Medications for Allergy

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Budesonide). A white or almost white, crystalline powder. Practically insoluble in water sparingly soluble in alcohol freely soluble in dichloromethane.

The United States Pharmacopeia 31, 2008 (Budesonide). A white to off-white, odourless, crystalline powder. Practically insoluble in water and in heptane sparingly soluble in alcohol freely soluble in chloroform. Store in airtight containers at a temperature of 20° to 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects, Treatment, Withdrawal, and Precautions

As for corticosteroids in general.

Inhalation of high doses of budesonide is associated with some adrenal suppression. Systemic absorption may follow nasal use, particularly after high doses or prolonged treatment. The dose of oral budesonide may need to be reduced in hepatic impairment (see also Administration in Hepatic Impairment, below). When applied topically, particularly to large areas, when the skin is broken, or under occlusive dressings, or when given intranasally corticosteroids may be absorbed in sufficient amounts to cause systemic effects.

Effects on the bones. For mention of the effects of inhaled budesonide on markers of collagen turnover and bone density in asthmatic children, see under Adverse Effects of Beclometasone. For the suggestion that inhalation once-daily in the morning may have less marked effects on growth and collagen turnover than twice-daily inhalation, see Administration, below.

Effects on the nervous system. Psychotic behaviour has been reported after use of inhaled budesonide.

Hypersensitivity. Contact dermatitis has been reported to topical or intranasal budesonide. An anaphylactoid reaction occurred 5 minutes after the first dose of oral budesonide in a patient who had previously reacted in a similar way to mesalazine.

Interactions

The interactions of corticosteroids in general are described.

Pharmacokinetics

For a brief outline of the pharmacokinetics of corticosteroids. Budesonide is rapidly and almost completely absorbed after oral administration, but has poor systemic availability (about 10%) due to extensive first-pass metabolism in the liver, mainly by the cytochrome P450 isoenzyme CYP3 A4. The major metabolites, 6-β-hydroxybudesonide and 16-α-hydroxy-prednisolone have less than 1% of the glucocorticoid activity of unchanged budesonide. Budesonide is reported to have a terminal half-life of about 2 to 4 hours.

Uses and Administration

Budesonide is a corticosteroid with mainly glucocorticoid activity. It is used by inhalation in the management of asthma, in usual doses of 400 micrograms daily in 2 divided doses from a me-tered-dose aerosol in severe asthma the dosage may be increased up to a total of 1.6 mg daily, and guidelines for the management of asthma permit up to 2 mg daily. Maintenance doses may be less than 400 micrograms daily but should not be below 200 micrograms daily. A dose for children is 50 to 400 micrograms inhaled twice daily. Budesonide is also available for the management of asthma in the form of a dry powder inhaler doses are 200 to 800 micrograms daily, as 2 divided doses or a single daily dose up to 800 micrograms twice daily may be given to adults if necessary. Patients for whom budesonide from a pressurised inhaler or dry powder formulation is unsatisfactory may use a nebulised solution. The usual adult dosage by this method is 1 to 2 mg inhaled twice daily. This may be increased if asthma is severe. Maintenance doses are 0.5 to 1 mg inhaled twice daily. For children between 3 months and 12 years of age, an initial dose is 0.5 to 1 mg twice daily with a maintenance dose of 0.25 to 0.5 mg twice daily.

Budesonide is also given by inhalation as a nebulised solution in the management of childhood croup. The usual dose is 2mg, as a single inhaled dose or 2 doses of 1 mg, given 30 minutes apart.

Budesonide is used topically in the treatment of various skin disorders, as a cream, lotion, or ointment containing 0.025%. For recommendations concerning the correct use of corticosteroids on the skin, and a rough guide to the clinical potencies of topical corticosteroids.

Budesonide is also used intranasally for the prophylaxis and treatment of rhinitis. In the UK, two nasal spray preparations are available, one containing 100 micrograms permetered spray, and one containing 64 micrograms per metered spray. The initial recommended dose for adults and children over 12 years is either 2 sprays into each nostril once daily in the morning, or 1 spray into each nostril twice daily. This may be subsequently reduced to 1 spray into each nostril once daily treatment can be continued for up to 3 months. In the USA and some other countries, a nasal spray and a nasal inhaler are available. The intranasal dose may be expressed in multiples of 32 micrograms, which is the quantity of budesonide delivered from the nasal adaptor. When given from a nasal inhaler, the recommended initial dose for adults and children over 6 years is 4 sprays into each nostril in the morning, or 2 sprays into each nostril twice daily, to give a total daily dose of 256 micrograms daily. This is reduced to the lowest dose adequate to control symptoms. If no benefit is seen after 3 weeks of treatment, budesonide should be stopped. When given as an aqueous nasal spray, the recommended initial dose for adults and children over 6 years is 1 spray into each nostril once daily (64 micrograms daily), increasing as necessary up to a maximum of 256 micrograms daily for adults and 128 micrograms daily for children aged less than 12 years. Budesonide is also used as a nasal spray in the management of nasal polyps (p.1508). In the UK, for adults and children over 12 years, 1 spray (containing 64 or 100 micrograms, as above) is given into each nostril twice daily for up to 3 months.

