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VALEANT/BAUSCH
SKU
24208034425

flunisolide 0.025% spray

Generic
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Uses

Flunisolide nasal solution is used for the symptomatic treatment of seasonal or perennial rhinitis when conventional therapy with antihistamines or decongestants is ineffective or produces intolerable adverse effects. In a comparative study in patients with seasonal allergic rhinitis, flunisolide nasal solution as Nasalide or Nasarel was more effective than either placebo vehicle, but there was no statistically significant difference in efficacy between the 2 flunisolide formulations; neither of these formulations currently is commercially available in the US. The US Food and Drug Administration (FDA) has determined that the generic (nonproprietary) formulation currently available in the US (Bausch & Lomb) is bioequivalent (and therefore therapeutically equivalent) to the previously available Nasalide formulation.

Rhinitis

In patients with seasonal or perennial rhinitis of allergic or nonallergic etiology, intranasal administration of flunisolide generally provides symptomatic relief of watery rhinorrhea, nasal congestion, sneezing, postnasal drip, and pharyngeal itching. However, intranasal flunisolide generally does not relieve symptoms of conjunctivitis or those involving the lower respiratory tract; this may reflect the absence of appreciable systemic activity when usual dosages of the drug are administered by nasal inhalation.

Flunisolide nasal solution appears to provide greater symptomatic relief in patients with allergic rhinitis (i.e., associated with IgE-mediated reactivity manifested as positive skin tests to common allergens or increased serum or nasal IgE concentrations) than in patients with nonallergic rhinitis. When intranasal flunisolide is added to a therapeutic regimen that includes an oral antihistamine, dosage of the antihistamine can often be decreased in allergic patients with seasonal or perennial rhinitis even during periods of peak exposure to pollen. Although the efficacy of intranasal flunisolide in the treatment of perennial nonallergic rhinitis has been questioned, most clinicians agree that a therapeutic trial with the drug is warranted in these patients since greater symptomatic relief occurs during intranasal flunisolide therapy than during intranasal placebo therapy. However, in one study in patients with perennial nonallergic rhinitis, intranasal flunisolide was no more effective than placebo, although both treatments resulted in measurable symptomatic improvement; it was suggested that the observed symptomatic relief may have resulted from the moisturizing effects of the vehicle in flunisolide nasal solution.

In patients with seasonal or perennial rhinitis, symptomatic relief is usually evident within 2-3 days of continuous intranasal flunisolide therapy; however, up to 2-3 weeks may be required for optimum effectiveness in some patients. Supplemental therapy with topical nasal decongestants and/or oral antihistamines may be necessary until an acceptable clinical response is achieved. In some patients, therapy with ophthalmic preparations may be necessary to relieve signs and symptoms of conjunctivitis not controlled by intranasal corticosteroids. Although ophthalmic products containing vasoconstrictors and antihistamines or corticosteroids may be effective in relieving ophthalmic inflammatory symptoms in patients with rhinitis, concurrent use of ophthalmic and intranasal corticosteroids is not generally recommended since the risk of adverse ophthalmic effects associated with corticosteroid therapy (e.g., glaucoma, cataract formation, exacerbation of ophthalmic infections) may be increased. In some patients with seasonal or perennial rhinitis, especially those with concurrent asthmatic conditions, continuous concomitant therapies (e.g., oral or orally inhaled corticosteroids, bronchodilators, antihistamines, decongestants) may be required to provide optimum symptomatic relief.

A poor clinical response to flunisolide can result from improper drug administration techniques, poor drug penetration (secondary to marked nasal congestion, presence of nasal polyps, or symptoms originating in the nasal sinuses), or localized infections of the nasal mucosa.

Intranasal administration of flunisolide (200 mcg/day in 2 divided doses) appears to be as effective as intranasal beclomethasone dipropionate (400 mcg/day in 4 divided doses) in the treatment of seasonal or perennial allergic rhinitis. In some patients with nasal crusting and dryness, flunisolide nasal solution may be more useful than beclomethasone dipropionate nasal aerosol since the vehicle for flunisolide may contribute to the overall therapeutic effect in these patients. Unlike beclomethasone dipropionate nasal aerosol, flunisolide nasal solution does not contain fluorocarbons which have been associated with excessive drying of the nasal mucosa in some patients. When intranasal flunisolide is administered concomitantly with orally inhaled beclomethasone dipropionate to patients with both perennial allergic rhinitis and asthma, the combination therapy generally results in greater overall symptomatic relief than either drug alone.

