Medications for Allergy

A recent report concludes that Zeneca Pharmaceutical’s Accolate ® (zafirlukast) Tablets appear to be effective in helping to reduce symptoms and maintain airway function in asthmatics who are allergic to cat allergen. Accolate, which is already known to help control asthma symptoms, was tested in 18 asthmatic patients, ages 18-49, who tested positively for cat allergen to collect data. It was found that FEV1 (Forced Expiratory Volume in one second) was reduced by 25 percent when the participants were exposed to cats after they had been treated with a placebo, but only 15 percent during the treatment phase in which they were treated with Accolate. The report was presented by University of California-Los Angeles’ Sheldon Spector, MD, at the annual meeting of the American Academy of Allergy Asthma & Immunology (AAAAI) in Orlando, Florida.

Brand Name Drug: Optivar
Active Ingredient Drug: azelastine hydrochloride
Indication: Treatment of itching of the eye associated with allergic conjunctivitis in adults and children over age 3
Company Name: ASTA Medica
Availability: Approved by FDA on May 22, 2000

Introduction

There’s a new prescription eyedrop available for the millions of Americans who suffer from itchy eyes – “allergic conjunctivitis” – during hayfever season: Optivar (azelastine hydrochloride ophthalmic solution). The FDA approved the drug, which is manufactured by ASTA Medica, on May 22, 2000. The recommended dosage of the Optivar is one drop in each affected eye twice daily. Optivar is an antihistamine that works quickly (within 3 minutes) and prevents itching for up to 8 hours.

Clinical Study Results

Clinical trials have established the effectiveness of Optivar for treating allergic conjunctivitis in both adults and children. In one study, Optivar was compared with placebo and levocabastine eye drops during a 14-day treatment period in 113 children (aged 4 to 12 years). The response rate in the Optivar group (74%) was significantly higher than that in the placebo group (39%) and was comparable to that in the levocabastine group.

Another study assessed the effectiveness of two strengths of Optivar – 0.025% and 0.05% – in 129 patients who had seasonal allergic conjunctivitis for at least a year. Seventy-three percent of patients responded to the 0.025% Optivar strength, 82% responded to 0.05% Optivar, and 56% responded to placebo. In a third study of 226 patients, the response rates were 43% for placebo, 52% for 0.025% Optivar, and 56% for 0.05% Optivar.

What You Should Know

The most common side effects reported by patients using Optivar were temporary eye burning/stinging, headaches, and bitter taste, all of which were generally mild.

Optivar should not be used to treat irritation related to contact lens wear. Benzalkonium chloride, the preservative in Optivar, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should wait at least 10 minutes after instilling Optivar before inserting their contact lenses. Patients should not wear contact lenses if their eyes are red.re inserting their contact lenses. Patients should be advised not to wear contact lenses if their eyes are red.

To prevent contaminating the dropper tip and solution, care should be taken not to touch any surface, the eyelids, or surrounding areas with the dropper tip of the bottle.

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Hydroxyzine Hydrochloride). A white or almost white, crystalline, hygroscopic powder. Freely soluble in water and in alcohol very slightly soluble in acetone. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Hydroxyzine Hydrochloride). A white, odourless, powder. Soluble 1 in 1 of water, 1 in 4.5 of alcohol, and 1 in 13 of chloroform slightly soluble in acetone practically insoluble in ether. Store in airtight containers.

Incompatibility. Hydroxyzine hydrochloride has been reported to be incompatible with aminophylline, benzylpenicillin salts, chloramphenicol sodium succinate, dimenhydrinate, doxorubicin hydrochloride (in a liposomal formulation), thioridazine, and some soluble barbiturates.

Stability. A mixture of hydroxyzine hydrochloride, chlorpromazine hydrochloride, and pethidine hydrochloride stored in glass or plastic syringes was found to be stable for 366 days at 4° and 25°.

Adverse Effects and Precautions

As for the sedating antihistamines in general. Intramuscular injection of hydroxyzine has been reported to cause marked local discomfort. Intravenous use has been associated with haemolysis.

Amputation. Accidental intra-arterial injection of hydroxyzine has led to necrosis of the extremity requiring amputation of the digits of the affected limb.