Local formulations of budesonide are used in the management of inflammatory bowel disease (see below). In mild to moderate Crohn’s disease affecting the ileum or ascending colon it is given orally as modified-release capsules intended for a topical effect on the gastrointestinal tract. The recommended dose is 9 mg daily for active disease, as either a single dose before breakfast or in 3 divided doses about 30 minutes before meals, depending on the preparation. Treatment is given for up to 8 weeks, and the dosage should be reduced 2 to 4 weeks before discontinuing therapy. For recurring episodes of active Crohn’s disease, an 8-week course maybe repeated. After an 8-week course for active disease, budesonide 6 mg once daily is recommended for maintenance of clinical remission, for up to 3 months thereafter, doses are tapered and therapy stopped, as continued treatment has not shown substantial clinical benefit. There is some absorption of budesonide from the gastrointestinal tract, and the dose may need to be reduced in patients with hepatic impairment, especially those with cirrhosis (see also Administration in Hepatic Impairment, below). Ulcerative colitis affecting the rectum and sigmoid colon may be treated locally with budesonide. A retention enema providing a dose of 2 mg in 100 niL is given daily at bedtime for 4 weeks, which may be extended to 8 weeks if the patient is not in remission after the initial 4-week course. Alternatively, a rectal foam can be used in a dose of 2 mg once daily, usually for 6 to 8 weeks. The dose may be given in the morning or the evening, but treatment is more effective if the bowel is emptied before a dose is given.

Local formulations of budesonide are also used in the management of collagenous colitis (see below). It is given orally as modified-release capsules in a dose of 3 mg three times daily for up to 8 weeks. The dosage should be reduced gradually during the last 2 weeks of therapy.

Administration. INHALATIONAL ROUTE. One study in 6 children aged up to 30 months found that about 75% of the nominal dose of nebulised budesonide was deposited in the neb-uliser system, while a study in 126 older children indicated that maintenance doses of budesonide could be halved when the dose was given by dry powder inhaler rather than nebuliser, without any loss of asthma control. Although oropharyngeal deposition is thought to play a role in the systemic effects of inhaled corticosteroids, another study indicated that only about 20% of the systemically available drug appeared to be derived from oropharyngeal deposition after inhalation from a dry powder inhaler.

There is evidence that the timing of inhaled therapy might influence some systemic effects. A study in children with mild asthma found that 800 micrograms of budesonide inhaled in the morning had less effect on measurements of short-term growth and collagen turnover than inhalation of 400 micrograms twice daily.

Administration in hepatic impairment. In a study of patients with primary biliary cirrhosis the clearance of oral budesonide was significantly reduced in those with cirrhosis (stage IV) compared with milder disease (stage I/II). Elevated budesonide concentrations were sufficient to suppress cortisol production, and believed to be associated with the development of portal vein thrombosis in 2 cirrhotic patients.

Asthma. References to the use of budesonide in asthma. Its use as a fixed-dose combination with formoterol has also been reviewed.

Chronic obstructive pulmonary disease. For discussion of the value of inhaled corticosteroids in chronic obstructive pulmonary disease, including reference to the use of budesonide. The use of a fixed-dose combination of budesonide and formoterol in chronic obstructive pulmonary disease has been reviewed.

Collagenous colitis. Budesonide has been used in a few small controlled studies of the management of collagenous colitis (see Microscopic Colitis). Treatment courses given orally for 6 or 8 weeks were found to improve symptoms and histology, and the short-term benefits have been confirmed by metaanalysis, although high rates of relapse after stopping treatment have been reported.

Cystic fibrosis. Cystic fibrosis is associated with bronchial hyper-responsiveness a small study has suggested that inhalation of budesonide 1.6 mg daily for 6 weeks improves hyper-responsiveness slightly and leads to improvement in cough and dyspnoea. A larger study of budesonide given for two successive 3-month treatment periods found improved hyper-responsiveness and a trend towards slower decline in lung function.

