Nasonex

Indications : Rhinitis, perennial allergic; Rhinitis, seasonal allergic

Pregnancy Category C

FDA Approved 1997 Sep

BRAND NAMES : Nasonex (US);

DESCRIPTION :

Mometasone furoate monohydrate is an anti-inflammatory corticosteroid having the chemical name, 9,21-Dichloro-11beta,17-dihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) monohydrate.

Mometasone furoate monohydrate is a white powder, with an empirical formula of C27H30CI2O8·H2O, and a molecular weight of 539.45. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone and chloroform; and freely soluble in tetrahydrofuran. Its partition coefficient between octanol and water is greater than 5000.

Nasonex nasal spray, 50 mug is a metered-dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, 0.25% w/w phenylethyl alcohol, citric acid, benzalkonium chloride, and polysorbate 80. The pH is between 4.3 and 4.9.

After initial priming (10 actuations), each actuation of the pump delivers a metered spray containing 100 mg of suspension containing mometasone furoate monohydrate equivalent to 50 mug of mometasone furoate calculated on the anhydrous basis. Each bottle of Nasonex nasal spray, 50 mug provides 120 sprays.

CLINICAL PHARMACOLOGY :

Mometasone furoate is a corticosteroid demonstrating anti-inflammatory properties. The precise mechanism of corticosteroid action on allergic rhinitis is not known. 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.

Mometasone furoate demonstrated no mineralocorticoid, androgenic, antiandrogenic, or estrogenic activity in preclinical studies. After administration of a single intranasal dose of mometasone furoate to adult male rats, the highest drug levels were seen in the esophagus, trachea, nasal passage, and mouth.

In two clinical studies utilizing nasal antigen challenge, mometasone furoate decreased some markers of the early- and late-phase allergic response. These observations included decreases (vs. placebo) in histamine and eosinophil cationic protein levels, and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known.

The effect of mometasone furoate on nasal mucosa following 12 months of treatment was examined in 46 patients with allergic rhinitis. There was no evidence of atrophy and there was a marked reduction in intraepithelial eosinophilia and inflammatory cell infiltration (e.g., eosinophils, lymphocytes, monocytes, neutrophils, and plasma cells).

Pharmacokinetics

Absorption : Mometasone furoate monohydrate administered as a nasal spray is virtually undetectable in plasma despite the use of a sensitive assay with a lower quantitation limit (LOQ) of 50 pcg/ml.

Metabolism : Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites.

Excretion : 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.

Special Populations

The effects of renal impairment, hepatic impairment, age, or gender on mometasone furoate pharmacokinetics have not been adequately investigated.

Pharmacodynamics

Three clinical pharmacology studies have been conducted in humans to assess the effect of mometasone furoate at various doses on adrenal function. In one study, daily doses of 200 and 400 mug of mometasone furoate and 10 mg of prednisone were compared to placebo in 64 patients with allergic rhinitis. Adrenal function before and after 36 consecutive days of treatment was assessed by measuring plasma cortisol levels following a 6-hour Cortrosyn (ACTH) infusion and by measuring 24-hour urinary-free cortisol levels. Mometasone furoate, at both the 200 and 400 mug dose, was not associated with a statistically significant decrease in mean plasma cortisol levels post-Cortrosyn infusion or a statistically significant decrease in the 24-hour urinary-free cortisol levels compared to placebo. A statistically significant decrease in the mean plasma cortisol levels post-Cortrosyn infusion and 24-hour urinary-free cortisol levels was detected in the prednisone treatment group compared to placebo.

A second study assessed adrenal response to mometasone furoate (400 and 1600 mug/day), prednisone (10 mg/day), and placebo, administered for 29 days in 48 male volunteers. The 24-hour plasma cortisol area under the curve (AUC0-24), during and after an 8-hour Cortrosyn infusion and 24-hour urinary-free cortisol levels were determined at baseline and after 29 days of treatment. No statistically significant differences of adrenal function were observed with mometasone furoate compared to placebo.

A third study evaluated single, rising doses of mometasone furoate (1000, 2000, and 4000 mug/day), orally administered mometasone furoate (2000, 4000, and 8000 mug/day), orally administered dexamethasone (200, 400, and 800 mug/day), and placebo (administered at the end of each series of doses) in 24 male volunteers. Dose administrations were separated by at least 72 hours. Determination of serial plasma cortisol levels at 8 AM and for the 24-hour period following each treatment were used to calculate the plasma cortisol area under the curve (AUC0-24). In addition, 24-hour urinary-free cortisol levels were collected prior to initial treatment administration and during the period immediately following each dose. No statistically significant decreases in the plasma cortisol AUC, 8 AM cortisol levels, or 24-hour urinary-free cortisol levels were observed in volunteers treated with either mometasone furoate or oral mometasone, as compared with placebo treatment. Conversely, nearly all volunteers treated with the 3 doses of dexamethasone demonstrated abnormal 8 AM cortisol levels (defined as a cortisol level <10 mug/dl), reduced 24-hour plasma AUC values, and decreased 24-hour urinary-free cortisol levels, as compared to placebo treatment.