Data from an unpublished study indicate that intranasal flunisolide (200 mcg/day) is as effective as intranasal dexamethasone phosphate (670 mcg/day) in the treatment of perennial rhinitis. Although the symptomatic relief provided by usual dosages of intranasal flunisolide, beclomethasone dipropionate, or dexamethasone phosphate is similar, flunisolide and beclomethasone dipropionate appear to be associated with fewer adverse systemic effects than dexamethasone phosphate; however, no direct comparison of the adverse effects of these drugs has been performed.

Following nasal inhalation in one study in patients with seasonal allergic rhinitis, flunisolide and cromolyn sodium provided similar symptomatic relief. However, intranasal flunisolide was more effective in relieving sneezing, and oral antihistamine dosage requirements were reduced to a greater extent in patients receiving flunisolide. Further comparative studies of intranasal flunisolide and intranasal cromolyn sodium are needed.

Other Uses

Intranasal flunisolide has been used for the treatment of serous otitis media (eustachian tube dysfunction, middle ear effusion) in children. In one study, flunisolide-treated children had an accelerated return to normal middle ear pressure compared with placebo-treated children; however, the specific role of the drug in the treatment of this condition has not been determined.

Although orally inhaled flunisolide is used in the treatment of asthma, the manufacturer recommends that the nasal solution not be used for this purpose, since the safety of polyethylene glycol in the vehicle of the nasal solution has not been established for this route of administration.

For other uses of flunisolide, see 68:04.

Dosage and Administration

Administration

Flunisolide is administered by nasal inhalation using a special nasal inhaler. Patients should be carefully instructed in the use of the nasal inhaler. To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer. An adult should carefully supervise a child in the administration of flunisolide nasal solution. The manufacturer states that flunisolide nasal solution should not be administered by oral inhalation, since the safety of polyethylene glycol in the vehicle of the nasal solution has not been established for this route of administration.

Prior to administration of flunisolide nasal solution, patients should clear their nasal passages; administration of a topical nasal decongestant about 5-15 minutes before flunisolide administration may be required in patients with blocked nasal passages during the first 2-3 days of therapy to ensure adequate penetration of the drug and to prevent loss of the drug from the nasal passages via excess secretions. Prior to initial use, the nasal inhaler must be assembled and primed. After assembly is complete, the patient should tilt his head slightly forward, insert the spray tip into one nostril, and point the tip toward the inflamed nasal turbinates and away from the nasal septum. For maximum therapeutic effect and to ensure adequate penetration of the drug, the patient should pump the drug into one nostril while holding the other nostril closed and should concurrently inspire through the nose; this procedure is then repeated for the other nostril.

The manufacturer recommends cleansing the nasal adapter and/or pump in warm water if the holes in the device become clogged. If the nasal inhaler is disassembled for any reason (including the cleansing procedure) or not used for 5 days or longer, it must be primed again prior to use. Opened containers of flunisolide nasal solution should be discarded after 3 months.

Dosage

After initial priming (5-6 sprays), the nasal inhaler delivers about 25 mcg of flunisolide per metered spray. The commercially available preparations deliver about 200 metered sprays. Dosage must be carefully adjusted according to individual requirements and response.

The therapeutic effects of intranasal corticosteroids, unlike those of decongestants, are not immediate. This should be explained to the patient in advance to ensure compliance and continuation of the prescribed treatment regimen. Full therapeutic benefit usually requires regular use and usually is evident within a few days. A longer period may be required in some patients. Response to the initial dosage generally should be assessed 4-7 days after starting therapy; about two-thirds of patients will experience some relief within this time period. Intranasal flunisolide should be discontinued in patients who do not experience clinically important benefit within 3 weeks of initiating therapy.

Rhinitis

For the symptomatic treatment of seasonal or perennial rhinitis, the usual initial adult dosage of flunisolide nasal solution is 50 mcg (2 sprays) in each nostril twice daily. When necessary, dosage may be increased to 50 mcg (2 sprays) in each nostril 3 times daily. Maximum daily dosage in adults should not exceed 200 mcg (8 sprays) in each nostril (400 mcg total). In children 6-14 years of age, the usual initial dosage of flunisolide nasal solution is 25 mcg (1 spray) in each nostril 3 times daily or 50 mcg (2 sprays) in each nostril twice daily. Maximum daily dosage in these children should not exceed 100 mcg (4 sprays) in each nostril (200 mcg total). The manufacturer states that the drug is not recommended for use in children younger than 6 years of age. (See Cautions: Pediatric Precautions.)