Inflammatory bowel disease. Budesonide has been given as an enema for the treatment of distal ulcerative colitis, in which context its potency and low systemic availability are advantageous. A rectal foam has also been developed, which may be easier to use, and retain in the bowel, than an enema. Budesonide is available as a modified-release oral dosage form for the management of active Crohn’s disease. Ileal-release preparations of budesonide have been indicated as first-line therapy in the treatment of mild to moderate ileal and right-sided colonic Crohn’s disease. Systematic review has suggested that it is slightly less effective than conventional corticosteroid therapy, but is associated with fewer adverse effects. Budesonide has also been effective in delaying relapse in quiescent disease. However, the benefit appears to be short-term (3 months) and it has been concluded that oral modified-release budesonide is not effective in long-term (12 months) maintenance of remission. Similarly, oral budesonide was ineffective in preventing postoperative recurrence after resection for Crohn’s disease. For a discussion of inflarnmatory bowel disease.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Airbude; Budefarma¤; Budeson; Cuteral; Despex¤; Entocort; Hypersol B; Kerpet; Nastizol Hidrospray; Neumocort; Neumotex; Proetzonide; Pulmo Lisoflam; Rino-B; Spirocort; Australia: Budamax; Entocort; Pulmicort; Rhinocort; Austria: Budo-san; Entocort; Miflonide; Predermid¤; Pulmicort; Rhinocort; Rhinocortol¤; Belgium: Budenofalk; Entocort; Miflonide; Preferid¤; Pulmicort; Rhinocort; Brazil: Budecort; Busonid; Cortasm¤; Entocort; Miflonide; Novopulmon; Pulmicort; Canada: Entocort; Pulmicort; Rhinocort; Chile: Aero-Bud; Aerovial; Budasmal; Budenofalk; Clebudan; Entocort¤; Inflammide; Pulmicort; Rhinocort; Czech Republic: Apulein; Budenofalk; Easi-Cort; Entocort; Giona; Inflammide; Miflonid; Pulmicort; Rhinocort; Tafen; Denmark: Entocort; Miflonide; Rhinocort; Rhinosol; Spirocort; Finland: Cortivent; Entocort; Pulmicort; Rhinocort; France: Entocort; Miflonil; Novopulmon; Pulmicort; Rhinocort; Germany: Aquacort; Benosid; Bronchocux¤; Budapp¤; Budecort; Budefat¤; Budenofalk; Budepur E¤; Budes; Budiair; Budon¤; Entocort; Miflonide; Novopulmon; Pulmicort; Respicort; Topinasal¤; Greece: Astrocast; Aurid; Biosonide; Budecol; Budenite; Budenofalk; Budesan; Budesoderm; Budesonal; Busonal; Butekont; Dedostryl; Dexalocal; Esonide; Farlidone; Ixor; Lydenal; Miflonide; Minalerg; Obecirol; Obusonid; Olfosonide; Olyspal; Pimoftal¤; Pulmicort; Resata; Rhinoside; Sonidal; Udesogel; Udesospray; Vericort; Vinecort; Zefecort; Zymacter; Hong Kong: Budenofalk¤; Cycortide; Eltair¤; Entocort; Pulmicort; Rhinocort; Hungary: Apulein; Entocort; Miflonide; Pulmicort; Rhinocort; India: Budecort; Budenase; Pulmicort; Rhinocort; Ireland: Budenofalk; Entocort; Preferid¤; Pulmicort; Rhinocort; Israel: Budeson; Budicort; Entocort; Miflonide; Nasocort; Pulmotide; Italy: Aircort; Bidien; Desonax; Eltair; Enterocir¤; Entocir; Miflonide; Preferid; Pulmaxan; Rhinocort; Spirocort; Malaysia: Butacort; Eltair; Inflammide; Pulmicort; Rhinocort; Mexico: Aerosial; Budosan; Entocort; Miflonide; Numark; Pulmicort; Rhinocort; Netherlands: Entocort; Preferid¤; Pulmicort; Rhinocort; Norway: Entocort; Preferid¤; Pulmicort; Rhinocort; New Zealand: Butacort; Eltair; Entocort; Hayclear¤; Pulmicort; Rhinocort¤; Portugal: Budo-san; Entocort; Miflonide; Pulmicort; Russia: Benacort (Бенакорт); Pulmicort (Пульмикорт); South Africa: Budeflam; Entocord; Inflacor; Inflammide; Inflanaze; Pulmicort; Rhinocort; Singapore: Budenofalk; Eltair; Entocort; Esonide; Inflammide; Pulmicort; Rhinocort; Spain: Budenofalk; Demotest; Entocord; Miflonide; Neo Rinactive; Novopulm; Olfex; Pulmicort; Pulmictan; Rhinocort; Ribujet; Ribusol¤; Rinactive¤; Sweden: Entocort; Preferid¤; Pulmicort; Rhinocort; Switzerland: Budenofalk; Cortinasal; Entocort; Miflonide; Preferid¤; Pulmicort; Rhinocort; Thailand: Budecort; Eltair; Inflammide; Pulmicort; Rhinocort; United Arab Emirates: Sonidar; United Kingdom: Budenofalk; Entocort; Preferid¤; Pulmicort; Rhinocort; United States: Entocort; Pulmicort; Rhinocort

The use of intranasal corticosteroids is increasingly becoming first-line therapy for many patients with allergic rhinitis, especially those with moderate to severe symptoms or those with perennial allergic rhinitis in which nasal symptoms predominate. Intranasal corticosteroids specifically inhibit the allergic inflammatory processes that contribute to the late-phase response of nasal congestion. When used prophylactically, they can also inhibit the early-phase response to allergens. Overall, they are effective in relieving sneezing, nasal itching, rhinorrhea, and congestion.

