Medications for Allergy

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In China, Europe, International, and Japan US allows either the anhydrous or monohydrate form. Europe also includes a separate monograph for the monohydrate.

European Pharmacopoeia, 6th ed. (Beclometasone Dipropionate, Anhydrous). A white or almost white, crystalline powder. Practically insoluble in water sparingly soluble in alcohol freely soluble in acetone. Protect from light.

European Pharmacopoeia, 6th ed. (Beclometasone Dipropionate Monohydrate). A white or almost white powder. Practically insoluble in water sparingly soluble in alcohol freely soluble in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Beclomethasone Dipropionate). It is anhydrous or contains one molecule of water of hydration. A white to cream white, odourless powder. Very slightly soluble in water freely soluble in alcohol and in acetone very soluble in chloroform.

Adverse Effects, Treatment, Withdrawal, and Precautions

As for corticosteroids in general. Adrenal suppression may occur in some patients treated with high-dose long-term inhalation therapy for asthma. It has been stated that in the majority of patients no significant suppression is likely to occur when total daily doses of less than 1.5 mg are used (but see Adrenal Suppression, below).

When applied topically, particularly to large areas, when the skin is broken, or under occlusive dressings, corticosteroids may be absorbed in sufficient amounts to cause systemic effects. Systemic absorption may also follow nasal use, particularly after high doses or prolonged treatment.

Adrenal suppression. The problem of adrenal suppression with corticosteroids is discussed. Listed below are some references and correspondence concerning adrenal suppression due to beclometasone inhalation therapy in some cases occurring with doses below 1.5 mg daily. However, one study found that function of the hyp othalamic-pituitary-adrenal axis remained normal in most patients at beclometasone doses below 3 mg daily.

Candidiasis. Results of a study involving 229 asthmatic children indicated that the presence of a sore throat or a hoarse voice was not related to the presence of Candida or to treatment with inhaled beclometasone. The occurrence of only one clinical case of oral candidiasis in 129 of the children receiving beclometasone confirmed previous observations that it is an uncommon finding in children compared with the reported incidence of between 4.5 and 13% in adults. The incidence of colonisation with Candida was greater in those children who received corticosteroids than in those who did not but was not affected by either the dose or type of inhaler used.

Effects on the bones. The adverse effects of corticosteroids in general on bones are discussed. Studies in healthy subjects have shown that inhaled beclometasone dipropionate can suppress bone metabolism. These studies measured biochemical markers such as serum-osteocalcin concentrations, serum alkaline phosphatase activity, and urinary hydroxyproline-creatinine ratio, over short periods of time. Another study found that markers of collagen turnover, but not osteocalcin, were reduced by beclometasone or budesonide 800 micrograms daily in mildly asthmatic children. Results are difficult to interpret since osteocalcin concentrations are reduced in patients with asthma regardless of treatment, and it is uncertain whether significant bone loss does occur in practice. One 12-month study in adults with asthma found that biochemical markers showed suppressed bone formation from inhaled beclometasone, and that there was some loss of bone mineral density from the hip. This study also found that inhaled fluticasone, in equivalent therapeutic doses, may have less adverse effect on bone. Another, smaller, study found no adverse effects from beclometasone or fluticasone on bone mass or metabolism. In a study of asthmatic children, comparing those treated with inhaled budesonide with those who received no corticosteroids, an average daily dose of about 500 micrograms budesonide for 3 to 6 years did not adversely affect bone density and mineral measures.

Effects on growth. Meta-analysis of 3 eligible studies (out of 92 examined) concluded that inhaled beclometasone therapy at a dose of 400 micrograms daily may cause a 1.54 cm/year decrease in growth in children with mild to moderate asthma. The long-term effects of treatment are unknown, and therefore it is not clear whether catch-up growth will occur on stopping therapy. The lowest possible dose of corticosteroid therapy should be used in asthma, and growth should be monitored. There is also evidence that long-term intranasal beclometasone for the treatment of allergic rhinitis can slow growth in children the effect on final height is unknown. For further details of the effects of corticosteroids on growth.

Effects on the lungs. Pulmonary eosinophilia has occurred in patients treated with inhaled beclometasone.

Hypersensitivity. There have been reports of asthmatic reactions to beclometasone dipropionate inhalations, possibly associated with materials used in their formulation, or with the containers.

Reformulation. Reformulation of some metered-dose inhalers to use a chlorofluorocarbon (CFC)-free propellant has resulted in a change of efficacy. One CFC-free product (Qvar, UK) is reported to be effective at about half the dose required with the standard product (see Uses and Administration, below) and the UK CSM has issued a reminder of the need for dosage reduction when converting from the conventional formulation to this product. An open-label, crossover study in healthy subjects also found higher beclometasone plasma concentrations after use of another brand (Beclozone, Eire) of CFC-free product. However, this dose reduction does not apply to all CFC-free formulations of beclometasone. A review concluded that good studies on the bioequivalence between the reference beclometasone preparation and the newer CFC-free formulations are not available.

Interactions

The interactions of corticosteroids in general are described.

Pharmacokinetics

For a brief outline of the pharmacokinetics of corticosteroids. Beclometasone is stated to be readily absorbed from sites of local application, and rapidly distributed to all body tissues. It is metabolised principally in the liver, but also in other tissues including gastrointestinal tract and lung enzymatic hydrolysis rapidly produces the monopropionate (which has some glucocorticoid activity), and, more slowly, the free alcohol, which is virtually devoid of activity. Only a small proportion of an absorbed dose is excreted in urine, the remainder being excreted in the faeces mainly as metabolites.

Uses and Administration

Beclometasone dipropionate is a corticosteroid with mainly glucocorticoid activity that is stated to exert a topical effect on the lungs without significant systemic activity at recommended doses (but see Adrenal Suppression under Adverse Effects, above). It is used by inhalation, generally from a metered-dose aerosol, for the prophylaxis of asthma (see below).

Many formulations are now available, with differing dosage regimens, and the appropriate product literature should be consulted before starting therapy or changing to another formulation. Furthermore in the UK the doses of beclometasone dipropionate for asthma and rhinitis are expressed in units of 50 micrograms or multiples thereof (dose supplied into the mouthpiece per actuation) whereas in the USA the dose-unit is 42 micrograms or multiples thereof (dose emitted from the mouthpiece) recommended doses therefore appear somewhat lower in the USA than the UK doses given below, although in practical terms there is probably no difference.

In the UK the adult dosage of the conventional aerosol and some dry powder inhalers is usually 400 micrograms daily, inhaled in 2 to 4 divided doses for maintenance treatment if necessary, 600 to 800 micrograms may be inhaled daily initially, subsequently adjusted according to the patient’s response. In patients with severe asthma or in those showing only a partial response to standard inhalation doses, high-dose inhalation therapy may be considered doses of 1 mg daily (250 micrograms four times daily or 500 micrograms twice daily) may be used and may be increased to 1.5 to 2 mg daily (500 micrograms three or four times daily) if necessary a maximum of 2 mg daily should not be exceeded. In children, 50 or 100 micrograms may be inhaled 2 to 4 times daily according to the response or alternatively, 100 or 200 micrograms may be inhaled twice daily.

Although beclometasone dipropionate is generally inhaled in aerosol form, inhalation capsules or discs containing powder for inhalation are available for patients who experience difficulty in using the aerosol. Owing to differences in the relative bioavailability to the lungs a 100-microgram dose from an inhalation capsule or disc is approximately equivalent in activity to a 50-microgram dose from a conventional aerosol. Recommended maintenance doses of beclometasone dipropionate from inhalation capsules or discs are therefore higher. 200 micrograms inhaled 3 or 4 times daily or 400 micrograms inhaled twice daily for adults, and 100 micrograms inhaled 2 to 4 times daily or 200 micrograms inhaled twice daily for children. Up to 800 micrograms twice daily may be inhaled if necessary in adults requiring high-dose therapy.

In some countries beclometasone dipropionate is now available as a CFC-free aerosol. Because of changes in particle size the dose required from some such inhalers may be lower than that from a conventional aerosol: typical UK doses for one product (Qvar) range from 100 to 200 micrograms daily in mild asthma to 400 to 800 micrograms daily in severe asthma, given as 2 divided doses.

Inhalation of nebulised beclometasone dipropionate has also been used in the management of asthma in children.

Beclometasone dipropionate is also used as a nasal spray in the prophylaxis and treatment of allergic and non-allergic rhinitis. Usual doses are 100 micrograms in each nostril twice daily or 50 micrograms in each nostril 3 or 4 times daily a total of 400 micrograms daily should not generally be exceeded. A dose of 50 micrograms in each nostril twice daily may be sufficient for prophylaxis. The nasal spray is also used to prevent recurrence of nasal polyps after surgical removal. Beclometasone dipropionate is also used topically in the treatment of various skin disorders. It is generally applied as a cream or ointment containing 0.025%. Beclometasone salicylate has also been used topically. For recommendations concerning the correct use of corticosteroids on the skin, and a rough guide to the clinical potencies of topical corticosteroids.