In patients with seasonal or perennial rhinitis, symptomatic relief is usually evident within 2-3 days of continuous therapy; however, up to 2-3 weeks may be required for optimum effectiveness in some patients. There is no evidence that higher than recommended dosages or increased frequency of administration of intranasal flunisolide are beneficial; exceeding the maximum recommended daily dosage may only increase the risk of adverse systemic effects (e.g., HPA-axis suppression, Cushing's syndrome). If symptomatic improvement is not observed following 3 weeks of continuous therapy, flunisolide should be discontinued and/or a reason for treatment failure should be sought.

Once the symptoms of seasonal or perennial rhinitis have been controlled, dosage of intranasal flunisolide should be gradually reduced to the lowest effective level. A maintenance dosage of 25 mcg (1 spray) in each nostril daily (50 mcg total) may be sufficient in some patients with perennial rhinitis.

Cautions

In a comparative study in patients with seasonal allergic rhinitis, the 2 formulations of flunisolide nasal solution as Nasalide or Nasarel differed in the nature and incidence of adverse effects. The incidence of nasal burning and stinging was greater with the Nasalide formulation, and there were more complaints related to taste, such as aftertaste, with Nasarel; these differences were attributed to differences in the respective vehicles, and some patients may prefer one formulation over the other. Both formulations usually are well tolerated, and adverse effects usually do not interfere with treatment; neither formulation currently is commercially available in the US. The US Food and Drug Administration (FDA) has determined that the generic (nonproprietary) formulation currently available in the US (Bausch & Lomb) is bioequivalent (and therefore therapeutically equivalent) to the previously available Nasalide formulation.

Nasopharyngeal Effects

The most frequent adverse effects of flunisolide nasal solution involve the nasal mucous membranes. Sensations of nasal burning occur in about 45% of patients receiving the nasal solution as the Nasalide formulation. In controlled clinical trials comparing this formulation with another one (Nasarel), the incidence of nasal burning and stinging was 13% with Nasarel. These sensations are usually of short duration (lasting from a few seconds to 1-2 minutes), decrease with continued therapy, and rarely require changes in or discontinuance of therapy. Sensations of nasal burning may result from excipients in the formulations of the commercially available preparations since the frequency and severity of these effects are similar in patients receiving an intranasal placebo vehicle. In addition, the similar occurrence of adverse nasal effects in flunisolide- or placebo-treated patients with seasonal or perennial rhinitis may result from physical contact and irritation of the characteristically sensitive nasal passages of these patients.

Other adverse nasopharyngeal effects occur in about 5% or less of patients receiving flunisolide nasal solution and include nasal congestion, sneezing, nasal secretions containing blood, nasal irritation or dryness, sore throat, hoarseness, bitter taste, and loss of taste or smell. Epistaxis occurred in 3-9% of patients receiving the drug as the Nasarel formulation. Nasal septal ulcerations and perforations have been reported rarely but have not been directly attributed to the drug.

Localized candidal infections of the nose and/or pharynx have occurred rarely during flunisolide therapy. Although Candida has been cultured from samples taken from the nose and pharynx of patients receiving intranasal flunisolide, this may represent the presence of Candida in normal flora rather than evidence of clinical infection. If a candidal infection is suspected, appropriate local anti-infective therapy and/or discontinuance of flunisolide therapy should be considered. Small, staphylococcal furuncles have occurred in the nose of a patient receiving flunisolide nasal solution, but the condition resolved spontaneously without discontinuing flunisolide therapy.

Although not reported to date in patients receiving flunisolide or other intranasal corticosteroids, some clinicians caution that atrophic rhinitis may develop during chronic therapy with an intranasal corticosteroid, since atrophic dermatitis has occurred in patients treated with topical corticosteroids to the skin for prolonged periods. Nasal biopsies in patients with perennial rhinitis treated continuously with intranasal flunisolide for 3 months have shown no evidence of serious mucosal damage. Some clinicians recommend that rhinoscopic examinations be performed every 6 months in patients receiving prolonged therapy with intranasal corticosteroids.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

Adrenal suppression, based on plasma cortisol determinations, has not been observed to date when intranasal flunisolide was administered in usual dosages for up to 6 months. In patients receiving high dosages (i.e., 2 mg daily for 3 months) of orally inhaled flunisolide, a decreased adrenal response to the metyrapone test has been observed. In studies in healthy adults receiving intranasal flunisolide at dosage 2-7 times the recommended daily dosage for several days, decreases in plasma cortisol and urinary 17-ketogenic steroid (17-KS) concentrations occurred. The manufacturer states that use of excessive dosages of intranasal flunisolide may suppress HPA function. The effect of intranasal flunisolide on the HPA-axis response to stress (e.g., surgery) is not known. Intranasal administration of usual dosages of flunisolide apparently produces less HPA-axis suppression than usual dosages of intranasal dexamethasone phosphate; however, comparative studies have not been conducted to date.

