatment may be required. Persistence of nasopharyngeal irritation may be an indication for discontinuing NASAL ALLERGY AND CONGESTION RELIEF.

Following the use of intranasal aerosolized corticosteroids, instances of nasal septum perforation have been reported very rarely.

Endocrine and Metabolism

There is no evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression following prolonged (12 months) treatment with mometasone furoate aqueous nasal spray. However, patients who are transferred from long-term administration of systemically active corticosteroids to NASAL ALLERGY AND CONGESTION RELIEF require careful attention. Systemic corticosteroid withdrawal in such patients may result in adrenal insufficiency for a number of months until recovery of HPA axis function. If these patients exhibit signs and symptoms of adrenal insufficiency, systemic corticosteroid administration should be resumed and other modes of therapy and appropriate measures instituted.

Although this has not been observed with mometasone furoate aqueous nasal spray, when intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects may occur, such as hypercorticism, suppression of HPA function and/or reduction of growth velocity in children or teenagers. Children should be maintained on the lowest dose which delivers adequate symptom control.

Immune

Patients receiving corticosteroids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs.

Ophthalmologic

Following the use of intranasal aerosolized corticosteroids, instances of increased intraocular pressure have been reported very rarely.

Visual disturbance may be reported with systemic and topical (including, intranasal, inhaled and intraocular) 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 of visual disturbances; this may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Special Populations

Pregnancy and Nursing Mothers

There are no adequate or well-controlled studies in pregnant or nursing women.

As with other nasal corticosteroid preparations, NASAL ALLERGY AND CONGESTION RELIEF should be used in pregnant women, nursing mothers or women of childbearing age only if the potential benefit justifies the potential risk to the mother, fetus, or infant. Infants born of mothers who received corticosteroids during pregnancy should be observed carefully for hypoadrenalism.

Pediatrics

Mometasone furoate aqueous nasal spray permitted normal growth in a placebo-controlled clinical trial in which pediatric patients were administered mometasone furoate aqueous nasal spray 100 mcg daily for one year.

Although not observed with mometasone furoate aqueous nasal spray, other intranasal corticosteroids have been shown to cause growth suppression in children and teenagers, particularly with higher doses over extended periods. If a child or teenager on any corticosteroids appears to have growth suppression, the possibility that they are particularly sensitive to this effect of steroids should be considered.

The potential of mometasone furoate aqueous nasal spray 50 mcg to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out.

ADVERSE REACTIONS

Rarely, immediate hypersensitivity reactions (e.g., bronchospasm, dyspnea) may occur after intranasal administration of mometasone furoate. Very rarely, anaphylaxis and angioedema have been reported.

Disturbances of taste and smell have been reported very rarely.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Allergic Rhinitis:

Adults and adolescents ≥12 years of age: Table 1 demonstrates the incidence of treatment related adverse reactions associated with mometasone furoate aqueous nasal spray based upon the pooled data from clinical trials.

Table 1 Treatment related adverse reactions occurring at an incidence of ≥1% and more commonly than placebo

Adverse Reactions

* 50 mcg to 800 mcg of mometasone furoate daily

Treatment-related local adverse events reported in clinical studies, headache, epistaxis (e.g., frank bleeding, blood-tinged mucus, and blood flecks), pharyngitis, and nasal ulceration are typically observed with use of a corticosteroid nasal spray. In addition, the following adverse events occurred at a frequency equal to or less than placebo, nasal burning (2% vs. 3%) and nasal irritation (2% vs. 2%), respectively.

Epistaxis was generally self-limiting and mild in severity, and occurred at a higher incidence compared to placebo (5%), but at a comparable or lower incidence compared to the active control nasal corticosteroids studied (up to 15%). The incidence of all other effects was comparable with that of placebo.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

The following additional treatment related adverse reactions occurred in clinical trials in patients using mometasone furoate aqueous nasal spray with an incidence of <1% and occurred at a greater incidence than placebo*:

Blood and lymphatic system disorders: lymphadenopathy

Cardiac disorders: palpitation, tachycardia

Eye disorders: lacrimation, conjunctivitis, dry eyes, abnormal vision

Ear and labyrinth disorders: earache, tinnitus

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, gastritis, nausea, tongue disorder, tooth disorder