CLINICAL STUDIES :

The efficacy and safety of mometasone furoate in the prophylaxis and treatment of seasonal allergic rhinitis and the treatment of perennial allergic rhinitis have been evaluated in 18 controlled trials, and one uncontrolled clinical trial, in approximately 3000 adults (age 17-85) and adolescents (age 12-16). This included 1757 males and 1453 females, including a total of 283 adolescents (182 boys and 101 girls) with seasonal allergic or perennial allergic rhinitis, treated with mometasone furoate at doses ranging from 50 to 800 mug/day. The majority of patients were treated with 200 mug/day. These trials evaluated the total nasal symptom scores that included stuffiness, rhinorrhea, itching, and sneezing. Patients treated with mometasone furoate 200 mug/day had a significant decrease in total nasal symptom scores compared to placebo-treated patients. No additional benefit was observed for mometasone furoate doses greater than 200 mug/day. A total of 350 patients have been treated with mometasone furoate for 1 year or longer.

In patients with seasonal allergic rhinitis, mometasone furoate demonstrated improvement in nasal symptoms (vs. placebo) within 2 days after the first dose. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing.

Prophylaxis of seasonal allergic rhinitis for patients 12 years of age and older with mometasone furoate, given at a dose of 200 mug/day, was evaluated in two clinical studies in 284 patients. These studies were designed such that patients received 4 weeks of prophylaxis with mometasone furoate prior to the anticipated onset of the pollen season, however, some patients received only 2 to 3 weeks of prophylaxis. Patients receiving 2 to 4 weeks of prophylaxis with mometasone furoate demonstrated a statistically significantly smaller mean increase in total nasal symptom scores with onset of the pollen season as compared to placebo patients.

INDICATIONS AND USAGE :

Mometasone furoate is indicated for the prophylaxis and treatment of the nasal symptoms of seasonal allergic rhinitis and the treatment of the nasal symptoms of perennial allergic rhinitis, in adults and children 12 years of age and older. In patients with a known seasonal allergen that precipitates nasal symptoms of seasonal allergic rhinitis, initiation of prophylaxis with mometasone furoate is recommended 2 to 4 weeks prior to the anticipated start of the pollen season.

CONTRAINDICATIONS :

Hypersensitivity to any of the ingredients of this preparation contraindicates its use.

WARNINGS :

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency and, in addition, some patients may experience symptoms of withdrawal (i.e., joint and/or muscular pain, lassitude, and depression). Careful attention must be given when patients previously treated for prolonged periods with systemic corticosteroids are transferred to topical corticosteroids, with careful monitoring for acute adrenal insufficiency in response to stress. This is particularly important in those patients who have associated asthma or other clinical conditions where too rapid a decrease in systemic corticosteroid dosing may cause a severe exacerbation of their symptoms.

If recommended doses of intranasal corticosteroids are exceeded or if individuals are particularly sensitive or predisposed by virtue of recent systemic steroid therapy, symptoms of hypercorticism may occur, including very rare cases of menstrual irregularities, acneiform lesions, and cushingoid features. If such changes occur, topical corticosteroids should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroid therapy.

Persons who are on drugs which 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 globin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

PRECAUTIONS :

General

In clinical studies with mometasone furoate, the development of localized infections of the nose and pharynx with Candida albicans has occurred only rarely. When such an infection develops, use of mometasone furoate should be discontinued and appropriate local or systemic therapy instituted, if needed.

Nasal corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infection of the respiratory tract, or in untreated fungal, bacterial, systemic viral infections, or ocular herpes simplex.

Rarely, immediate hypersensitivity reactions may occur after the intranasal administration of mometasone furoate monohydrate. Extreme rare instances of wheezing have been reported.

Rare instances of nasal septum perforation and increased intraocular pressure have also been reported following the intranasal application of aerosolized corticosteroids. As with any long-term topical treatment of the nasal cavity, patients using mometasone furoate over several months or longer should be examined periodically for possible changes in the nasal mucosa.