Arrhythmias. ECG abnormalities, particularly alterations in T-waves, were associated with anxiolytic doses of hydroxyzine hydrochloride and were similar to those produced by thioridazine and tricyclic antidepressants.

Effects on sexual function. A 32-year-old man had prolonged penile erections (priapism) after taking two separate doses of hydroxyzine for a skin rash. It was suggested that the effect might be due to a hydroxyzine metabolite that was found to be structurally similar to a metabolite of trazodone, a drug known to induce penile erections.

Effects on the skin. Four children given hydroxyzine hydrochloride for restlessness developed a fixed drug eruption of the penis. All recovered on drug withdrawal and subsequently had positive rechallenges.

Liver disorders. A study has suggested that hydroxyzine should only be given once daily for the relief of pruritus in patients with primary biliary cirrhosis. The mean serum elimination half-lives of hydroxyzine and its metabolite cetirizine in 8 patients with primary biliary cirrhosis were 36.6 and 25.0 hours respectively.

Porphyria. Hydroxyzine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for the sedating antihistamines in general.

Pharmacokinetics

Hydroxyzine is rapidly absorbed from the gastrointestinal tract and is metabolised. Metabolites include cetirizine, which has antihistaminic activity. An elimination half-life of about 20 hours has been reported.

Liver disorders. For reference to a prolonged half-life of hydroxyzine in patients with primary biliary cirrhosis, see under Adverse Effects and Precautions, above.

Uses and Administration

Hydroxyzine, a piperazine derivative, is a sedating antihistamine with antimuscarinic and significant sedative properties it is also an antiemetic. Its main use is as an anxiolytic but see Anxiety Disorders below. It is also used as an adjunct to pre- and postoperative medication (see Anaesthesia) and in the management of pruritus and urticaria and has been used as an adjunct to opioid analgesia in the management of cancer pain. Hydroxyzine may be given orally as the hydrochloride or the embonate doses are expressed in terms of the hydrochloride. Hydroxyzine embonate 170 mg is equivalent to about 100 mg of hydroxyzine hydrochloride.

The usual oral doses in adults are: 50 to 100 mg four times daily for the short-term management of anxiety for pruritus an initial dose of 25 mg given at night, increased if necessary to 25 mg three or four times daily and 50 to 100 mg for pre- or postoperative sedation. For pruritus in children over 6 years of age the initial dose is 15 to 25 mg daily increased if necessary to 50 to 100 mg daily in divided doses for children 6 months to 6 years old the initial dose is 5 to 15 mg daily increased if necessary to 50 mg daily in divided doses.

Alternatively, 1 mg/kg daily may be given in divided doses, to a maximum of 2.5 mg/kg daily in children aged 1 to 6 years, and to a maximum of 2 mg/kg daily in those aged 6 years and over. The pre- or postoperative sedative dose in children is 600 micrograms/kg. Dosage should be reduced in patients with hepatic or renal impairment, see below.

Hydroxyzine hydrochloride may also be given by deep intramuscular injection. For prompt control of anxiety or agitation in adults 50 to 100 mg is injected intramuscularly initially, and the dose may be repeated every four to six hours as required. For other indications when oral dosage is not practical, the intramuscular dose is 25 to 100 mg for adults and 1.1 mg/kg for children. Hydroxyzine should not be given by intravenous injection since haemolysis may result.

Administration in hepatic or renal impairment. In patients with hepatic impairment, UK licensed product information recommends a 33% reduction in the total oral daily dose of hydroxyzine. In patients with moderate or severe renal impairment, a dose reduction of 50% is recommended.

Anxiety disorders. Although hydroxyzine is used in the management of anxiety, there is little evidence to support its efficacy in anxious patients, and the BNF considers that use of antihistamines solely for their sedative effect in anxiety is not appropriate.

Preparations

The United States Pharmacopeia 31, 2008: Hydroxyzine Hydrochloride Injection Hydroxyzine Hydrochloride Syrup Hydroxyzine Hydrochloride Tablets Hydroxyzine Pamoate Capsules Hydroxyzine Pamoate Oral Suspension.