Adenoidal hypertrophy. Although normally managed by surgery (or if less severe simply by symptomatic relief) adenoidal hypertrophy in children was reported to respond to aqueous nasal beclometasone 336 micrograms daily in an 8-week crossover study. Improvements in adenoidal obstruction and symptom scores were enhanced in a subsequent 16-week follow-on study using 168 micrograms daily. Another similar study, of an initial 4-week crossover period followed by 24 weeks of open-label treatment, found symptomatic improvements in about half of the patients, and at 100 weeks there was a decrease in the rate of adenotonsillectomy in children who had responded to beclometasone compared with nonresponders.

Asthma. Corticosteroids and beta₂-adrenoceptor agonists form the cornerstone of the management of asthma. Patients requiring only occasional relief from symptoms may be managed with an inhaled short-acting beta₂ agonist, and an inhaled corticosteroid such as beclometasone is added if symptomatic relief is needed more than once daily. In more severe asthma other drugs may be added (combination with a long-acting beta₂ agonist may have synergistic benefits), or the dose of inhaled corticosteroid may be increased.

High-dose regimens may pose problems of compliance if beclometasone must be inhaled several times daily. However, one study found once-daily inhalation to be as effective as the same dose divided into 2 daily inhalations in short-term control of moderate asthma. Also there have been doubts that increasing the dose of inhaled beclometasone brings about increased benefits, but guidelines and clinical practice suggest that improved control can often be achieved by increasing the dose. A systematic review noted that while there was little evidence of an effect of dose titration above 400 micrograms daily in those with mild to moderate asthma, evidence was lacking in patients with more severe disease (who are more likely to be given high-dose therapy), and studies were needed to resolve the question. Inhalation of beclometasone dipropionate as a nebulised solution has been found to be useful in the management of severe asthma in children aged 2 years or under previously unresponsive to other drugs Nebulised beclometasone dipropionate was also effective in the management of recurrent episodes of bronchopulmo-nary obstruction following bronchiolitis in children under 2 years of age. However, in other reports nebulised beclometasone dipropionate, although more effective than saline in pre-school children, produced a response less than that usually observed with inhalation of beclometasone from an aerosol or capsules, or no benefit at all. This may have been due to beclometasone somehow failing to reach the lungs. In pre-school children able to use a spacer device with a metered aerosol, intermittent therapy with high-dose beclometasone dipropionate, given at the first sign of symptoms, reduced the severity of acute episodic asthma.

Chronic obstructive pulmonary disease. For discussion of the value of inhaled corticosteroids in chronic obstructive pulmonary disease.

Cough. In children with recurrent cough inhalation of beclometasone 200 micrograms twice daily from a conventional aerosol or salbutamol 200 micrograms twice daily had no effect on cough frequency or severity. However, in another study of 200 adults, use of beclometasone, salbutamol, or sodium cromoglicate (all in aerosol formulation) given 15 minutes before anaesthesia, significantly decreased coughing caused by fentanyl when compared with placebo. Of the 50 patients given beclometasone, none experienced coughing.

Graft-versus-host disease. Beclometasone is under investigation for its topical effect in the treatment of intestinal graft-versus-host disease (GVHD). A study in patients with acute intestinal GVHD after bone marrow transplantation (see Haematopoietic Stem Cell Transplantation) found that addition of oral beclometasone to prednisolone therapy was associated with a greater proportion of durable responses after 30 days. Repeated courses may be needed in some patients to achieve and maintain response, but prolonged therapy appears to be feasible.

Inflammatory bowel disease. Beclometasone 500 micrograms given nightly as an enema was as effective as betamethasone 5 mg enemas in the treatment of acute attacks of distal ulcerative colitis. Although betamethasone produced slightly superior histological improvement and faster disappearance of blood from the stools, systemic adverse effects observed with betamethasone therapy were absent in patients treated with beclometasone.

Comparisons of beclometasone dipropionate enemas (3 mg) with prednisolone sodium phosphate enemas (30 mg) or me-salazine enemas (1 g) found them to be equally effective. Treatment was well tolerated. Beclometasone dipropionate has also been investigated for the oral treatment of ulcerative colitis. For a review of the management of inflammatory bowel disease, including the role of corticosteroids.

Preparations

British Pharmacopoeia 2008: Beclometasone Cream; Beclometasone Nasal Spray; Beclometasone Ointment; Beclometasone Powder for Inhalation; Beclometasone Pressurised Inhalation

Proprietary Preparations

Australia:: Aldecin † Becloforte † Beconase Beconase Hayfever Becotide Qvar

Austria: Aerocortin Beclomet Beconase Becotide

Belgium: Beclometatop Beclophar Beconase Becotide † Qvar

Brazil: Alerfin Beclosol Genii Miflasona

Canada: Gen-Beclo Propaderm Qvar Rivanase

Czech Republic: Aldecin Beclazone † Becloforte Beclomet Becodisks Beconase Becotide Clenil Ecobec Miflason-P Nasobec

Denmark: AeroBec Beclomet Beconase

Finland: AeroBec Beclomet Beclonasal Beconase Becotide †

France: Asmabec Beclo-Rhino Beclojet Beclone Beclospin Beconase Becotide Bemedrex Ecobec Humex Rhume des Foins Niflasone Nexxair Prolair Qvar Spir †

Germany: AeroBec Beclo Beclo Siozwo † Beclobreathe Beclohexal Beclomet Beclorhinol Becloturmant Beconase Aquosum Bronchocort Junik ratioAllerg Rhinivict Sanasthmax Sanasthmyl Ventolair Viarox †

Hungary: Aldecin † Beclomet † Beclonasal Ecobec †

India: Beclate

Indonesia: Beclomet Beconase Becotide Geniderm

Ireland: AeroBec † Asmabec Beclazone Beclo-Rhino Becodisks † Beconase Becotide Nasobec Qvar

Israel: Becloforte Beconase † Becotide † Rhinocort Viarex

Italy: Becotide Becotide A † Bronco-Turbinal † Clenil Genilexx Clipper Klostenal Nenaderm Simplex Prontinal Rino Clenil Topster Propaderm Rhinocort Salcoat

Malaysia: Atomase † Beclate Beclazone Becloforte † Beclomet Beconase Becotide † Clenil Qvar

Mexico: Beclazone Beconase Becotide Dobipro Riferina

The Netherlands: AeroBeec Aldecin Beclodin Becloforte Beconase Becotide Clenil Qvar Viarin

Norway: AeroBec Beclomet Becotide

New Zealand: Alanase Atomase Atomide † Beclazone Beconase Hayfever Niflasone † Qvar Respocort

Philippines: Qvar

Poland: Becodisk Cortare Nasobec

Portugal: Beclotaide Beconase Clenil Ecobec

Russia: Aldecin Beclazone Becloforte Beclojet Becodisk Beconase † Becotide Clenil Nasobec

Spain: Asmabec † Beclo Asma Beclo Rino Becloenema Becloforte Beclomet Beclosona Beconase Becotide Betsuril † Broncivent † Decasona † Dereme Nenaderm Simple Qvar † Recto Nenaderm N †

Sweden: AeroBec Beclomet Becotide

Switzerland: AeroBec † BECeco Becloforte † Beclomet † Beclonarin Becodisk Beconase Beconasol Becotide †

Thailand: Atomase Becloforte † Beclomet Becodisk † Beconase Becotide † Bemase Clenil Rino Clenil

Turkey: Becloforte Becodisks Becotide Bekamet Beklazon Filair

UAE: Beclohale

UK: AeroBec Asmabec Beceze Beclazone Becloforte † Beclogen Becodisks Beconase Becotide † Clenil Clipper Filair Hayfever Relief Nasal-Beec Nasobec Pollenase Nasal Propaderm † Pulvinal Beclometasone Dipropionate Qvar Vivabec

USA: Beclovent Beconase Qvar Vancenase †

(BANM, US Adopted Name, rINNM)

Drug Nomenclature

Note. Cabastine (rINN) is the racemate of levocabastine.

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (bevocabastine Hydrochloride). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol and in a 0.2% solution of sodium hydroxide sparingly soluble in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008 (bevocabastine Hydrochloride). Protect from light.

Adverse Effects and Precautions

As for the antihistamines in general. The most common adverse effects reported with levocabastine eye drops are transient stinging and burning of the eyes, urticaria, dyspnoea, drowsiness, and headache. With nasal use headache, nasal irritation, somnolence, and fatigue have been noted. The use of levocabastine nasal spray is not recommended in those with significant renal impairment.

Pharmacokinetics

Levocabastine is absorbed after both nasal and ocular use. Systemic availability has been estimated at 60 to 80% after nasal doses and 30 to 60% after ocular use. However absolute peak plasma concentrations are low. Plasma protein binding is about 55%. An elimination half-life of 35 to 40 hours has been reported for all routes of delivery. Elimination of levocabastine is primarily renal with 70% excreted as unchanged drug and 10% as an inactive acetylglucuronide metabolite the remaining 20% is excreted unchanged in the faeces. Trace amounts of levocabastine have been found in breast milk after ocular and nasal use.