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

Glaucoma and cataract formation was evaluated in one controlled study of 12 weeks’ duration and one uncontrolled study of 12 months’ duration in patients treated with mometasone furoate at 200 mug/day, using intraocular pressure measurements and slit lamp examination. No significant change from baseline was noted in the mean intraocular pressure measurements for the 141 mometasone furoate-treated patients in the 12-week study, as compared with 141 placebo-treated patients. No individual mometasone furoate-treated patient was noted to have developed a significant elevation in intraocular pressure or cataracts in this 12-week study. Likewise, no significant change from baseline was noted in the mean intraocular pressure measurements for the 139 mometasone furoate-treated patients in the 12-month study and again, no cataracts were detected in these patients. Nonetheless, nasal and inhaled corticosteroids have been associated with the development of glaucoma and/or cataracts. Therefore, close follow-up is warranted in patients with a change in vision and with a history of glaucoma and/or cataracts.

When nasal corticosteroids are used at excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, mometasone furoate should be discontinued slowly, consistent with accepted procedures for discontinuing oral steroid therapy.

Information for the Patient

Patients being treated with mometasone furoate should be given the following information and instructions. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all intended or possible adverse effects. Patients should use mometasone furoate at regular intervals (once daily) since its effectiveness depends on regular use. Improvement in nasal symptoms of allergic rhinitis has been shown to occur within 2 days after the first dose. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing. Patients should take the medication as directed and should not increase the prescribed dosage by using it more than once a day in an attempt to increase its effectiveness. Patients should contact their physician if symptoms do not improve, or if the condition worsens. To assure proper use of this nasal spray, and to attain maximum benefit, patients should read and follow the accompanying Patient’s Instructions for Use carefully.

Patients should be cautioned not to spray mometasone furoate into the eyes.

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles, and patients should also be advised that if they are exposed, medical advice should be sought without delay.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at an inhalation dose of 67 mug/kg (approximately 3 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis). In Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at an inhalation dose of 160 mug/day (approximately 4 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis).

At cytotoxic doses, mometasone furoate produced an increase in chromosome aberrations in vitro in Chinese hamster ovary-cell cultures in the nonactivation phase, but not in the presence of rat liver S9 fraction. Mometasone furoate was not mutagenic in the mouse-lymphoma assay and the Salmonella /E.coli /mammalian microsome mutation assay, a Chinese hamster lung cell (CHL) chromosomal-aberrations assay, an in vivo mouse bone-marrow erythrocyte-micronucleus assay, a rat bone-marrow clastogenicity assay, and the mouse male germ-cell clastogenicity assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.

In reproductive toxicity studies in rats, mometasone furoate administered subcutaneously caused prolonged gestation, prolonged and difficult labor, reduced offspring survival, and reduced maternal body weight gain following treatment at 15 mug/kg (approximately ¾ the maximum recommended daily intranasal dose in adults on a mug/m2 basis). Impairment of fertility in rats was not produced by subcutaneous doses up to 15 mug/kg.

Pregnancy Category C

Teratogenic Effects : Mometasone furoate caused cleft palate in mice at subcutaneous doses of 60 and 180 mug/kg, (approximately 2 and 4 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis, respectively). Offspring survival was reduced in the 180 mug/kg group. The nonteratogenic subcutaneous dose level in mice was 20 mug/kg (approximately ½ the maximum recommended daily intranasal dose in adults on a mug/m2 basis).

In rabbits, mometasone furoate was teratogenic and caused flexed front paws at a topical dermal dose of 150 mug/kg (approximately 14 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis).

In rats, mometasone furoate produced umbilical hernia, cleft palate, and delayed ossification at a topical dermal dose of 600 mug/kg (approximately 30 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis). At 1200 mug/kg (approximately 60 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis), microphthalmia, umbilical hernias, and delayed ossification were observed in rat pups.

In these teratogenicity studies, there were also reductions in maternal body weight gain and effects on fetal growth (lower fetal body weights and/or delayed ossification) in mice (60 and 180 mug/kg), rabbits (150 mug/kg), and rats (600 mug/kg).

In an oral teratology study in rabbits, at 700 mug/kg, (approximately 70 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis), increased incidences of resorptions and malformations, including cleft palate and/or head malformations (hydrocephaly or domed head) were observed. Pregnancy failure was observed in most rabbits at 2800 mug/kg (approximately 270 times the maximum recommended daily intranasal dose in adults on a mug/m2 basis).

There are no adequate, and well-controlled studies in pregnant women. Mometasone furoate, like other corticosteroids, should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.

Nonteratogenic Effects : Hypoadrenalism may occur in infants born to women receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Nursing Mothers

It is not known if mometasone furoate is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be used when mometasone furoate is administered to nursing women.