Proprietary Preparations

Argentina: Ataraxone; Hidroxina †; Hyderax

Austria: Atarax

Belgium: Atarax

Brazil: Hixizine; Prurizin

Canada: Atarax

Chile: Dalun; Fasarax; Nexit

Czech Republic: Atarax

Denmark: Atarax

Finland: Atarax

France: Atarax

Germany: AH 3 N; Atarax; Elroquil N

Greece: Atarax Iremofar

Hong Kong: Atarax; Qualidrozine

Hungary: Atarax

India: Atarax

Indonesia: Bestalin; Iterax

Israel: Otarex

Italy: Atarax

Malaysia: Atarax

Mexico: Atarax

The Netherlands: Atarax; Navicalm †

Norway: Atarax

New Zealand: Serecid

Philippines: Iterax

Poland: Atarax

Portugal: Atarax; Coraphene

Russia: Atarax

South Africa: Aterax; Neurax

Singapore Atarax; Hizin; Phymorax †

Spain: Atarax

Sweden: Atarax

Switzerland: Atarax

Thailand: Abacus; Allerax; Antizine; Atano; Atarax; Cerax; Daraxl; Drazine; Hadarax; Histan; Hizin; Honsa; Hydroxinl; Katrax; Masaraxf; Med-Xyzarax; Polizine; Postarax; R-Rax; Taraxin; Trandrozine; Unamine

Turkey: Atarax; Validol

UK: Atarax; Ucerax

USA: Atarax; Vistaril; Vistazine.

Multi-ingredient

Austria: Diligan

Brazil: Marax

Germany: Diligan †

India: Marax

Portugal: Diligan; Vesparax †

South Africa: Geratar

Spain: Calmoplex; Dolodens

USA: Hydrophed; Marax; Theomax D †

Venezuela: Marax.

Drug Nomenclature

Adverse Effects and Precautions

Headache, an increased incidence of respiratory-tract infection (in the elderly), and gastrointestinal disturbances have been reported with zafirlukast and other leukotriene antagonists. Other adverse effects have included generalised and abdominal pain, arthralgia, myalgia, fever, malaise, insomnia, and dizziness. Elevations in liver enzyme values have occurred, and rarely, symptomatic hepatitis or hyperbilirubinaemia (see also below) fatalities have occurred. Hyper sensitivity reactions, including rashes, pruritus, urticaria, and angioedema, have been reported. There have also been rare reports of agranulocytosis, bleeding, bruising and oedema. There have been a few reports of systemic eosinophilia consistent with Churg-Strauss syndrome in patients receiving zafirlukast (see below) treatment should be withdrawn in these patients. Zafirlukast and other leukotriene antagonists should not be used for the treatment of acute asthma attacks. Zafirlukast is contra-indicated in patients with hepatic impairment or cirrhosis.

Incidence of adverse effects. An observational study of 7976 patients prescribed zafirlukast found it to be generally well tolerated. Similarly to UK licensed product information, the most frequently reported adverse effects (1 to 2% of patients) were headache, rash, abdominal pain, malaise, and gastrointestinal disturbances such as nausea, diarrhoea, and dyspepsia. Dizziness and palpitations were more common in the first month of treatment. An increased incidence of depression was also noted.

Churg-Strauss syndrome. Pulmonary infiltrates and eosinophilia, resembling the Churg-Strauss syndrome, with dilated cardiomyopathy, were reported after withdrawal of corticosteroid therapy in 8 patients taking zafirlukast. Symptoms responded to withdrawal of zafirlukast and treatment with corticosteroids, with or without cyclophosphamide. It has been suggested that the patients original asthmatic symptoms had been part of an unrecognised vasculitic syndrome that was unmasked by stopping corticosteroids. However, others have reported Churg-Strauss syndrome associated with zafirlukast in those not receiving corticosteroids, although these cases were not inconsistent with the view that treatment with leukotriene antagonists was coincidental. It has also been noted that leukotriene receptor antagonists tend to be prescribed for patients with more severe asthma, which may be a precursor to the development of Churg-Strauss syndrome. In addition, eosinophilic syndromes have been reported for other anti-asthma drugs including inhaled fluticasone and sodium cromoglicate, evidence supporting a non-drug-related aetiology. However, the number of reports with zafirlukast and the other leukotriene antagonists, montelukast and pranlukast, means that a particular class-effect cannot be ruled out. It has been suggested that patients should be monitored carefully (e.g. by measuring erythrocyte sedimentation rate, C reactive protein, and eosinophil counts) if the introduction of an anti-asthma drug such as a leukotriene antagonist permits the reduction of oral corticosteroid dosage. In addition, in patients with asthma and features of multisystem disease, the possibility of underlying Churg-Strauss syndrome may be worth considering.