General disorders and administration site conditions: dry mouth, allergy aggravated, chest pain, edema, face edema, fever, influenza like symptoms, thirst, taste perversion

Infections and infestations: cold sore non herpetic, infection, bacterial infection

Investigations: hepatic enzymes increased

Musculoskeletal and connective tissue disorders: arthralgia, myalgia

Nervous system disorders: tremor, vertigo, migraine

Psychiatric disorders: depression, paranoia, somnolence

Respiratory, thoracic and mediastinal disorders: dysphonia, bronchitis, dyspnea, laryngitis, nasal septum ulceration, sinusitis, wheezing

Skin and subcutaneous tissue disorders: acne, dermatitis, erythematous rash

Vascular disorders: hypertension

*Events reported by more than 1 patient

Post-Market Adverse Drug Reactions

The following adverse reactions have been identified during the post-marketing period for mometasone furoate aqueous nasal spray: anaphylaxis and angioedema, disturbances in smell and nasal septal perforation, vision blurred. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS

Drug-Drug Interactions

Mometasone furoate aqueous nasal spray has been administered concomitantly with loratadine with no apparent effect on plasma concentrations of loratadine or its major metabolite. In these studies, mometasone furoate plasma concentrations were not detectable using an assay with a LLOQ of 50 pg/mL. The combination therapy was well tolerated.

Inhibitors of Cytochrome P450 3A4: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. Mometasone furoate is metabolized by CYP3A4. After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased, and plasma cortisol levels appeared to decrease.

Co-treatment with CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, saquinavir, ritonavir, cobicistat-containing products), is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

DOSAGE AND ADMINISTRATION

Dosing Considerations

The therapeutic effects of corticosteroids, unlike those of decongestants, are not immediate. Since the effect of NASAL ALLERGY AND CONGESTION RELIEF depends on its regular use, patients should be instructed to take the nasal inhalation at regular intervals and not, as with other nasal sprays, as they feel necessary.

In the presence of excessive nasal mucous secretion or edema 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 2 to 3 days prior to starting treatment with NASAL ALLERGY AND CONGESTION RELIEF.

Recommended Dose and Dosage Adjustment

Treatment of seasonal or perennial allergic rhinitis:

Adults (including geriatric patients) and children 12 years of age and older: The usual recommended dose is two sprays (50 mcg/spray) in each nostril once daily (total daily dose of 200 mcg). Once symptoms are controlled, dose reduction to one spray in each nostril once daily (total daily dose 100 mcg) may be effective for maintenance.

If symptoms are inadequately controlled, the dose may be increased to four sprays in each nostril once daily (total daily dose of 400 mcg). Dose reduction is recommended following control of symptoms.

Clinically significant onset of action occurs as early as 12 hours after the first dose.

Administration

Each actuation delivers approximately 100 mg of mometasone furoate suspension, containing 50 mcg mometasone furoate. Prior to administration, NASAL ALLERGY AND CONGESTION RELIEF pump should be primed by actuating the pump 10 times (until a uniform spray is observed). If the spray pump has not been used for 14 days or longer, it should be reprimed with 2 actuations, until a uniform spray is observed, before next use.

SHAKE CONTAINER WELL BEFORE EACH USE.

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.

OVERDOSAGE

Because the systemic bioavailability is <1% (using a sensitive assay with a lower quantitation limit of 0.25 pg/mL) after administration of mometasone furoate via mometasone furoate aqueous nasal spray, overdose is unlikely to require any therapy other than observation, followed by initiation of the appropriate prescribed dosage.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties at doses that are minimally systemically active.

Pharmacodynamics

In two clinical studies utilizing nasal antigen challenge, mometasone furoate aqueous nasal spray has shown anti-inflammatory activity in both the early- and late-phase allergic responses. This has been demonstrated by decreases (vs. placebo) in histamine and eosinophil activity and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these finding is not known.

Two Phase I studies conducted to assess the systemic exposure and tolerability of mometasone furoate aqueous nasal spray in children aged 3 to 12 years showed no clinically relevant systemic exposure to mometasone furoate aqueous nasal spray and indicated that mometasone furoate aqueous nasal spray was well tolerated. A third Phase I study in children aged 6 to 12 years showed normal short-term lower leg growth velocity.