Uses and Administration

Levocabastine, a piperidine derivative, is a long-acting and potent antihistamine with a rapid onset of action. Levocabastine hydrochloride equivalent to 0.05% levocabastine is used topically twice daily as eye drops or as a nasal spray in the treatment of allergic conjunctivitis and rhinitis, respectively, in adults and children aged 9 years and over. The frequency of the dose in both conditions may be increased to 3 or 4 times daily if necessary. In conjunctivitis it is recommended that treatment should be stopped if there is no improvement within 3 days.

Preparations

Proprietary Preparations

Argentina: Histimet

Australia: Livostin

Austria: Livostin

Belgium: Livostin

Brazil: Livostin

Canada: Livostin

Czech Republic: Livostin

Denmark: Livostin

Finland: Livostin

France: Levophta

Germany: Levophta Livocab

Greece: Livostin

Hungary: Livostin

Israel: Livostin

Italy: Levostab Livocab Livostin

Japan: Livostin

Mexico: Livostin

The Netherlands: Livocab

Norway: Livostin

New Zealand: Livostin

Portugal: Livostin

South Africa: Livostin

Spain: Bilina Livocab

Sweden: Livostin

Switzerland: Livostin

Thailand: Livostin

Turkey: Livostin

United Kingdom: Livostin

USA: Livostin

Venezuela: Livostin

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Ipratropium Bromide). White or almost white crystalline powder. Soluble in water slightly soluble in alcohol freely soluble in methyl alcohol. ThepHofa 1 % solution in water is 5.0 to 7.5.

The United States Pharmacopeia 31, 2008 (Ipratropium Bromide). A white to off-white, crystalline powder. Soluble in water slightly soluble in alcohol freely soluble in methyl alcohol. A 10% solution has apH of 5 to 7. Store in airtight containers.

Stability. In a study of the stability of admixtures of ipratropium and salbutamol nebuliser solutions equal ratio mixtures were found to retain more than 90% of their initial concentrations after storage for 5 days at 4° or 22° in the dark or at 22° under continuous fluorescent lighting.

Adverse Effects and Precautions

Ipratropium and other inhaled antimuscarinic bronchodilators commonly cause dry mouth and constipation, and rarely, urinary retention. They should be used with care in prostatic hyperplasia. Acute angle-closure glaucoma has been reported the mist or solution should not be allowed to enter the eyes, particularly in patients susceptible to glaucoma. As with other bronchodilators, paradoxical bronchospasm has occurred. Tachycardia, palpitations, and arrhythmias have been reported with ipratropium. Hypersensitivity reactions, including urticaria, angioedema, rash, and anaphylaxis have occurred rarely. Nausea and vomiting, dyspepsia, headaches, and dizziness have also been reported. Intranasal ipratropium has been associated with nasal dryness, irritation, and epistaxis. For details of the adverse effects of, and precautions for, antimuscarinics in general, see Atropine.

Buccal ulceration. A report of inflammation and ulceration of the buccal mucosa associated with the use of an ipratropium bromide inhaler.

Effects on the eyes. Ocular complications have been reported with the use of aerosolised ipratropium. A patient with a history of glaucoma developed angle-closure glaucoma after use of ipratropium from a metered dose inhaler (MDI) with nebulised salbutamol. Pupillary dilatation and blurred vision have been reported in association with ipratropium given through a spacer device in patients also given salbutamol therapy, and a 4-year-old child who attempted to self-administer an ipratropium MDI developed anisocoria (unequal dilatation of the pupils) and ataxia. Angle-closure glaucoma, pupillary dilatation, and anisocoria have been reported in patients given nebulised ipratropium, usually with salbutamol, through a poorly fitting face mask. The antimuscarinic effects of ipratropium can lead to impaired drainage of aqueous humour in the eyes of patients predisposed to angle-closure glaucoma use with salbutamol may intensify this problem by increasing the production of aqueous humour. Studies suggest that patients with a history of angle-closure glaucoma might be at an increased risk of developing glaucoma when nebulised ipratropium and salbutamol are used together.

Effects on the gastrointestinal tract. Paralytic ileus developed shortly after starting ipratropium therapy in 2 patients, apparently due to the inadvertent swallowing of the drug during inhalation. Both patients also had other predisposing factors for paralytic ileus (cystic fibrosis, spastic diplegia).

Effects on the respiratory tract. Antimuscarinics typically inhibit mucociliary clearance and inhibit secretions of the nose, mouth, pharynx, and bronchi. However, inhaled ipratropium bromide has virtually no effect on sputum viscosity or volume and, in contrast to atropine, it does not affect mucociliary function in the respiratory tract.

BRONCHOSPASM. Paradoxical bronchoconstriction occurring after the use of ipratropium was reported in 3 patients. A further report of paradoxical bronchoconstriction after nebulised salbutamol and ipratropium suggested that this adverse effect might have been caused by benzalkonium chloride present in the nebuliser solutions. Nebuliser solutions of ipratropium in some countries contain benzalkonium chloride as a preservative. Solutions available in the UK are preservative-free but licensed product information still recommends that the first doses of ipratropium nebuliser solution should be inhaled under medical supervision.

Effects on the urinary tract. Treatment with nebulised ipratropium bromide has resulted in urinary retention in elderly men especially those with prostatic hyperplasia.

Increased mortality. A case-control study found an unexpected association between death from asthma and treatment with ipratropium, which was not explained by co-morbidity due to chronic obstructive airways disease. A retrospective cohort study of elderly patients found no increase in all-cause mortality associated with the use of ipratropium for chronic obstructive pulmonary disease (COPD). In patients with asthma there was a slight increase in the risk of death, but this may have been due to the confounding effect of disease severity. A later longitudinal cohort study of 1100 patients with obstructive lung disease found an increased risk of premature death associated with ipratropium in both asthma and COPD patients. After adjusting for confounding factors such as forced expiratory volume, smoking status, BMI, and presence of cor pulmonale, ipratropium was associated with a mortality risk ratio (RR) of 2.4 in asthmatic patients and 1.6 in COPD patients. Again, residual confounding by disease severity could not be ruled out.

Interactions

For interactions associated with antimuscarinics in general, see Atropine. However, these interactions are not usually seen with antimuscarinics, such as ipratropium, given by inhalation.

Salbutamol. For reference to nebulised salbutamol exacerbating the adverse effects of nebulised ipratropium in patients predisposed to angle-closure glaucoma, see under Effects on the Eyes, above.

Pharmacokinetics

After inhalation, around 10 to 30% of a dose is deposited in the lungs where it exerts its therapeutic effect. Only a small amount of ipratropium reaches the systemic circulation. The majority of a dose is swallowed but is poorly absorbed from the gastrointestinal tract. Ipratropium and its metabolites are eliminated in the urine and faeces.

Uses and Administration

Ipratropium bromide is a quaternary ammonium antimuscarinic. It is used by inhalation as a bronchodilator in the treatment of reversible airways obstruction, as in asthma and chronic obstructive pulmonary disease (see below).

In the UK the dose of ipratropium bromide from the metered-dose aerosol is expressed in terms of the amount of drug released from the valve into the mouthpiece (20 micrograms) whereas in the USA it is expressed in terms of the dose emitted from the mouthpiece (17 micrograms, equivalent to 21 micrograms released from the valve) recommended doses may therefore appear lower in the USA. For reversible airways obstruction, the usual UK dose from a metered-dose aerosol is 1 or 2 inhalations (20 or 40 micrograms) three or four times daily single doses of up to 4 inhalations may be required. Comparable doses are used in the USA, but it is recommended that the daily dose should not exceed 12 inhalations.

Dry powder inhalation capsules are also available the usual dose is 40 micrograms three or four times daily, to a maximum of 320 micrograms daily.

Ipratropium bromide may be given by inhalation as a nebulised solution in doses of 250 to 500 micrograms up to 4 times daily.

Ipratropium bromide, given intranasally, is also used in the management of rhinorrhoea associated with rhinitis. A dose of 42 micrograms is given into each nostril by metered-dose nasal spray 2 or 3 times daily. US licensing also permits higher doses of 84 micrograms into each nostril 3 or 4 times daily, for up to 4 days when rhinorrhoea is associated with the common cold doses of 84 micrograms may be given into each nostril 4 times daily, for up to 3 weeks when rhinorrhoea is associated with seasonal allergic rhinitis.

For details of doses in children, see Administration in Children, below.

Administration in children. Children may be given ipratropium bromide via a metered dose aerosol in the treatment of reversible airways obstruction. UK licensed product information recommends doses by age as follows:

• under6years: 1 inhalation of 20 micrograms three times daily

• 6 to 12 years: 1 or 2 inhalations of 20 micrograms three times daily

• 12 years and over: adult doses, see above

Dry powder inhalation capsules are also available, and are licensed for use in children from 12 years of age using the adult dose, see above.