Effects on the liver. Severe hepatotoxicity has been associated with zafirlukast. The Canadian manufacturer reported in April 2004 that from worldwide postmarketing surveillance of zafirlukast there had been 46 reports of hepatitis, 14 of hepatic failure, 3 of which progressed to fulminant hepatitis, and 59 reports of other clinically significant hepatic dysfunction 7 fatalities had occurred. In most, but not all, cases symptoms had abated and liver enzymes had returned to normal after stopping zafirlukast. It was important that prescribers, patients and/or their carers were alert to the signs and symptoms of hepatotoxicity. Licensed product information for zafirlukast advises stopping treatment if hepatotoxicity is suspected, and performing liver function tests

Lupus. Zafirlukast was thought to be responsible for the development of lupus in a 9-year-old girl.

Renal impairment. The UK licensed product information states that zafirlukast should be used with caution in patients with moderate or severe renal impairment because of limited experience in this group. However, the US product information mentions no such caution, and states that the pharmacokinetics of zafirlukast in patients with renal impairment do not appear to differ from those in patients with normal renal function. Only about 10% of a dose is reported to be excreted in the urine.

Interactions

Zafirlukast is metabolised by hepatic cytochrome P450, specifically the CYP2C9 isoenzyme, and has been shown to inhibit the activity of isoenzymes CYP2C9 and CYP3A4. Therefore, use with other drugs that are metabolised by these hepatic enzymes may result in increases in plasma concentrations, and possibly, adverse effects. Patients receiving warfarin may develop prolongation of the prothrombin time and anticoagulant dosage should be adjusted accordingly. Erythromycin, terfenadine, and theophylline may reduce plasma concentrations of zafirlukast zafirlukast has rarely been reported to increase plasma-theophyl-line concentrations. Increased plasma concentrations of zafirlukast have been seen when given with high doses of aspirin.

Pharmacokinetics

Peak plasma concentrations of zafirlukast occur about 3 hours after oral doses. The absolute bioavailability is uncertain, but taking it with food reduces both the rate and extent of absorption, decreasing bioavailability by about 40%. Zafirlukast is about 99% bound to plasma proteins. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP2C9, and excreted principally in faeces, as unchanged drug and metabolites. About 10% of a dose is excreted in urine as metabolites. The terminal elimination half-life of zafirlukast is about 10 hours. Studies in animals suggest that small amounts cross the placenta it is also distributed into breast milk.

Uses and Administration

Zafirlukast is a selective and competitive antagonist of the leukotriene C₄, D₄, and E₄ receptors, stimulation of which by circulating leukotrienes is thought to play a role in the pathogenesis of asthma. The drug suppresses both early and late bronchoconstrictor responses to inhaled antigens or irritants, but is not suitable for the management of acute attacks of asthma. Zafirlukast is used in the management of chronic asthma (see below). It is given orally in doses of 20 mg twice daily, taken at least 1 hour before or 2 hours after meals. For details of doses in children, see below.

Administration in children. In the management of chronic asthma, US licensed product information recommends a zafirlukast dose of 10 mg twice daily orally in children aged from 5 to 11 years. Children 12 years of age and over may be given the adult dose, see above. In the UK, zafirlukast is unlicensed in children under 12 years of age.

Asthma. Zafirlukast produces modest improvement in mild-to-moderate asthma, which was of a similar order to that seen with inhaled sodium cromoglicate in one study, but less than that of inhaled salmeterol in another It has also been found to be less effective than inhaled fluticasone in persistent asthma. Guidelines for the management of asthma permit the use of zafirlukast as an alternative to inhaled corticosteroids in patients with mild persistent asthma, who cannot be managed with inhaled beta₂ agonists on an asneeded basis alone. It can also be considered for use in moderate or severe persistent asthma, usually added to standard therapy of inhaled corticosteroids and long-acting inhaled beta₂ agonists. Combination of anti-leukotriene drugs with inhaled corticosteroids alone seems, however, to be less effective than a combination of the latter with long-acting inhaled beta₂ agonists. In a study in patients presenting to the emergency room with acute severe asthma, adding zafirlukast to standard therapy in hospital and for 28 days after discharge was associated with a reduced rate of relapse, and a reduction in the need for extended care.