The results of Phase II and Phase III studies indicated no evidence of HPA (hypothalamic-pituitary-adrenal) axis suppression following treatment with mometasone furoate aqueous nasal spray and demonstrated that mometasone furoate aqueous nasal spray can alleviate the allergic symptoms in pediatric patients aged 3 to 12 years with seasonal and perennial allergic rhinitis.

Pharmacokinetics

Absorption:

Mometasone furoate, administered as a nasal spray, has a systemic bioavailability of <1% in plasma, using a sensitive assay with a lower quantitation limit (LLOQ) of 0.25 pg/mL. Mometasone furoate suspension is very poorly absorbed from the gastrointestinal tract, and the small amount that may be swallowed and absorbed undergoes extensive first-pass metabolism prior to excretion in urine and bile.

Distribution:

The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.

Metabolism:

Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6ß-hydroxymometasonefuroate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4 (CYP3A4).

Elimination:

Following intravenous administration, the effective plasma elimination half-life of mometasone furoate is 5.8 hours. Any absorbed drug is excreted as metabolites mostly via the bile, and to a limited extent, into the urine.

STORAGE AND STABILITY

NASAL ALLERGY AND CONGESTION RELIEF should be stored between 2°C and 25°C

(36°F and 77°F) and protected from light. Do not freeze.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

NASAL ALLERGY AND CONGESTION RELIEF is formulated as an aqueous nasal suspension for nasal administration via a metered-dose manual pump spray delivering 140 doses of 50 mcg mometasone furoate.

Composition

Each actuation delivers approximately 100 mg of mometasone furoate suspension, containing 50 mcg of mometasone furoate.

The nonmedicinal ingredients include benzalkonium chloride, citric acid, glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, polysorbate 80, purified water and sodium citrate dihydrate.

Packaging

NASAL ALLERGY AND CONGESTION RELIEF is supplied in a single pack (1 bottle).

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Mometasone furoate

Chemical Name: 1) Pregna-1,4-diene-3,20-dione, 9,21-dichloro-17-[(2-furanylcarbonyl)

oxy]-11-hydroxy-16-methyl-, (11 β, 16α)-

1. 2) 9,21-Dichloro-11β, 17-dihydroxy-16α-methylpregna-1,4-diene-3,20 -dione 17-(2-furoate)
2. 3) 9,21-Dichloro-11β-hydroxy-16α-methyl-3,20-dioxopregna-1,4-dien-17-yl furan-2-carboxylate

Molecular formula: C₂₇H₃₀Cl₂O₆

Molecular weight: 521.43 g/mol

Structural Formula:

O O O Cl O O CH₃ OH CH₃ Cl CH₃ H H

Physicochemical properties:

Description: White to off-white powder

Solubility: Practically insoluble in water, slightly soluble in methanol, ethanol (96%) and isopropanol, soluble in acetone, chloroform and methylene chloride, freely soluble in tetrahydrofuran.

CLINICAL TRIALS

Comparative Bioavailability Studies

A clinical efficacy study was conducted between August and November 2005 to demonstrate bioequivalence. The study consisted of a double blind, multi-center, placebo controlled, parallel group, randomized clinical study. Of the 559 subjects (male and female) who completed the placebo run-in period (Period 1) and were randomized to one of the three treatments (Period 2),

506 subjects met the criteria for clinical equivalency analysis and 555 subjects were eligible for the clinical efficacy analysis. Drug concentration/time profiles and pharmacokinetic parameters were not determined in this study.

The primary efficacy and equivalence measures were based on the average morning and evening Reflective TNSS of rhinorrhea, nasal congestion, nasal itchiness and sneezing. The endpoint was the change in Reflective TNSS from baseline to the average of the data from the 14 days of treatment.