Ipratropium bromide may also be given by inhalation as a nebulised solution. UK licensed product information recommends the following doses:

• under 6 years, for the treatment of acute asthma only: 125 to 250 micrograms, given no more often than every 6 hours up to a total daily dose of 1 mg

• 6 to 12 years, for the treatment of acute or chronic asthma: 250 micrograms, repeated if necessary up to a total daily dose of 1 mg

• 12 years and over: adult doses, see above.

Ipratropium bromide is used in the management of rhinorrhoea associated with rhinitis. A dose of 42 micrograms may be given into both nostrils two or three times daily. In the UK this dose may be given to children from 12 years of age, but in the USA this dose is licensed in children from 6 years of age. US licensing also permits higher doses for up to 4 days when rhinorrhoea is associated with the common cold:

• 5 to 11 years: 84 micrograms into each nostril three times daily

• 12 years and over: adult doses, see above

Higher doses are also permitted in the USA for up to 3 weeks when rhinorrhoea is associated with seasonal allergic rhinitis. Children 5 years of age and over may be given the same dose as adults, see above.

Asthma. Ipratropium bromide is currently recommended as an adjunct to beta₂ agonists in the management of acute severe asthma. Antimuscarinic drugs, mainly ipratropium but also including oxitropium, glycopyrronium and atropine, have been reviewed in the treatment of both acute and chronic asthma. A systematic review and meta-analysis of the effectiveness of antimuscarinics in the treatment of acute asthma in children and adults, found they produced significant reductions in hospital admissions. Combined treatment with an inhaled beta₂ agonist also produced a significant increase in respiratory function.

Systematic reviews of antimuscarinic drugs have concluded that there is currently insufficient evidence to justify their routine use in adults or children with chronic asthma.

Chronic obstructive pulmonary disease. Inhaled antimuscarinics, such as ipratropium bromide, are currently recommended as bronchodilators in chronic obstructive pulmonary disease (COPD) guidelines. A systematic review compared regular treatment with ipratropium (given for at least 4 weeks) with treatment using regular short-acting beta₂ agonists in stable COPD it found small benefits on lung function outcomes and quality of life with ipratropium compared with a short-acting beta₂ agonist a reduction in the requirements for oral corticoster-oids was also seen. Combination therapy with ipratropium and a short-acting beta₂ agonist was associated with some clinically meaningful lung function outcomes compared with the beta₂ agonist alone, but these were not reflected in subjective improvements or symptom scores.

A systematic review comparing ipratropium with a long-acting beta₂ agonist in stable COPD, found that salmeterol had more effect than ipratropium on lung function, but no major differences were seen between symptom responses to ipratropium and salmeterol. Combination treatment with these two drugs was better than salmeterol alone in terms of quality of life.

Rhinitis. Ipratropium bromide is used intranasally for the treatment of rhinorrhoea in allergic and non-allergic rhinitis. It has also relieved rhinorrhoea and sneezing associated with the common cold. References.

Preparations

British Pharmacopoeia 2008: Ipratropium Nebuliser Solution; Ipratropium Powder for Inhalation; Ipratropium Pressurised Inhalation.

Proprietary Preparations

Argentina: Aerotrop Atrovent Iprabron

Australia: Aeron Apoven Atrovent Ipratrin Ipravent

Austria: Atrovent Itrop

Belgium: Atronase Atrovent

Brazil: Alventf Ares Atrovent Bromovent Iprabon Ipraneo

Canada: Apo-lpravent Atrovent Novo-lpramide

Chile: Atrovent Neorinoll

Czech Republic: Atrovent Itrop

Denmark: Atrovent

Finland: Atrovent

France: Atrovent

Germany: Atrovent Itrop

Greece: Atrovent

Hong Kong: Atrovent Cyclovent Ipravent

Hungary: Atrovent

India: Ipranase Ipravent

Indonesia: Atrovent

Ireland: Atrovent Rinatec

Israel: Aerovent Apovent Atrovent

Italy: Atem Rinovagos

Japan: Atrovent

Malaysia: Atrovent

Mexico: Atrovent

The Netherlands: Atrovent Ipraxa

Norway: Atrovent Respontin

New Zealand: Apo-lpravent Atrovent Ipra †

Philippines: Atrovent

Poland: Atrovent

Portugal: Atrovent

Russia: Atrovent

South Africa: Atrovent Ipvent

Singapore: Atrovent

Spain: Atrovent

Sweden: Atrovent

Switzerland: Atrovent Rhinovent

Thailand: Atrovent

Turkey: Atrovent

United Arab Emirates: Atropulm

UK: Atrovent Respontin Rinatec

USA: Atrovent

Venezuela: Alovent

Multi-ingredient

Australia: Combivent

Austria: Berodual Berodualin Combivent Di-Promal

Belgium: Combivent Duovent

Brazil: Combivent Duovent

Canada: Combivent Duovent ratio-lpra Sal UDV

Chile: Berodual Combivent Salbutral AC

Czech Republic: Berodual Combivent †

Denmark: Berodual Combivent

Finland: Atrodual Atrovent Comp

France: Bronchodual Combivent

Germany: Berodual

Greece: Berodual Berovent

Hong Kong: Berodual Combivent

Hungary: Berodual

India: Duolin Fenovent

Indonesia: Berodual Combivent

Ireland: Combivent Duovent Ipramol

Italy: Breva Duovent Iprafen

Mexico: Berodual Combivent

The Netherlands: Berodual Combivent

New Zealand: Combivent Duolin

Poland: Berodual

Portugal: Berodual Combivent

Russia: Berodual

Spain: Berodualf Combivent Legis †

Sweden: Combivent

Switzerland: Berodual Dospir

Turkey: Combivent

UK: Combivent Duovent Ipramol

USA: Combivent DuoNeb

(British Approved Name Modified, rINNM)

Drug Nomenclature

Pharmacopoeias. In Chin, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed. (Sodium Cromoglicate). A white or almost white, hygroscopic, crystalline powder. Soluble in water practically insoluble in alcohol. Store in airtight containers. Protectfrom light.

The United States Pharmacopeia 31, 2008 (Cromolyn Sodium). A white, odourless, hygroscopic, crystalline powder. Soluble in water insoluble in alcohol and in chloroform. Store in airtight containers.

Adverse Effects

Inhalation ofsodium cromoglicate may cause transient bronchospasm, wheezing, cough, nasal congestion, and irritation of the throat. Nausea, headache, dizziness, an unpleasant taste, and joint pain and swelling have been reported. Other reactions include aggravation of existing asthma, urticaria, rashes, pulmonary infiltrates with eosinophilia, dysuria, and urinary frequency. Severe reactions such as marked bronchospasm, laryngeal oedema, angioedema, and anaphylaxis have been reported rarely. Intranasal use ofsodium cromoglicate may cause transient irritation of the nasal mucosa, sneezing, and occasionally epistaxis. Nausea, skin rashes, and joint pains have occurred when it is taken orally. Transient burning and stinging have occasionally been reported after use ofsodium cromoglicate eye drops.

Formulation. Some of the adverse effects reported with sodium cromoglicate may be due to its formulation: there is a view that some of the irritant effects reported on inhalation may be due to the use of dry powder inhalers. It has also been suggested that in some patients receiving sodium cromoglicate via a nebuliser, hypotonicity of the nebuliser solution may induce bronchospasm, although others consider this debatable. Nausea, bloating, abdominal cramps, and flatulence developed in a 24-year-old lactase-deficient woman 2 hours after the use ofsodium cromoglicate (Intal) inhalation capsules via a turbo-haler for exercise-induced asthma. These symptoms recurred on rechallenge and were attributed to ingestion of lactose contained within the capsules.

Precautions

Sodium cromoglicate has no role in the treatment of acute asthmatic attacks. Withdrawal ofsodium cromoglicate may lead to recurrence of the symptoms of asthma. Should withdrawal be necessary it has been suggested that the dose be reduced gradually over a period of one week patients in whom sodium cromoglicate therapy has permitted a reduction of corticosteroid dosage may require restoration of full corticosteroid cover.

Systemic corticosteroid therapy that has been reduced or stopped in asthmatic patients may need to be reinstated if symptoms increase, during periods of stress such as infection, illness, trauma, or severe antigen challenge, or where airways obstruction impairs inhalation of sodium cromoglicate.

Pharmacokinetics

Sodium cromoglicate is poorly absorbed from the gastrointestinal tract, with a reported bioavailability of only 1%. It has been reported that on inhalation as a fine powder only about 8% of a dose is deposited in the lungs from where it is rapidly absorbed and excreted unchanged in the urine and bile. Less than 7% of an intranasal dose appears to be absorbed. The majority of an inhaled or an intranasal dose is swallowed and excreted unchanged via the gastrointestinal tract. About 0.03% of an ophthalmic dose is reported to be absorbed. The terminal elimination half-life has been reported to be about 20 minutes after intravenous dosage, but the elimination half-life after oral doses or inhalation is about 80 minutes.