Rhinitis. Although it was reported to improve symptoms of seasonal allergic rhinitis in one study, zafirlukast 20 mg twice daily was not effective when compared with placebo and intranasal beclometasone in another. Some benefits have been reported in perennial allergic rhinitis, in particular an improvement in nasal obstruction. A review of the role of leukotrienes in allergic rhinitis concluded that leukotriene receptor antagonists have modest efficacy given alone but can be usefully added to other treatments.

Urticaria. Leukotriene antagonists, such as zafirlukast, are reported to have some benefit in the management of chronic urticaria.

Proprietary Preparations

Argentina: Accolate Vanticon Zafinasmal

Australia: Accolate

Belgium: Accolate Resma

Brazil: Accolate

Canada: Accolate

Chile: Accolate

Czech Republic: Accolate

Finland: Accolate

Hong Kong: Accolate

Hungary: Accolate

India: Zuvair

Ireland: Accolate

Italy: Accoleit Zafirst

Mexico: Accolate

Philippines: Accolate

Poland: Accolate

Portugal: Accolate

Russia: Accolate

South Africa: Accolate

Singapore: Accolate

Spain: Accolate Aeronix Olmoran

Switzerland: Accolate

Thailand: Accolate

Turkey: Accolate

UK: Accolate

USA: Accolate

Venezuela: Accolate.

Amlexanox

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, Spanish):

Profile

Amlexanox has a stabilising action on mast cells resembling that of sodium cromoglicate and also acts as a leukotriene inhibitor. It is given orally in the management of asthma and for allergic rhinitis a dose of 25 or 50 mg three times daily has been suggested. Amlexanox is also given as a metered-dose nasal spray for allergic rhinitis.

Amlexanox is also applied as a 5% oral paste four times daily in the management of aphthous ulcers (see Mouth Ulceration). A 2-mg biodegradable oral disc designed to deliver amlexanox locally is also available.

Proprietary Preparations

Japan: Solfa

The Netherlands: Miraftil

USA: Aphthasol

Pranlukast

Drug Approvals

(British Approved Name, rINN)

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

Profile

Pranlukast is a selective antagonist of the leukotriene C₄, D₄, and E₄ receptors with similar properties to zafirlukast. It is used in the management of asthma and allergic rhinitis, at a usual oral dose of pranlukast hydrate 225 mg twice daily. For details of doses in children, see below.

Administration in children. Children with asthma may be given 3.5 mg/kg of pranlukast hydrate orally twice daily. The maximum daily dose is 10 mg/kg, not to exceed the usual adult daily dose of 450 mg (see above).

Churg-Strauss syndrome. Churg-Strauss syndrome has been reported with the use of pranlukast. For discussion of the unresolved role of leukotriene antagonists in this disorder and precautions to be observed, see under Zafirlukast.

Proprietary Preparations

Japan: Orion

Mexico: Azlaire

Venezuela: Azlaire.

Suplatast Tosilate

Drug Nomenclature

Profile

Suplatast tosilate is an anti-allergic given orally in the prophylactic management of asthma and other allergic conditions.

Proprietary Preparations

Japan: IPD.

Drug Approvals

(US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Adverse Effects and Precautions

Adverse effects reported with tranilast have included gastrointestinal disturbances, headache, drowsiness or insomnia, dizziness, malaise, and skin rashes and generalised pruritus. Rarely, liver function disturbance or jaundice, renal dysfunction, cystitislike symptoms, anaemia, leucopenia, thrombocytopenia, palpitations, oedema, facial flushing, and stomatitis may occur. Tranilast should be used with caution in patients with impaired hepatic or renal function. Haematological monitoring is recommended. Irritation and blepharitis have been reported after topical application to the eye.

Ticensed product information advises against the use of tranilast in pregnancy because of teratogenicity in animal studies. Tranilast should not be used for the treatment of acute asthma attacks. The general cautions described under sodium cromoglicate also apply.