The secondary efficacy and equivalence measures were based on the average morning and evening Instantaneous TNSS of rhinorrhea, nasal congestion, nasal itchiness and sneezing. The endpoint was the change in Instantaneous TNSS from baseline to the average of the data from the 14 days of treatment. The following tables summarize the results of the clinical study:

A randomized, single dose, 2-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male and female volunteers. The rate and extent of absorption of mometasone furoate was measured and compared following a 200 mcg dose (total of 4 sprays of 50 mcg, administered as 2 sprays into each nostril) of NASAL ALLERGY AND CONGESTION RELIEF (mometasone furoate) 50 mcg/metered dose aqueous nasal spray (Apotex Inc.) and NASONEX^® Nasal Spray (mometasone furoate), 50 mcg (Schering corporation in 94 volunteers. The results from measured data for 90 volunteers are summarized in the following table:

Treatment of allergic rhinitis

Seasonal allergic rhinitis in adolescents and adults

The safety and efficacy of mometasone furoate aqueous nasal spray in the treatment of patients with seasonal allergic rhinitis (aged 12 years and over) was investigated in six clinical trials. Altogether, these trials enrolled a total of 2544 patients of whom 718 were randomized to treatment with mometasone furoate aqueous nasal spray 200 mcg once daily.

The results of three phase III clinical trials (14- or 28-day studies) with a total of 788 patients who received mometasone furoate aqueous nasal spray or placebo and evaluated for efficacy are presented in Table 2. The primary efficacy endpoint was the change from baseline in Physician-Evaluated Total Nasal Symptom Score (TNSS) after one week of therapy in Study I92-200. In studies C93-013 and I94-001, the primary efficacy endpoint was the change from baseline in Patient-Evaluated Total Nasal Symptom Score over Days 1 to 15.

Table 2 Effect of Mometasone furoate nasal spray in Phase III, Randomized, Placebo-Controlled Trials in patients with SAR

* P < 0.01 vs. placebo.

¹ Physician-Evaluated Total Nasal Symptom Score (TNSS). Total of individual nasal symptoms combined (rhinorrhea, nasal stuffiness/congestion, nasal itching and sneezing). Symptoms were scored according to the following rating system; 0 = none, 1 = mild, 2 = moderate, 3 = severe.

² Patient-Evaluated Total Nasal Symptom Score (TNSS). Total of individual nasal symptoms combined (rhinorrhea, nasal stuffiness/congestion, nasal itching and sneezing). Symptoms were scored according to the following rating system; 0 = none, 1 = mild, 2 = moderate, 3 = severe.

³ Percent change is the difference between post treatment mean score and baseline mean score divided by Baseline mean score, multiplied by 100.

Perennial allergic rhinitis in adolescents and adults

The safety and efficacy of mometasone furoate aqueous nasal spray in the treatment of patients (aged 12 and over) with perennial allergic rhinitis (PAR) was investigated in three phase III clinical trials of 12-week duration in 875 patients who received mometasone furoate aqueous nasal spray or placebo and evaluated for efficacy.

The primary efficacy endpoint was the change from baseline in Patient-Evaluated Total Nasal Symptom Score (TNSS) from Days 1 to 15. Results of these studies are presented in Table 3.

Table 3 Patient-Evaluated Total Nasal Symptom Score¹ (TNSS) Results of Trials in Patients with PAR

* P = 0.01 vs. placebo; ** P < 0.01 vs. placebo.

¹ Total of individual nasal symptoms combined (rhinorrhea, nasal stuffiness, nasal itching and sneezing). Symptoms were scored according to the following rating system; 0 = none, 1 = mild, 2 = moderate, 3 = severe.

² Percent change is the difference between post treatment mean score and baseline mean score divided by Baseline mean score, multiplied by 100.

DETAILED PHARMACOLOGY

Animal

Pharmacodynamics

In cell culture, mometasone furoate was shown to be at least ten times more potent than other steroids, including beclomethasone dipropionate (BDP), betamethasone, hydrocortisone and dexamethasone, at inhibiting the synthesis/release of IL-1, IL-6 and TNFa. Mometasone furoate (IC₅₀ = 0.12 nM) was also at least six times more potent than BDP and betamethasone at inhibiting IL-5 production.

In a preclinical model, the compound has been shown to reduce the accumulation of eosinophils markedly at the site of an allergic reaction. For example, in allergic mice with IgE-mediated allergy, inhaled mometasone furoate at doses as low as 13 mcg/kg inhibited eosinophil infiltration into bronchoalveolar lavage fluid and the lung bronchi and bronchioles. Additionally, mometasone furoate reduced the number of lymphocytes, and the levels of messenger RNA for the proallergic cytokines IL-4 and IL-5.