A study in patients with exercise-induced asthma concluded that the plasma concentration of cromoglicate was almost certainly not related directly to its protective effect, although another study in asthmatic children given sodium cromoglicate by drypowder inhalation, found both blood concentration and clinical response to be correlated with inhalation technique.

Uses and Administration

Sodium cromoglicate is used for the prevention of allergic reactions. Although its precise mode of action remains uncertain, it is believed to act primarily by preventing release of mediators of inflammation from sensitised mast cells through stabilisation of mast-cell membranes. It has no direct antihistamine or anti-inflammatory action.

Sodium cromoglicate can prevent the asthmatic response to a variety of allergic and non-allergic stimuli. It is used in the management of chronic asthma that cannot be managed with inhaled beta₂ agonists alone it is not used for acute attacks of asthma. Sodium cromoglicate is also used in the prophylaxis and treatment of seasonal and perennial allergic rhinitis and allergic conditions of the eye including acute and chronic allergic conjunctivitis and vernal keratocon-junctivitis. It has been given orally, with dietary restriction, for the prevention of food allergies, and is also used in the treatment of mastocytosis. It is important that the regular use of sodium cromoglicate is maintained, both in the prophylactic control of asthma and in the management of other allergic conditions. Beneficial effects may take several weeks to become established.

In the prophylaxis of asthma, sodium cromoglicate is given by inhalation either as a dry powder, or as a nebulised solution, or from a metered-dose aerosol. The usual dose as dry powder or nebulised solution is 20 mg by inhalation 4 times daily increased, if necessary, to 6 or 8 times daily. Once the asthma has been stabilised it may be possible to reduce the dosage. In different countries, sodium cromoglicate is available in different strengths of metered-dose aerosol. Using a metered-dose aerosol providing 5 mg per inhalation, the usual dose is 10 mg four times daily, increased to 6 to 8 times daily if necessary it may be possible to reduce the dosage to 5 mg four times daily once the asthma has been stabilised. Additional doses as the aerosol or dry powder may be taken before exercise. Metered-dose aerosols providing 1 mg per inhalation are also available. The usual dose is 2 mg four times daily, which can be doubled if necessary. The adequacy of the lower dosage has been questioned (see under Administration, below).

Inhalation of sodium cromoglicate may cause bronchospasm separate inhalation of a beta₂ agonist such as salbutamol a few minutes beforehand should prevent this. Use of a combination product containing a beta₂ agonist is not recommended as this is liable to be used inappropriately for relief of bronchospasm rather than for its prophylactic effect. For the prophylaxis of allergic rhinitis, a 2 or 4% sodium cromoglicate solution can be given as a spray into both nostrils. The 2% spray contains about 2.5 mg per actuation and is given 4 to 6 times daily, and the 4% spray contains about 5 mg per actuation and is given 2 to 4 times daily. Prophylactic treatment for seasonal allergic rhinitis should begin 2 to 3 weeks before exposure to the offending allergen and should continue throughout the season. In allergic conjunctivitis and vernal keratoconjnnctivitis, sodium cromoglicate is used as drops of 2 or 4%, applied 4 to 6 times daily. In food allergy and in mastocytosis, sodium cromoglicate may be given in oral doses of 200 mg four times daily before meals. If satisfactory control is not achieved within 2 to 3 weeks the dosage may be doubled, but should not exceed 40 mg/kg daily a reduction in dosage may be possible once symptoms have been controlled.

For details of doses in children, see Administration in Children below.

Action. Sodium cromoglicate has a range of actions at cellular level that may be important for its protective effect in asthma. It is known as a mast cell stabiliser that inhibits the release of his-tamine and other inflammatory mediators from sensitised mast cells. Other reported actions include a direct effect on airway nerves and antagonism of substance P, which ties up with its inhibition of the effects of platelet activating factor (PAF). There have been a few reports of sodium cromoglicate producing bronchodilatation. However, in practice other drugs with accepted bronchodilating activity are used for this effect in asthma treatment schedules.

Administration. The effectiveness of sodium cromoglicate 2 mg four times daily by metered-dose aerosol inhaler has been reported by controlled studies in adults and children with asthma. However, although sodium cromoglicate 2 mg by inhalation from a metered-dose aerosol was reported to be as effective as 20 mg inhaled as powder, the tenfold difference in dosage has been questioned, and others have reported contrary results. It has been suggested that an aerosol supplying 5 mg per metered dose (see Uses and Administration, above) would be preferable. In a comparison of single-dose pretreatment from metered-dose inhalers, sodium cromoglicate 10 mg (2×5 mg puffs) was as effective as beclometasone dipropionate 200 micrograms in inhibiting bronchial responsiveness to histamine. Care is required if inhaled sodium cromoglicate is given via a spacer device evidence suggests that these may greatly influence the amount of drug delivered, reducing it to one-third of the dose delivered by inhaler actuation in some cases.

Administration in children. Children may be given sodium cromoglicate for prophylactic management of asthma and allergic rhinitis, and in the prophylaxis and treatment of acute and chronic allergic conjunctivitis and vernal keratoconjunctivitis, using adult doses, see Uses and Administration, above. Different countries may have different licensed lower age limits and some inhalation dosage forms are unsuitable in very young children. In food allergy and in mastocytosis, sodium cromoglicate may be given orally to children from 2 years of age. A dose of 100 mg is given four times daily before meals. If satisfactory control is not achieved within 2 to 3 weeks the dosage may be doubled but should not exceed 40 mg/kg daily a reduction in dosage may be possible once symptoms have been controlled. For food allergy, adult doses may be given to children from 14 years of age, and from 13 years for mastocytosis, see above.

Asthma. Sodium cromoglicate is used as a prophylactic agent in the management of chronic asthma, but in practice inhaled corticosteroids are preferred if regular prophylactic treatment is indicated, i.e. if the condition cannot be managed with occasional use of an inhaled short-acting beta₂ agonist alone. Even in children, in whom cromoglicate has tended to be more widely used, inhaled corticosteroids are considered first-line preventers. A systematic review comparing sodium cromoglicate with inhaled corticosteroids found that inhaled corticosteroids were superior in terms of asthma control and lung function for both children and adults with chronic asthma. However, guidelines still specify the use of cromoglicate or nedocromil as a valid alternative to inhaled corticosteroids in some circumstances. Response to treatment with nebulised sodium cromoglicate was found to be age-related in a study of children under 2 years of age with recurrent or persistent wheezy bronchitis and a history of allergic symptoms. It was effective in children of 12 to 24 months of age but not in those below 12 months. Similarly, nebulised sodium cromoglicate was no more effective than placebo in the treatment of a group of 31 infants with persistent wheezing aged under 1 year, and long-term inhalation therapy was ineffective in children aged 1 to 4years.

Cogan’s syndrome. Sodium cromoglicate eye drops improved blurred vision in a patient who had had Cogan’s syndrome for 18 years. Sodium cromoglicate capsules [by mouth] also reduced the frequency of fever attacks in this patient.

Cough. Sodium cromoglicate has been used with modest success by aerosol inhalation to suppress the cough associated with ACE inhibitor therapy in some patients. However, inhalation of nedocromil sodium was not helpful in the treatment of ACE inhibitor induced cough in 6 diabetic patients. A systematic review considered that there was no good evidence to support the use of inhaled cromoglicate or nedocromil in the treatment of non-specific cough in children.

Eczema. Application of a 4% sodium cromoglicate lotion was found to be of benefit in improving symptoms and reducing topical corticosteroid use in a study in children with moderately severe atopic dermatitis.

Food allergy. Oral sodium cromoglicate has been used in the prophylaxis of food allergy reactions. However, efficacy has not been unequivocally established.

Mastocytosis. Mastocytosis is a rare condition characterised by abnormal proliferation of mast cells and their accumulation in body tissues. Signs and symptoms of the disease result from the spontaneous or induced release of mast cell mediators. Mastocytosis occurs in cutaneous or systemic forms, which are further subdivided based on clinical presentation and prognosis. Clinical algorithms and recommendations for diagnosis, treatment, and response criteria have been developed.

• Cutaneous mastocytosis most often manifests as urticaria pigmentosa (disseminated red-brown macules, papules, or plaques) other symptoms include flushing, pruritus, urticaria, blistering, and dermatographism. Mastocytomas may occur as brownish solitary or multiple nodular accumulations of mast cells. In children with cutaneous mastocytosis, symptoms will resolve in about half by adolescence.

• Systemic mastocytosis can involve diverse organs and tissues including the bones, liver, spleen, lymph nodes, haematopoietic system, gastrointestinal tract, and also the skin. General symptoms include fatigue, weight loss, fever, and sweats. Gastrointestinal complaints such as abdominal pain and diarrhoea are common, and some patients may experience malabsorption, steatorrhoea, or peptic ulcer disease. Bone marrow involvement may result in bone pain, osteoporosis, fractures, bone marrow fibrosis, and myeloproliferative and myelodysplastic diseases. Other systemic effects include lymphadenopathy, hepatosplenomegaly, headache and other neuropsychiatric symptoms, syncope, and anaphylactoid reactions.