Pediatric Use

Safety and effectiveness in children less than 12 years of age have not been established.

Geriatric Use

A total of 203 patients above 64 years of age (age range 64-85) have been treated with mometasone furoate for up to 3 months. The adverse reactions reported in this population were similar in type and incidence to those reported by younger patients.

ADVERSE REACTIONS :

In controlled US and International clinical studies, a total of 3210 patients received treatment with mometasone furoate at doses of 50 to 800 mug/day. The majority of patients (n = 2103) were treated with 200 mug/day. A total of 350 patients have been treated for 1 year or longer. The overall incidence of adverse events for patients treated with mometasone furoate was comparable to patients treated with the vehicle placebo. Also, adverse events did not differ significantly based on age, sex, or race.

Three percent of patients in clinical trials discontinued treatment because of adverse events; this rate was similar for the vehicle and active comparators.

All adverse events reported by 5% or more of patients (regardless of relationship to treatment) who received mometasone furoate 200 mug/day in clinical trials, and that were more common with mometasone furoate than placebo, are displayed in the table below.

TABLE 1 Adverse Events From Controlled Clinical Trials in Seasonal Allergic and Perennial Allergic Rhinitis (Percent of Patients Reporting)
Mometasone furoate 200 mug (N = 2103)
Vehicle Placebo (N = 1671)
Headache
26
22
Viral Infection
14
11
Pharyngitis
12
10
Epistaxis/Blood-Tinged Mucus
11
6
Coughing
7
6
Upper Respiratory Tract Infection
6
2
Dysmenorrhea
5
3
Musculoskeletal Pain
5
3
Sinusitis
5
3

 

Other adverse events which occurred in less than 5% but greater than or equal to 2% of mometasone-treated patients (regardless of relationship to treatment), and more frequently than in the placebo group included: arthralgia, asthma, bronchitis, chest pain, conjunctivitis, diarrhea, dyspepsia, earache, flu-like symptoms, myalgia, nausea, and rhinitis.

Rare cases of nasal ulcers and nasal and oral candidiasis were also reported in patients treated with mometasone furoate, primarily in patients treated for longer than 4 weeks.

OVERDOSAGE :

There are no data available on the effects of acute or chronic overdosage with mometasone furoate. Because of low systemic bioavailability, and an absence of acute drug-related systemic findings in clinical studies, overdose is unlikely to require any therapy other than observation. Intranasal administration of 1600 mug (8 times the recommended dose of mometasone furoate) daily for 29 days, to healthy human volunteers, was well tolerated with no increased incidence of adverse events. Single intranasal doses up to 4000 mug have been studied in human volunteers with no adverse effects reported. Single oral doses up to 8000 mug have been studied in human volunteers with no adverse events reported. Chronic overdosage with any corticosteroid may result in signs or symptoms of hypercorticism (see PRECAUTIONS). Acute overdosage with this dosage form is unlikely since one bottle of mometasone furoate contains approximately 8500 mug of mometasone furoate.

DOSAGE AND ADMINISTRATION :

Adults and Children 12 Years of Age and Older : The usual recommended dose for prophylaxis and treatment of the nasal symptoms of seasonal allergic rhinitis and treatment of the nasal symptoms of perennial allergic rhinitis is two sprays (50 mug of mometasone furoate in each spray) in each nostril once daily (total daily dose of 200 mug).

In patients with a known seasonal allergen that precipitates nasal symptoms of seasonal allergic rhinitis, prophylaxis with mometasone furoate (200 mug/day) is recommended 2 to 4 weeks prior to the anticipated start of the pollen season.

Improvement in nasal symptoms generally occurs within 2 days after the first dose. Maximum benefit is usually achieved within 1 to 2 weeks. Patients should use mometasone furoate only once daily at a regular interval.

Prior to initial use of mometasone furoate, the pump must be primed by actuating ten times or until a fine spray appears. The pump may be stored unused for up to 1 week without repriming. If unused for more than 1 week, reprime by actuating two times, or until a fine spray appears.

Directions for Use : Illustrated Patient’s Instructions for Use accompany each package of mometasone furoate.

HOW SUPPLIED :

Nasonex nasal spray, 50 mug contains 17 g of product formulation, 120 sprays, each delivering 50 mug of mometasone furoate per actuation.
Store between 2-25°C (36-77°F). Protect from light.
When Nasonex nasal spray, 50 mug is removed from its cardboard container, prolonged exposure of the product to direct light should be avoided. Brief exposure to light, as with normal use, is acceptable.
SHAKE WELL BEFORE EACH USE.

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