Mometasone furoate is devoid of androgenic, antiandrogenic, estrogenic or antiestrogenic activity but, like other glucocorticosteroids, it exhibits some antiuterotrophic activity and delays vaginal opening in animal models at high oral doses of 56 mg/kg/day and 280 mg/kg/day. In general pharmacodynamic activity studies, mometasone furoate did not show mineralocorticoid activity. MF did not exert prominent effects on the central or autonomic nervous system. No significant effect was seen on blood pressure, heart rate, or ECG recordings. Mometasone furoate did not alter secretion of gastric acid, pepsin or bile. Mometasone furoate increased urine volume and potassium secretion only at very high doses given subcutaneously. No effect was seen on basic respiratory function. These results suggest no particular adverse effect or class of effects associated with administration of mometasone furoate.

Pharmacokinetics

The intranasal administration of mometasone furoate suspension resulted in either very low / dose-proportional / gender independent or nonquantifiable plasma drug concentrations. Similar results were seen for total radioactivity upon intranasal dosing with radiolabeled drug.

By comparison with the AUC following IV dosing, the absolute bioavailability of MF following intranasal administration was less than 1% in rats and dogs, and following PO (suspension) administration was 1.4% in rats and 1.7% in mice. In dogs, plasma drug concentrations were generally not quantifiable following PO administration of the MF suspension. The pharmacokinetics of mometasone furoate in the mouse, rat and especially dog, were quite comparable to those obtained in humans.

Human

Pharmacology

Mometasone furoate significantly inhibits the release of leukotrienes from leukocytes of allergic patients. In addition, it is an inhibitor of the production of the Th₂ cytokines, IL-4 and IL-5, from human CD4+ T-cells.

In two clinical studies using nasal antigen challenge, mometasone aqueous nasal spray has shown anti-inflammatory activity in both the early and late phase allergic responses. This has been demonstrated by decreases (versus placebo) in histamine and eosinophil activity and reductions (versus baseline) in eosinophils, neutrophils and epithelial cell adhesion proteins. The clinical significance of these findings is not known.

In patients with seasonal allergic rhinitis, mometasone furoate aqueous nasal spray demonstrated a clinically significant onset of action within 12 hours of the first dose.

In children, results from plasma samples assayed for mometasone furoate aqueous nasal spray from one clinical study (Phase III) and two multiple-dose Phase I studies confirmed the general absence of systemic plasma concentrations following intranasal administration of mometasone furoate aqueous nasal spray.

Pharmacokinetics

Mometasone furoate, administered as an aqueous nasal spray, has a systemic bioavailability of <1% in plasma, using a sensitive assay with a lower quantitation limit (LLOQ) of 0.25 pg/mL. Mometasone furoate suspension is very poorly absorbed from the gastrointestinal tract, and the small amount that may be absorbed undergoes extensive first-pass hepatic metabolism prior to excretion in urine and bile.

TOXICOLOGY

In a series of studies designed to maximize exposure to mometasone furoate, there was no unique or special finding regardless of route of administration or formulation. In single- and multiple-dose toxicology studies and in reproductive toxicity studies, all findings were typical glucocorticoid class effects and obeyed the well-established dose-response and dose-duration relationships for systemic pharmacologic effects of glucocorticoids. Difficult and prolonged parturition observed in Segment I and Segment III reproduction studies may be related to the progestational effect of mometasone furoate. Reductions in maternal weight gain, fetal weight, and offspring viability, and the occurrence of typical malformations and skeletal variations (reduced ossification) were glucocorticoid class effects.

Based on results of multiple mutagenicity studies and of two carcinogenicity studies, one each in mice and rats, mometasone furoate should not pose a genetic hazard or increase the risk of cancer to patients exposed in a clinical setting. In particular, there was no statistically significant dose-response relationship for any tumour type in either the mouse or rat carcinogenicity study. In the study with mice, an apparent increase in mesenchymal tumours of the bladder and seminal vesicles was considered to have no relevance to assessment of human risk because it is a species- and strain- specific finding without a human correlate. An apparent increase in incidence of pancreatic cell hyperplasia in mid- and high-dose groups (1.0 and 2.0 mcg/L, respectively), and islet cell neoplasia in the high-dose group of male rats was attributed to the well-established metabolic effects of prolonged administration of glucocorticoids (increased glucose and/or insulin resistance). Increases in the incidence of tumours of islet cells are induced by other steroids, and reflect a non-genotoxic mechanism in a species with unique endocrinologic sensitivity.