Avoidance of trigger factors is an important measure in the management of mastocytosis. Such factors include exposure to extremes of cold or heat (hot bath or sunbathing), emotional stress, mechanical irritation (vigorous towel rubbing, massage), infections, alcohol, some drugs (e.g. aspirin, NSAIDs, opioid analgesics, sympathomimetics, polymyxin B, dextran, radiographic dyes), and animal venoms.

Treatment is aimed at relieving symptoms and does not alter the course of the disease. H_rantagonist antihistamines such as hydroxyzine and cyproheptadine are used to provide relief of flushing, pruritus, urticaria, blistering, and abdominal pain. Patients at risk of anaphylactoid reactions should carry adrenaline for self-injection, and those who have repeated reactions should be given prophylactic antihistamines. H₂-antagonist antihistamines such as cimetidine, and proton pump inhibitors such as omeprazole, are used to manage gastrointestinal symptoms, particularly gastritis and peptic ulcer disease. Bisphosphonates may be helpful for osteopenia and bone pain. Sodium cromoglicate is given to manage abdominal pain, nausea, and diarrhoea. It may also provide some relief of headache, neuropsychiatric symptoms, and skin symptoms in some patients. Photochemotherapy using an oral psoralen with ultraviolet A irradiation (PUVA) has been used to reduce cutaneous manifestations of mastocytosis, but urticaria pigmentosa usually recurs within several weeks. Topical PUVA appears to be ineffective. Mastocytomas that cause symptoms may be treated with local PUVA or potent topical corticosteroids. Although surgical removal may be considered, the majority of mastocytomas will involute spontaneously.

Other treatments have also been tried in the treatment of small numbers of patients with aggressive systemic mastocytosis. Mixed results have been reported with the use of interferon alfa. There is a report of ciclosporin with methylprednisolone being used successfully. Imatinib has been used successfully in systemic mastocytosis with associated eosinophilia and with a mutation of the platelet-derived growth factor receptor-α gene on chromosome 4ql 2. Beneficial responses to cladribine have also occurred in a small number of patients with systemic disease.

Rhinitis and conjunctivitis. Many drugs, including sodium cromoglicate, are used in the management of allergic rhinitis and conjunctivitis. There is some evidence that nedocromil or lodoxamide may be more effective than cromoglicate in the management of vernal keratoconjunctivitis.

Preparations

British Pharmacopoeia 2008: Sodium Cromoglicate Eye Drops; Sodium Cromoglicate Powder for Inhalation

The United States Pharmacopeia 31, 2008: Cromolyn Sodium Inhalation Powder; Cromolyn Sodium Inhalation Solution; Cromolyn Sodium Nasal Solution; Cromolyn Sodium Ophthalmic Solution

Proprietary Preparations

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

Argentina: Claroftal; Clo-5¤; Intal; Klonalcrom; Sificrom¤; Australia: Cromese; Intal; Opticrom; Rynacrom; Vistacrom¤; Austria: Acromax; Aeropaxyn; Allercrom¤; Allergo-COMOD; Coldacrom; Cromal; Cromoglin; Cromophtal; Dilospir¤; Intal; Lomusol; Opticrom¤; Pulmosin¤; Vividrin; Belgium: Lomudal; Lomusol; Opticrom; Vividrin¤; Brazil: Cromabak¤; Cromocato; Cromolerg; Intal; Maxicrom; Opticrom¤; Rilan; Canada: Apo-Cromolyn; Cromolyn; Gen-Cromolyn¤; Intal; Nalcrom; Novo-Cromolyn¤; Opticrom; Rynacrom¤; Solu-Crom; Vistacrom¤; Chile: Oftacon; Czech Republic: Allergo-COMOD; Allergocrom; Cromobene; Cromogen; Cromohexal; Cromolyn; Cusicrom; DNCG; Hay-Crom; Intal; Lecrolyn; Nalcrom; Stadaglicin; Steri-Neb Cromogen; Vividrin; Denmark: Hexacroman; Lecrolyn; Lomudal; Finland: Glinor; Lecrolyn; Lomudal; France: Alerion¤; Allergo-COMOD; Alloptrex; Cromabak; Cromadoses; Cromoptic; Cromosoft; Intercron; Lomudal; Lomusol; Multicrom; Nalcron; Ophtacalm; Opticron; Germany: Acecromol; Alerg; Allergo-COMOD; Allergocrom; Allergoval; Colimune; Crom-Ophtal; Cromo; Cromoglicin-ratiopharm¤; Cromoglicin¤; Cromohexal; Cromol¤; Cromolind; Cromolyn¤; Cromopp; Diffusyl; Dispacromil; DNCG; duracroman; Esirhinol¤; Fenistil¤; Flenid¤; Flui-DNCG; Gelodrin¤; Intal; Logomed Heuschnupfen-Spray¤; Lomupren; Nasivin gegen Heuschnupfen¤; Opticrom; Otriven H¤; Padiacrom; Pentacrom¤; Pentatop; Prothanon cromo¤; Pulbil; Siozwo Allerg; Sofro¤; Stadaglicin¤; Vividrin; Greece: Allergojovis; Allergostop; Allergotin; Botastin; Crolidin¤; Cromabak; Cromo-Pos; Cromolergin UD; Duobetic¤; Erystamine-K; Fluvet¤; Indoprex¤; Iopanchol; Kaosyl; Lomudal; Spaziron; Ufocollyre; Vekfanol; Vividrin; Zineli; Zulboral; Hong Kong: Cromabak; Cusicrom¤; Intal¤; Opticrom¤; Rynacrom M¤; Stadaglicin; Hungary: Cromohexal; Cromolyn; Cusicrom; Intal; Lecrolyn; Opticrom; Stadaglicin; Taleum; India: Cromal; Fintal; Ireland: Cromogen; Hay-Crom; Intal; Nalcrom; Opticrom; Rynacrom; Steri-Neb Cromogen¤; Vividrin; Israel: Cromogen¤; Cromolyn; Cromoptic; Cromunal¤; Cronase; Lomudal; Nalcrom¤; Opticrom; Vicrom; Italy: Acticrom; Cromantal; Cromosan¤; Cronacol¤; Frenal Rinologico¤; Frenal; Gaster¤; Gastrofrenal; Glicacil¤; Lomudal; Lomuspray; Nalcrom; Sificrom; Japan: Intal; Malaysia: Allergocrom; Cusicrom; Intal¤; Opticrom; Stadaglicin; Vividrin¤; Mexico: Alercrom; Cusicrom¤; Exaler; Intal; Maxicrom; Oftacon; Opticrom; Rynacrom; Spralyn; Monaco: Cromedil; Netherlands: Allerg-Abak; Allergocrom¤; Lomudal; Lomusol; Nalcrom; Opticrom; Otrivin hooikoorts; Prevalin; Rynacrom¤; Vividrin; Norway: Lecrolyn; Lomudal; New Zealand: Cromolux; Intal; Nalcrom; Opticrom; Optrex Hayfever Allergy; Rynacrom; Vicrom; Portugal: Croglina; Cromex; Cusicrom; Fenolip; Intal; Opticrom; Rynacrom¤; Russia: Cromohexal (Кромогексал); Cropoz (Кропоз); Hay-Crom (Хай-кром); Ifiral (Ифирал); Intal (Интал); Lecrolyn (Лекролин); South Africa: Cromabak; Cromal¤; Cromogen¤; Cromohexal; Hay-Crom¤; Kiddicrom¤; Lomudal¤; Nalcrom¤; Opticrom¤; Rynacrom¤; Stop-Allerg; Vividrin; Singapore: Cromabak; Cusicrom¤; Intal; Opticrom; Rynacrom; Sificrom; Stadaglicin¤; Vividrin; Spain: Alergocrom; Cromo Asma¤; Cusicrom; Farmacrom; Frenal; Gastrofrenal; Intal¤; Nalcrom¤; Nebulasma; Nebulcrom; Oralcrom¤; Poledin¤; Primover; Renocil; Rinilyn¤; Rinofrenal; Vividrin¤; Sweden: Lecrolyn; Lomudal; Pollyferm; Rinil¤; Switzerland: Allergo-COMOD; Cromabak; Cromodyn; Cromosol ophta; Cromosol UD; Glicinal; Intal Nasal¤; Lomudal; Lomusol; Nalcrom; Novacrom¤; Opticrom; Vividrin; Thailand: Ifiral¤; Intal; Lecrolyn¤; Opticrom¤; Rynacrom; Stadaglicin¤; Vividrin; United Kingdom: Broleze¤; Clariteyes; Clarityn; Cromogen; Cusilyn¤; Hay-Crom; Hayfever Eye Drops; Intal; Nalcrom; Opticrom; Optrex Allergy; Pollenase Allergy; Resiston Two¤; Rynacrom; Vivicrom; Vividrin; Viz-On¤; United States: Crolom; Gastrocrom; Intal; Nasalcrom; Opticrom; Venezuela: Alergocrom; Cromo-Spray; Cromoftal; Maxicrom