Uses and Administration

Tranilast has a stabilising action on mast cells resembling that of sodium cromoglicate. It is also stated to inhibit collagen synthesis in fibroblasts. It is used in the prophylactic management of asthma and in allergic rhinitis, conjunctivitis, and eczema. It is also used in the management of keloids and hypertrophic scarring. The usual oral adult dose is 100 mg three times daily. For details of doses in children, see below. Eye drops containing tranilast 0.5% are used four times daily for allergic conjunctivitis. Tranilast has been investigated for the prevention of restenosis after coronary artery revascularisation procedures but was found to be ineffective.

Administration in children. Tranilast is given to children for the prophylactic management of asthma, in allergic rhinitis and eczema, and in the management of keloids and hypertrophic scars. An oral daily dose of 5 mg/kg, given in 3 divided doses, may be used.

Sarcoidosis. For a mention of possible benefit from tranilast in cutaneous sarcoidosis.

Proprietary Preparations

Japan: Rizaben.

Drug Approvals

(US Adopted Name, rINNM)

Profile

Pemirolast potassium has mast cell stabilising properties like sodium cromoglicate and may also be a leukotriene inhibitor. It has been used in the treatment of chronic asthma and in the prophylaxis of allergic rhinitis and conjunctivitis. Pemirolast potassium has no bronchodilator properties and should not be used for the treatment of acute asthma attacks.

For asthma, the usual dose is 10 mg orally twice daily after food. For allergic rhinitis the dose is halved. Pemirolast potassium 0.1% eye drops are instilled 4 times daily in the prophylactic management of allergic conjunctivitis. For details of doses in children, see below.

Pemirolast has also been investigated for the prevention of reste-nosis after coronary artery stent placement.

Administration in children. Pemirolast potassium may be used in the management of asthma in children in the following oral doses:

• 1 to 4 years: 2.5 mg twice daily after food

• 5 to 10 years: 5 mg twice daily after food

• 11 years and above: use adult doses, see above For allergic rhinitis, the above doses are halved.

Pemirolast potassium 0.1% eye drops can be used four times daily in children over 3 years with allergic conjunctivitis.

Proprietary Preparations

Hong Kong: Pemirox

Indonesia: Alegysal

Japan: Alegysal

Philippines: Alegysal

Thailand: Pemirox

USA: Alamast

Drug Approvals

(British Approved Name, rINN)

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

Adverse Effects and Precautions

As for the non-sedating antihistamines in general. Mizolastine has only a weak potential to prolong the QT interval (see also Arrhythmias) and has not been associated with arrhythmias. However, the manufacturers have warned against the use of mizolastine in patients with significant cardiac or hepatic disease, with hypokalaemia or other electrolyte imbalance, or with known or suspected QT prolongation. Use with drugs liable to interfere with the hepatic metabolism of mizolastine or with other potentially arrhythmogenic drugs should also be avoided (see under Interactions, below).

Interactions

As for the non-sedating antihistamines in general. Moderate increases in plasma concentrations of mizolastine have been reported with erythromycin and ketoconazole use with macrolide antibacterials or systemic imidazole antifungals is contra-indicated by the manufacturer. They also advise against use of mizolastine with drugs known to prolong the QT interval, such as class I and III antiarrhythmics.

Other potent inhibitors of or substrates for the hepatic metabolism of mizolastine include cimetidine, ciclosporin, and nifedipine caution is advised if given together.

Pharmacokinetics

Mizolastine is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations being reached after about 1.5 hours. Plasma protein binding is about 98%. The mean elimination half-life is about 13 hours. Mizolastine is mainly metabolised by glucuronidation although other metabolic pathways are involved, including metabolism by the cytochrome P450 isoenzyme CYP3 A4, with the formation of inactive hydroxylated metabolites.

Uses and Administration

Mizolastine is a non-sedating antihistamine with a long duration of action. It does not have significant antimuscarinic actions it is reported to have mast-cell stabilising properties. Mizolastine is used for the symptomatic relief of allergic conditions including rhinitis, conjunctivitis, and skin disorders such as urticaria. The oral dose is 10 mg daily.