Acute Toxicity

Two acute inhalation toxicity studies were conducted in mice (i.e., 4-hr whole-body exposure to micronized, pure, mometasone furoate powder). In the first study, the mean estimated doses were 582 mg/kg (in mice) and 394 mg/kg (for rats), assuming 100% deposition. No clinical signs were observed in either species during the 36-day post-exposure observation period. However, lower body weights compared to pre-treatment values were observed in both species. In the second study, rats were exposed by whole body exposure to 0.68 mg/L micronized mometasone furoate powder for 4 hours, and then observed for 3 weeks. Weight loss occurred during the observation period; while rales, ano-genital staining, soft stools and emaciation were the principal clinical observations. At necropsy, several rats had discoloured lungs, small spleens and discoloured brown skin.

Multiple-Dose Toxicity

The intranasal irritation potential of mometasone furoate aqueous nasal suspensions were assessed in beagle dogs administered daily doses of up to 4.0 mg/dog for three days, one week or one month. The aqueous nasal suspensions did not induce irritation in the nasal mucosa, and no compound-related changes were observed after one month of administration.

Mometasone furoate aqueous nasal suspension was well tolerated in toxicity studies conducted in rats and dogs for 6 months. Rats received doses of up to 0.600 mg/kg (0.18 mg/day; 70 times the proposed human dose); dogs received doses of up to 0.15 mg/kg (2.0 mg/day; 35 times the proposed human dose). Rats treated with 0.6 mg/kg experienced hair loss on the back during the last 5 weeks, which correlated with hypotrichosis. The no-effect dose for pharmacologic effects in rats was 0.050 mg/kg based on low body weight gains at higher doses. Dogs treated with 0.15 mg/kg demonstrated eosinophil counts, which were lower than pre-test and concurrent controls after 4, 13 and 26 weeks. In addition, ACTH response in the 0.045 and 0.15 mg/kg dose groups was lower than control. These differences were dose-related and were attributed to mometasone furoate. No evidence of nasal irritation was present at any dose in either the rat or the dog study. No target organs of systemic toxicity were identified in either study.

Mometasone furoate aqueous nasal spray was well tolerated when administered intranasally to dogs for one year at doses of up to 2.0 mg/day. In the 2.0 mg/day dose group, an increased incidence of alopecia, minimal decreases in lymphocytes and eosinophils, decreases in basal and post-ACTH cortisol response, lower adrenal gland weights, small or atrophied adrenal glands, epidermal atrophy, minimal splenic lymphoid atrophy, minimal focal epithelial attenuation in the nasal turbinates and retained luminal mucus were observed. Dogs treated with ≥ 0.2 mg/day demonstrated a dose-related increase in smaller or absent lymphoid aggregates. With the exception of minimally increased retained luminal mucus in the 2.0 mg/day dose group, there was no evidence of irritation or inflammation in the nasal turbinates of mometasone furoate-treated dogs. Thus, the changes in the lymphoid aggregates were considered a localized corticosteroid response associated with application and were not considered to be of toxicologic significance.

Mutagenicity

Mometasone furoate was nonmutagenic in the mouse lymphoma assay and the salmonella/mammalian microsome mutagenicity bioassay. Mometasone furoate was negative in the mouse bone marrow erythrocyte micronucleus assay, the rat bone marrow clastogenicity assay, the UDS assay in rat hepatocytes and the mouse mitotic male germ-cell clastogenicity assay, and the Chinese hamster lung cell chromosomal aberrations assay. At cytotoxic doses in Chinese hamster ovary cell cultures, mometasone furoate induced a dose-related increase in simple chromosome aberrations when continuously exposed (7.5 hours) in the nonactivation phase, but not in the presence of rat liver S9 fraction. This finding is not considered to be of significance in the risk assessment of mometasone furoate, since the S9 phase of the chromosomal-aberration assay and all in vivo assays were negative.