Other Adverse Effects

Aftertaste occurred in 17% of patients receiving intranasal flunisolide as the Nasarel formulation, which was more common with this preparation than with the Nasalide formulation in comparative studies. Aftertaste usually did not interfere with treatment, although such differences in adverse effects between the formulations may affect patient preference.

Other adverse effects associated with intranasal flunisolide therapy include headache, dizziness, watery eyes, nausea, vomiting, and abdominal bloating. Increases in serum AST (SGOT) concentrations have been reported rarely during intranasal flunisolide therapy, but a direct causal relationship to the drug has not been established.

Ophthalmologic abnormalities have not been observed during intranasal flunisolide therapy when slit-lamp or tonometric studies were conducted following 6 and 12 months of treatment. Although prolonged use of systemic and ophthalmic corticosteroids has been associated with the development of posterior subcapsular cataracts and increased intraocular pressure, these effects have not been associated with intranasal flunisolide administration to date.

Precautions and Contraindications

Higher than recommended dosages of flunisolide nasal solution should be avoided since suppression of HPA function may occur. Flunisolide nasal solution should be used with caution in patients receiving systemic prednisone or another systemic corticosteroid in an alternate-day or daily dosing regimen for any disease, since concomitant use of the drugs could increase the likelihood of HPA-axis suppression compared with therapeutic dosages of either drug alone.

Patients who have received systemic corticosteroids for prolonged periods and are being switched to treatment with flunisolide nasal solution should be carefully monitored since corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression), acute adrenal insufficiency, or severe symptomatic exacerbation of asthma or other clinical conditions may occur. Systemic corticosteroid dosage should be tapered, and patients should be carefully monitored during dosage reduction. In general, the greater the dosage and duration of systemic corticosteroid therapy, the greater the time required for withdrawal of systemic corticosteroids and replacement by intranasal corticosteroids.

Although signs and symptoms of Cushing's syndrome (e.g., hypertension, glucose intolerance, cushingoid features) have not been associated with intranasal flunisolide therapy to date, the possibility of their occurrence should be considered in patients who are particularly sensitive to corticosteroid effects or when usual dosages of the drug are exceeded.

Patients should be advised that intranasal flunisolide must be used at regular intervals to be therapeutically effective. In addition, patients should be advised that the drug will not provide immediate symptomatic relief and use of topical nasal decongestants or oral antihistamines may be necessary until the effects of intranasal flunisolide are fully manifested. Patients should also be advised not to exceed the prescribed dosage. (See Dosage and Administration: Dosage.) Patients with severe allergies should be instructed to avoid exposure to allergens during intranasal flunisolide therapy to prevent the occurrence of severe allergic symptoms in the eyes and/or lower respiratory tract. Patients should be instructed to contact their physician during intranasal flunisolide therapy if signs or symptoms of the condition do not improve, if the condition worsens, or if sneezing or nasal irritation occurs.

Flunisolide nasal solution should be used with caution until healing occurs in patients with recent nasal septal ulcers, nasal surgery, or nasal trauma since the drug may inhibit wound healing. Intranasal flunisolide therapy should be used with extreme caution, if at all, in patients with clinical tuberculosis or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract; untreated fungal or bacterial infections; or ocular herpes simplex or untreated, systemic viral infections. In addition, use of flunisolide nasal solution may result in localized candidal infections of the nose or pharynx. When infection occurs, appropriate local treatment of the infection may be necessary and/or discontinuance of intranasal flunisolide therapy may be required.

Flunisolide nasal solution is contraindicated in patients with known hypersensitivity to the drug or other ingredients in the formulation (the formulation does not contain fluorocarbons).

Pediatric Precautions

Safety and efficacy of flunisolide nasal solution in children younger than 6 years of age have not been established. Intranasal flunisolide may be a useful therapeutic alternative to oral corticosteroids in children 6 years of age or older with seasonal or perennial allergic rhinitis, since intranasal flunisolide is associated with a decreased risk of adverse systemic effects. Further studies with flunisolide nasal solution in children are necessary to determine any possible adverse effects of the drug on growth and development.

Mutagenicity and Carcinogenicity

It is not known if flunisolide is mutagenic or carcinogenic in humans. Long-term studies in mice and rats receiving flunisolide orally revealed evidence of an increased incidence of pulmonary adenomas in mice but not rats, and an increased incidence of mammary adenocarcinoma in female rats at the highest dosage level tested. An increased incidence of the latter tumor also has been observed with other corticosteroids, but a correlation between these findings in rats and any potential risk in humans has not been established.