Proprietary Preparations

Argentina: Mistamine †

Austria: Mizollen

Belgium: Mistamine † Mizollen

Chile: Mistamine †

Czech Republic: Mizollen

Denmark: Mizollen

Finland: Mizollen

France: Mizollen

Germany: Mizollen Zolim

Greece: Mizollen Oriens

Hungary: Mizollen †

India: Elina

Ireland: Mistamine †

Israel: Mizollen

Italy: Mizollen Zolistam

Mexico: Mistamine

The Netherlands: Mizollen

Poland: Mizollen

Portugal: Mistamine † Mizollen Zolistam

South Africa: Mizollen

Spain: Mistamine † Mizolen Zolistan

Sweden: Mizollen

Switzerland: Mistamine Mizollen

UK: Mizollen.

Antazoline Hydrochloride

Drug Approvals

(British Approved Name Modified, rINNM)

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

Pharmacopoeias. In China, and Europe.

European Pharmacopoeia, 6th ed. (Antazoline Hydrochlonde). A white or almost white crystalline powder. Sparingly soluble in water soluble in alcohol slightly soluble in dichloromethane.

Antazoline Mesilate

Drug Approvals

(British Approved Name Modified, rINNM)

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

Pharmacopoeias. In Poland.

Antazoline Phosphate

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Antazoline Phosphate). A white to off-white crystalline powder. Soluble in water practically insoluble in ether and in benzene sparingly soluble in methyl alcohol. pH of a 2% solution in water is between 4.0 and 5.0. Store in airtight containers.

Antazoline Sulfate

Note. The above molecular formula is that provided in the It P. Other sources give a molecular formula of C₁₇H₁₉N3,H₂S04.

Pharmacopoeias. In ltaly.

Adverse Effects and Precautions

As for the antihistamines in general.

Hype rsen sit ivity. Reports of acute interstitial pneumonitis (with fever, rash, and dyspnoea) and of immune thrombocytopenic purpura were attributed to hypersensitivity reactions after the oral use of antazoline.

Uses and Administration

Antazoline, an ethylenediamine derivative, is an antihistamine used topically for the treatment of allergic conjunctivitis.

It is used as the hydrochloride, phosphate, or sulfate in eye drops, most commonly in a concentration of 0.5% the mesilate has also been used. Antazoline salts are often used with a vasoconstrictor such as naphazoline hydrochloride or nitrate or xylometazoline hydrochloride.

The hydrochloride and sulfate salts of antazoline have been used topically for the treatment of minor skin irritations, but as with other antihistamines there is a risk of sensitisation. The hydrochloride has also been given by mouth.

Preparations: multi-ingredient

Australia: Albalon-A Antistine-Privine In A Wink Allergy!

Austria: Histophtal

Belgium: Zincfrin Antihistaminicum †

Canada: Albalon-A Vasocon-A † Zincfrin-A

Chile: Albasol A Bacitopic Compuesto Nasomin Oftalirio Red Off Plus Spersallerg

Czech Republic: Sanorin-Analergin Spersallerg

Denmark: Ansal Antistina-Privin Sesal

Finland: Antistin-Privin Zincfrin-A †

Germany: Allergopos N Antistin-Privin Spersallerg

Greece: Spersallerg

Hong Kong: Spersallerg

Hungary: Spersallerg

Indonesia: Indofrin-A

Irland: Otrivine-Antistin RBC

Israel:Antistin-Privin

Italy: Antistin-Privina

Malaysia: Alergoftal Napha A Spersallerg

Mexico: Midazol Ofteno Oftalirio Zincfrin-A

Norway: Spersallerg

New Zealand: Albalon-A Otrivine-Antistin

Philippines: Spersallerg

Poland: Dermophenazol Oftophenazol Rhinophenazol Spersallerg

Portugal: Alergiftalmina

Russia: Sanorin-Analergin Spersallerg

South Africa: Albalon-A Antistin-Privin Covosan Gemini Oculerge Safyr Bleu Antihistamine Spersallerg Zincfrin-A

Singapore: Antistin-Privin Spersallerg

Spain: Alergoftal

Sweden: Antasten-Privin

Switzerland: Antistin-Privin Spersallerg

Thailand: Antazallerge Histaoph Opsa-His Opsil-A Spersallerg

Turkey: Alergoftal Sulfarhin

UK: Otrivine-Antistin

USA: Antazoline-V Vasocon-A.

(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