Carcinogenicity

The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 mcg/L was investigated in 24-month studies in mice and rats. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumour types. The apparent increase in mouse bladder/seminal vesicle mesenchymal tumours is considered to have no relevance in human carcinogenic risk assessment since it is a species- and strain-specific finding with no human correlate. The greater incidence of pancreatic islet cell hyperplasia in male rats who received 1.0 and 2.0 mcg/L is attributed to the well-established metabolic effects (increased glucose and/or insulin resistance) following prolonged administration of glucocorticoids. Increases in pancreatic islet cell tumours, which are induced by other steroids, reflects a non-genotoxic mechanism operative in an endocrinologically uniquely sensitively species.

Reproductive Toxicology

In subcutaneous Segment I and III studies, mometasone furoate was well tolerated at doses up to 7.5 mcg/kg (2.6 times the human dose by inhalation). At 15 mcg/kg, prolonged gestation and prolonged and difficult labour occurred with a reduction in offspring survival and body weight gain or body weight gain. There was no effect on fertility. Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal), and/or subcutaneous routes. Umbilical hernia occurred in rats administered ≥ 600 mcg/kg dermally, cleft palate in mice administered 180 mcg/kg subcutaneously, and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits administered ≥ 150 mcg/kg dermally. In these teratogenicity studies, there were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.

REFERENCES

1. 1. Hebert JR, Nolop K, Lutsky BN. Once-daily mometasone furoate aqueous nasal spray (NASONEX^®) in seasonal allergic rhinitis: an active- and placebo-controlled study. Allergy 1996;51:569-576.
2. 2. Drouin M, Yang WH, Bertrand B et al. Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclomethasone dipropionate for treating perennial allergic rhinitis patients. Ann Allergy Asthma Immunol 1996;77:153-160.
3. 3. Brannan MD, Herron JM, Affrime MB. Safety and tolerability of once daily mometasone furoate aqueous nasal spray in children. Clin Ther 1997;19:1330-1339.
4. 4. Davies RJ, Nelson HS. Once-Daily mometasone furoate nasal spray: Efficacy and Safety of a New intranasal glucocorticoid for allergic rhinitis. Clinical Therapeutic, Vol 19, No. 1, 1997.
5. 5. Mandl M., Nolop K, Lutsky BN. Comparison of once daily mometasone furoate (NASONEX^®) and fluticasone propionate aqueous nasal sprays for the treatment of perennial rhinitis. Annals of Allergy, asthma & Immunology, Oct 1997, pp. 370-378.
6. 6. Minshall E, Graffar O, Cameron L et al. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (NASONEX^®) in the treatment of perennial rhinitis. Otolaryngology-head and neck surgery, Volume 118, Number 5, pp. 648-654.
7. 7. Stjärne P, Mösges, R, Jorissen M et al. A randomized controlled trial of mometasone furoate nasal spray for the treatment of nasal polyposis. Otolaryngology-head and neck surgery, Volume 132, Feb 2006, pp. 179-185.
8. 8. Small BC, Hernandez J, Reyes A et al. Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. J Allergy Clin Immunol, Volume 116, Number 6, December 2005, pp. 1275-1281.
9. 9. Meltzer E, Bachert C et al. Treating Acute Rhinosinusitis: Comparing Efficacy and safety of mometasone furoate nasal spray, amoxicillin and placebo., J Allergy Clin Immunol, Volume 116, Number 6, December 2005, pp. 1289-1295.
10. 10. P05002. SCH 32088: Evaluation of the Nasal and Sinus Deposition, Nasal Retention Pattern, and Systemic Exposure to Mometasone Furoate After Nasal Inhalation From a NASONEX^® Nasal Spray and Alternative Formulations/Devices.
11. 11. NASONEX ALLERGY AND CONGESTION (mometasone furoate monohydrate nasal spray, 50 mcg/metered spray), Submission Control 170095, Product Monograph, Schering-Plough Canada Inc. (June 19, 2014)
12. 12. APO-MOMETASONE (mometasone furoate aqueous nasal spray, 50 mcg/metered spray), Submission Control 268344, Product Monograph, Apotex Inc. (November 2, 2022)