Multi-ingredient Preparations

Argentina: Duotec¤; Hyalcrom; Rinogel; Austria: Aarane¤; Allergospasmin¤; Ditec; Lomusol comp¤; Belgium: Lomusol plus Xylometazoline¤; Czech Republic: Allergocrom Kombi; Ditec; Intal Plus; Denmark: Kombicrom¤; Germany: Aarane N; Allergospasmin; Asthmocupin¤; Ditec; Intal compositum¤; Lomupren compositum¤; Vividrin comp¤; Hong Kong: Rynacrom Compound¤; Hungary: Duotec; India: Asthacrom; Ireland: Rynacrom Compound¤; Italy: Cromozil; Frenal Compositum¤; Rinofrenal; Visuglican; Malaysia: Rynacrom Compound¤; Mexico: Aerocrom¤; Netherlands: Cromovist¤; Lomudal Compositum¤; Portugal: Rinoglin¤; Rynacrom Composto¤; Russia: Ditec (Дитек); South Africa: Lomudal Comp¤; Singapore: Rynacrom Compound¤; Spain: Cromoftol¤; Frenal Compositum; Frenal Rinologico¤; Rinofrenal Plus; Switzerland: Aarane; Allergospasmine¤; Lomusol-X; Thailand: Rynacrom Compound¤; United Kingdom: Aerocrom¤; Intal Compound¤; Resiston One¤; Rynacrom Allergy¤; Rynacrom Compound¤

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Mometasone Furoate). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol soluble in acetone and in dichloromethane.

The United States Pharmacopeia 31, 2008 (Mometasone Furoate). A white to off-white powder. Soluble in acetone and in dichloromethane.

Profile

Mometasone furoate is a corticosteroid used topically for its glucocorticoid activity in the treatment of various skin disorders. It is usually used as a cream, ointment, or lotion containing 0.1%.

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. The effects of topical corticosteroids on the skin are described. For recommendations concerning the correct use of corticosteroids on the skin, and a rough guide to the clinical potencies of topical corticosteroids.

A nasal suspension of mometasone furoate 0.05%, as the monohydrate, is given in the treatment and prophylaxis of the symptoms of allergic rhinitis. The usual adult dose is the equivalent of 100 micrograms of mometasone furoate in each nostril once daily, increased if necessary to 200 micrograms in each nostril daily. Once symptoms are controlled a dose of 50 micrograms in each nostril daily may be effective for maintenance. In the UK, the dose for children aged between 6 and 11 years is the equivalent of 50 micrograms in each nostril once daily. In the USA, similar doses may be given to treat allergic rhinitis in children from 2 years of age.

The nasal suspension is also given for the treatment of nasal polyps in patients 18 years and older the recommended initial dose in the UK is 100 micrograms into each nostril once daily, increased after 5 to 6 weeks to twice daily if needed. In the USA the recommended initial dose is 100 micrograms in each nostril twice daily, although once daily administration may be sufficient in some patients.

Mometasone furoate is used by dry powder inhaler for the prophylaxis of asthma. Doses may differ between countries and dosage units may be expressed differently, as either the amount of drug released per actuation or the amount delivered from the mouthpiece. UK licensed product information includes an initial dose of 400 micrograms inhaled once daily in the evening for mild to moderate asthma in adults and adolescents aged 12 years and older. This may be adjusted to a maintenance dose of 200 micrograms once or twice daily. In severe asthma, an initial dose of 400 micrograms twice daily is used, then titrated to the lowest effective dose once symptoms are controlled. US doses are provided in terms of the amount of drug released per actuation (an actuation that releases 110 micrograms delivers 100 micrograms from the mouthpiece). An initial dose of 220 micrograms once daily in the evening is used in adults and adolescents, aged 12 years and older, who have been treated with inhaled therapy only (bronchodilators or corticosteroids) this may be increased to a maximum of 440 micrograms daily as a single dose or 2 divided doses. Patients receiving oral corticosteroids may be started on 440 micrograms twice daily. Children aged 4 to 11 years may be given 110 micrograms once daily in the evening, regardless of prior therapy this is the maximum recommended daily dose.

Preparations

British Pharmacopoeia 2008: Mometasone Aqueous Nasal Spray Mometasone Cream Mometasone Ointment Mometasone Scalp Application

The United States Pharmacopeia 31, 2008: Mometasone Furoate Cream Mometasone Furoate Ointment Mometasone Furoate Topical Solution.

Proprietary Preparations

Argentina: Elocon Fenisona Metason Momeplus Nasonex Novasone Uniclar

Australia:: AllerMax † Elocon Nasonex Novasone

Austria: Asmanex Elocon Elovent Nasonex

Belgium: Elocom Nasonex

Brazil: Asmanexf Elocom Nasonex Topison

Canada: Elocom Nasonex

Chile: Dermenet Dermosona Elocom Flogocort Lisoder Momelab Nasonex Rinoval Uniclar

Czech Republic: Asmanex Elocom Nasonex

Denmark: Asmanex Elocon Nasonex

Finland: Asmanex Elocon Nasonex

France: Nasonex

Germany: Asmanex Ecural Nasonex

Greece: Asmanex Bioelementa Ecelecort Elocon Elovent Esine F-Din Fremomet Makiren Metason Mofur Molken Momecort Movesan Mozeton Nasamet Nasonex Pharmecort Yperod

Hong Kong: Elomet Nasonex Topcort

Hungary: Elocom Nasonex

India: Elocon Metaspray Momate Topcort

Indonesia: Dermovel Elocon Eloskin Elox Intercon Mefurosan Mesone Mofacort Mofulex Momet Motaderm Moteson Nasonex

Ireland: Asmanex Elocon Nasonex

Israel: Elocom Nasonex

Italy: Altosone Elocon Nasonex Rinelon Uniclar

Malaysia: Elomet Momate Nasonex

Mexico: Elica Elomet Elovent Rinelon Uniclar

The Netherlands: Asmanex Elocon Elovent Nasonex

Norway: Elocon Nasonex

New Zealand: Asmanex Bronconex Elocon

Philippines: Elica Elocon Momate Nasonex Rinelon

Poland: Elocom Elosone Nasonex

Portugal: Asmanex Elocom Elomet Elovent Nasomet Prospiril

Russia: Elocom Nasonex

South Africa: Elica Elocon Nasonex Rinelon

Singapore: Elomet Nasonex

Spain: Asmanexf Elica Elocom Nasonex Rinelon

Sweden: Asmanex Elocon Nasonex

Switzerland: Asmanex Elocom Nasonex

Thailand: Elomet Nasonex Rineloir †

Turkey: Elocon M-Furo Nasonex

UK: Asmanex Elocon Nasonex

USA: Asmanex Elocon Nasonex

Venezuela: Asmanex Cortynase Dergentil Elocon Eloconex † Elomet Nasonex Uniclar

Multi-ingredient

Argentina: Elosalic †

Austria: Elosalic

Chile: Velosalic

Czech Republic: Momesalic Monsalic †

Germany: Elosalic

Hong Kong: Elosalic

India: Momate-S

Indonesia: Elosalic

Poland: Elosalic

Portugal: Monsalic

Russia: Elocom-S

South Africa: Elosalic

Sweden: Elosalic

Thailand: Elosalic †

Turkey: Elosalic

Venezuela: Elosalic

Drug Approvals

(BANM, US Adopted Name, rINNM)

Note. Nedocromil Calcium is also USAN.

Adverse Effects and Precautions

Inhaled nedocromil sodium may cause headache, gastrointestinal disturbances (nausea, vomiting, dyspepsia, and abdominal discomfort). An unusual or unpleasant taste is reported rarely. Paradoxical bronchospasm may occur. Eye drops may cause transient burning and stinging.

It should not be used for the treatment of acute asthma attacks. The general cautions described under sodium cromoglicate also apply.

Incidence of adverse effects. A review of nedocromil sodium noted that adverse effects were infrequent, mild, and shortlived. The most common effect appeared to be an unpleasant or bitter taste, which was experienced by 12 to 13% of patients, although less than 1 % of patients stopped treatment because of it. Other adverse effects included cough (in 7%), headache (6%), sore throat (5.7%), nausea (4%), and vomiting (1.7%).

Pharmacokinetics

Nedocromil sodium is poorly absorbed from the gastrointestinal tract about 10% of the inhaled dose is absorbed from the lungs. Absorption is also poor after topical ophthalmic use, and occurs mainly through the nasal mucosa. Nedocromil sodium is excreted unchanged in the urine and faeces. The half-life is stated to range from about 1 to 3.3 hours.