Pregnancy, Fertility, and Lactation

Pregnancy

Flunisolide nasal solution should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Since adrenal insufficiency may occur in neonates born to women who received corticosteroids during pregnancy, these neonates should be carefully monitored for signs and symptoms of this condition. Although there are no adequate and controlled studies to date in humans, flunisolide has been shown to be teratogenic and fetotoxic in rabbits and rats at oral dosages of 40 and 200 mcg/kg per day, respectively. Teratogenic effects in these animals included cleft palate and reduced ossification, which are similar to observations noted with other corticosteroids.

Fertility

It is not known whether flunisolide affects fertility in humans. Reproduction studies in female rats using oral flunisolide dosages of 200 mcg/kg per day have shown some evidence of impaired fertility.

Lactation

Flunisolide should be used with caution in nursing women, since it is not known whether the drug is distributed into milk. Other corticosteroids are distributed into milk and may cause adverse effects such as growth suppression in nursing infants.

Drug Interactions

Although there have been no reports to date of clinically important drug interactions with flunisolide, it should be noted that phenobarbital and other agents that induce hepatic microsomal enzymes may enhance the metabolism of corticosteroids.

Pharmacokinetics

Absorption

Flunisolide is readily absorbed following nasal inhalation. Although it is not clear to what extent absorption through the mucosa of the nose and/or other areas of the upper respiratory tract contributes to overall absorption of flunisolide, about 50% of an intranasal dose of the drug reaches systemic circulation unmetabolized. Only about 20% of an oral dose of flunisolide reaches systemic circulation unmetabolized because of extensive first-pass metabolism in the liver. (See Pharmacokinetics: Elimination.)

Following nasal inhalation of a 117-mcg dose of the drug in healthy adults, peak plasma flunisolide concentrations occur within 10-30 minutes and range from 0.4-1 ng/mL. In most individuals, the drug is undetectable in plasma 4 hours after a single intranasal dose. A correlation between plasma flunisolide concentrations and therapeutic effects has not been determined; however, it is thought that systemically absorbed drug contributes little to the effect of the drug on the nasal mucosa.

Flunisolide nasal solution in an aqueous vehicle (Nasarel; no longer commercially available in the US) was not bioequivalent with another aqueous formulation of the drug (Nasalide) following nasal inhalation. In a comparative study, total systemic absorption and peak plasma concentrations of flunisolide as Nasarel were 25 and 30% lower, respectively, than those achieved with Nasalide following nasal inhalation. However, the clinical importance of these differences is likely to be small, particularly since clinical efficacy is attributable to a local effect on the nasal mucosa. The commercially available generic formulation (Bausch & Lomb) has been shown to be bioequivalent to the previously available Nasalide formulation.

Distribution

Although flunisolide is widely distributed into most tissues following IV administration, distribution following intranasal administration has not been described. At a plasma concentration of 1-20,000 ng/mL, flunisolide is about 50% bound to plasma albumin. Flunisolide does not appear to bind to corticosteroid-binding globulin.

Although it is not known if flunisolide crosses the placenta in humans, the drug apparently crosses the placenta in animals since teratogenic and fetotoxic effects have occurred following oral administration of the drug. It is not known if flunisolide is distributed into milk; however, other corticosteroids are distributed into milk.

Elimination

The plasma half-life of flunisolide following intranasal administration is 1-2 hours. Following IV administration of the drug, plasma flunisolide concentrations appear to decline in a biphasic manner. In adults with normal renal function, the half-life in the initial phase (t½α) averages about 6 minutes and the half-life in the terminal phase (t½β) averages about 1.8 hours.

Flunisolide is rapidly metabolized in the liver. Drug that is swallowed undergoes extensive first-pass metabolism in the liver. Flunisolide that is absorbed directly from the nasopharyngeal mucosa bypasses this initial metabolism. It is not known if the drug undergoes metabolism in the GI tract. The drug undergoes dehalogenation followed by hydroxylation at the 6β-position. The 6β-hydroxylated (6β-OH) metabolite is formed rapidly, and plasma concentrations of this metabolite are usually greater than those of flunisolide. Following IV administration of flunisolide, the 6β-OH metabolite has a plasma half-life of 3.9-4.6 hours. The 6β-OH metabolite has glucocorticoid and mineralocorticoid activity. (See Pharmacology.) Flunisolide and its 6β-OH metabolite are conjugated in the liver with glucuronic acid and/or sulfate. It is not known if these conjugates have glucocorticoid and/or mineralocorticoid activity.

The excretory fate of flunisolide and its metabolites following intranasal administration has not been described; however, following IV or oral administration, the drug and its metabolites are excreted in approximately equal proportions in feces via biliary elimination and in urine.

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