Table 3 lists available intranasal corticosteroids, along with dosing information and comparative costs. In general, these agents are considered more cost-effective for use as monotherapy than 2nd-generation antihistamines. A recent meta-analysis found intranasal corticosteroids to be more effective than oral antihistamines in reducing nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, and total nasal symptoms. No significant difference was detected for nasal discomfort, nasal resistance, and eye symptoms. No particular product has demonstrated clinical superiority, selection of drug should be based on factors such as response, ease of administration, cost, and formulation.

Table 3 Intranasal corticosteroids

Application site irritation (e.g., nasal irritation, burning, or sneezing after administration) is the most commonly encountered side effect. Patients complaining of local irritation may be switched to various aqueous formulations. Although rare, mucosal erosion and septal perforations have been reported with long-term use. To minimize septal irritation, patients should be instructed to direct the spray upwards and toward the lateral portion of the nose. Periodic examination of the nasal septum should be performed.

Although systemic effects from intranasal corticosteroids at recommended doses are considered minimal, there are some concerns regarding long-term exposure. Reports of posterior subcapsular cataract formation have been linked with the use of intranasal or inhaled corticosteroids; however, more recent prospective trials did not reveal evidence of posterior subcapsular cataract formation or elevation in intraocular pressure.

In 1998, the FDA’s advisory committees on pulmonary and allergy drugs and on metabolic endocrine drugs convened to assess data suggesting that intranasal corticosteroids may have an effect on growth velocity in children. Consequently, a new class labeling for pediatric use of inhaled and intranasal corticosteroids was mandated. At this time, the long-term significance of growth velocity reduction on final adult height is unknown. The FDA recommends routine monitoring of growth in pediatric patients using intranasal corticosteroids and titration to the lowest effective dose to minimize systemic risks.

Patient education is essential in ensuring proper use and compliance to intranasal corticosteroid therapy. Patients should be instructed on instillation techniques and informed about the possible delay in symptomatic response. Assessment of maximal response may require a therapeutic trial of several weeks. The drug should be administered regularly on a daily basis, rather than as needed for rescue relief.

For patients with severe disease, the combined use of intranasal corticosteroids and antihistamines may be necessary to control symptoms. The use of oral corticosteroids should be reserved for patients with severe exacerbations or intractable disease due to high risk of systemic adverse effects.

Most intranasal corticosteroids (CS) take a few days to work with the exception of the newer, more potent agents fluticasone and mometasone. Regardless, the maximum effect requires 1-2 weeks and possibly up to 3 weeks. Patients should be encouraged to contact their healthcare provider if no benefit is seen in this time. Often anti-allergy therapy is prescribed on a presumptive basis. Patients may be on intranasal CS therapy and not be aware of which allergens they are sensitive to. Skin prick allergy testing can easily assess allergy status. Once specific allergens are identified, appropriate environmental controls can be instituted.

When a patient exhibits intolerance to a specific intranasal corticosteroids product, an excipient in the formulation may be the cause. A suggested intervention would be to switch to an alternative product. For example, an alcohol-free product could be recommended over a product containing alcohol. Additional reinforcement should target instructions on proper nasal CS administration, and nasal conditioning (moisturizing). Often overlooked are patient-specific nasal behaviors. For example, a patient may be reporting nosebleeds, and through further inquiry reveals he is a frequent nose-picker; another patient may irrigate the nose with hydrogen peroxide. If nosebleeds remain problematic for the patient, referral to an Ear, Nose and Throat Specialist may be warranted. To facilitate tailoring patient therapy, Table 8 compares various intranasal corticosteroids available in the U.S.

Conclusion

Allergic rhinitis is characterized by acute and late phase reactions. Inflammation plays a dominant role in maintaining the late phase and contributes to the increased risk of complications. Intranasal steroids have been proven effective treatment for allergic rhinitis and are superior to oral antihistamines. Therefore, first-line treatment of allergic rhinitis should be intranasal steroids in patients with allergic rhinitis of perennial or seasonal pattern with persistent or moderate symptoms. Environmental control measures should target allergens relevant to the individual. Pharmacists are in a unique position to provide balanced information and take patient-specific factors into consideration when evaluating an individual patient for specific therapy for allergic rhinitis.