The extent of absorption or bioavailability of nedocromil sodium after inhalation in healthy subjects was 7 to 9% of the dose, including 2 to 3% oral absorption and 5 to 6% absorption from the respiratory tract. After inhalation of nedocromil sodium 4 mg the mean peak plasma concentration was 3.3 nanograms/mL in healthy subjects and 2.8 nanograms/mL in asthmatic patients, with peak values being reached at about 20 and 40 minutes respectively. The mean total urinary excretion 24 hours after a single dose was 5.4% of the dose in healthy subjects and 2.3% in asthmatics.

Uses and Administration

Nedocromil sodium has a stabilising action on mast cells resembling that of sodium cromoglicate and is used similarly in the management of chronic asthma. It should not be used to treat an acute attack of asthma.

For asthma, nedocromil sodium is inhaled from a metered-dose aerosol. The usual dose for adults and children from 6 years of age is 4 mg inhaled four times daily which may be decreased to 4 mg twice daily after control of symptoms is achieved. Clinical improvement may not be obtained for 1 week or longer after beginning therapy.

Nedocromil sodium is also used topically in the treatment of allergic conjunctivitis and allergic rhinitis. For seasonal and perennial allergic conjunctivitis it is given as a 2% solution, instilled into each eye twice daily. This may be increased to 4 times daily if necessary, which is the usual dose in vernal keratoconjunctivitis. In seasonal allergic conjunctivitis, treatment is usually given for no more than 12 weeks. In allergic rhinitis nedocromil sodium is used as a 1 % nasal spray: one spray is given into each nostril 4 times daily. For details of doses in children, see Administration in Children, below.

Administration in children. Nedocromil sodium is given by metered-dose aerosol inhalation for the treatment of asthma in children from 6 years of age at the adult dose, see above. Although unlicensed in the UK for younger children, the BNFC recommends the same dose from 5 years of age. Similarly, for the topical treatment of seasonal allergic conjunctivitis and vernal keratoconjunctivitis, the adult dose may be given to children from 6 years of age, see above. Treatment of perennial allergic conjunctivitis with nedocromil sodium is not licensed in children in the UK, but the BNFC recommends adult doses from 6 years of age.

Asthma. Nedocromil sodium is generally considered to be an alternative to sodium cromoglicate in the management of asthma. Nedocromil has been shown to improve symptoms and reduce bronchodilator intake in adults and children with chronic asthma. However, a systematic review of nedocromil for chronic asthma in children subsequently found that although a number of small studies have shown that nedocromil improves airflow limitation, reduces symptoms, and reduces bronchial hyperresponsiveness, this has not been confirmed in a larger long-term study of children with milder asthma. Its place in relation to other asthma therapies for children is also unclear. It may be used before exercise to reduce exercise-induced bronchoconstriction, and appears to be as effective as sodium cromoglicate for this indication.

Cough. For references indicating a positive response to sodium cromoglicate but not to nedocromil sodium in the management of cough induced by ACE inhibitor therapy, see Cough.

Rhinitis and conjunctivitis. Nedocromil has been used in the management of allergic rhinitis and conjunctivitis. In the management of seasonal allergic rhinitis, there is some evidence that prophylactic mometasone furoate reduces symptoms more effectively than nedocromil. In vernal keratoconjunctivitis nedocromil may be more effective than cromoglicate, but is less effective than fluorometholone.

Preparations

Proprietary Preparations

Australia: Tilade

Austria: Tilade Tilarin Tilavist

Brazil: Tilade

Canada: Alocril Tilade

Czech Republic: Tilade Tilarin Tilavist

Denmark: Tilade Tilavist

Finland: Tilade Tilarin Tilavist †

France: Tilavist

Germany: Halamid † Irtan Tilade

Greece: Tilade

Hong Kong: Tilade

Hungary: Tilade

Ireland: Tilade Tilavist †

Israel: Tilade Tilavist

Italy: Kovilen Kovinal Tilade Tilarin Tilavist

Mexico: Irtan

The Netherlands: Tilade Tilavist

Norway: Tilavist

New Zealand: Tilade

Portugal: Tilavist

Russia: Tilade

Spain: Brionil Cetimil Tilad Tilavist

Sweden: Tilavist

Switzerland: Tilade Tilarin Tilavist

Turkey: Tilade

UK: Rapitil Tilade

USA: Alocril Tilade

Multi-ingredient

Italy: Zarent

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

Adverse Effects and Precautions

As for the non-sedating antihistamines in general. Acrivastine should be given with care in renal impairment UK licensed product information recommends that it should not be given to patients with significant renal impairment, while product information in other countries, such as Switzerland for example, contra-indicates its use in those with a creatinine clearance of less than 50 mL/minute. Acrivastine should not be used in patients hypersensitive to triprolidine.

Sedation. For a discussion of the sedative effects of antihistamines.

Interactions

As for the non-sedating antihistamines in general.

Pharmacokinetics

Acrivastine is well absorbed from the gastrointestinal tract peak plasma concentrations are achieved in about 1.5 hours. The plasma half-life of acrivastine is about 1.5 hours and the drug does not appear to cross the blood-brain barrier to a significant extent. Acrivastine along with an active metabolite is excreted principally in the urine.

Uses and Administration

Acrivastine is anon-sedating antihistamine structurally related to triprolidine. It does not have any significant sedative or antimuscarinic actions. It is used for the symptomatic relief of allergic conditions such as rhinitis and various types of urticaria when it is given in oral doses of 8 mg three times daily. It is also used with a decongestant such as pseudoephedrine hydrochloride.

Preparations

Proprietary Preparations

Austria: Semprex

Czech Republic: Semprex

Denmark: Benadryl

Finland: Benadryl Semprex

Hong Kong: Semprex

Italy: Semprex

Malaysia: Semprex

The Netherlands: Semprex

Philippines: Semprex

Russia: Semprex

South Africa: Semprex

Singapore: Semprex

Sweden: Semprex

Switzerland: Semprex

Thailand: Semprex

Turkey: Semprex

United Kingdom: Benadryl Allergy Relief

Multi-ingredient

Austria: Duact

Denmark: Duact

Finland: Duact

Turkey: Duact

UK: Benadryl Plus

USA: Semprex-D

Drug Approvals

(BANM, US Adopted Name, rINNM)

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Fexofenadine Hydrochloride). A white or almost white powder. Slightly soluble in water freely soluble in methyl alcohol very slightly soluble in acetone. It exhibits polymorphism.

The United States Pharmacopeia 31, 2008 (Fexofenadine Hydrochloride). Store at a temperature of 20° to 25°, excursions permitted between 15° and 30°. Protect from light.

Adverse Effects and Precautions

As for the non-sedating antihistamines in general.

Arrhythmias. A 67-year-old man suffered syncope after taking fexofenadine 180 mg daily for 2 months. His ECG showed an abnormally prolonged QT interval which shortened once fexofenadine was stopped, although the interval tended to be long even without drug therapy. Nonetheless rechallenge was positive. The manufacturers of fexofenadine have commented that the patient was at risk of developing arrhythmias before taking the drug.

The ECG effects of fexofenadine have been studied in normal subjects and doses of up to 480 mg daily [4 times the recommended dose for seasonal allergic rhinitis] did not prolong the QT interval.

Breast feeding. No adverse effects have been seen in breastfed infants whose mothers were receiving fexofenadine, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding.

See also under Adverse Effects and Precautions, in Terfenadine.

Psoriasis. Exacerbation of psoriasis has been reported in association with the use of fexofenadine.

Interactions

As for the non-sedating antihistamines in general.

Plasma concentrations of fexofenadine have been increased when given with erythromycin or ketocona-zole, but, unlike terfenadine, licensed product information states that this was not associated with adverse effects on the QT interval.

Antacids containing aluminium and magnesium hydroxide have reduced the absorption of fexofenadine. Fruit juices including grapefruit may reduce the bioa-vailability of fexofenadine and use together should be avoided.

Pharmacokinetics

Fexofenadine is rapidly absorbed after oral doses with peak plasma concentrations being reached in 2 to 3 hours. It is about 60 to 70% bound to plasma proteins. About 5% of the total dose is metabolised, mostly by the intestinal mucosa, with only 0.5 to 1.5% of the dose undergoing hepatic biotransformation by the cyto-chrome P450 system. Elimination half-life of about 14 hours has been reported although this may be prolonged in patients with renal impairment. Excretion is mainly in the faeces with only 10% being present in the urine. Fexofenadine does not appear to cross the blood-brain barrier.

Fexofenadine is a metabolite of terfenadine and as such has been detected in breast milk after the administration of terfenadine.

Uses and Administration

Fexofenadine, an active metabolite of terfenadine, is a non-sedating antihistamine. It does not possess significant sedative or antimuscarinic actions. Fexofenadine is used as the hydrochloride in the symptomatic relief of allergic conditions including seasonal allergic rhinitis and chronic urticaria.

In the UK a dose of fexofenadine hydrochloride 120 mg once daily is given orally in the treatment of seasonal allergic rhinitis the recommended dose in chronic idiopathic urticaria is 180 mg once daily. US licensed product information suggests a dose of 60 mg twice daily or 180 mg once daily for both indications.

Fexofenadine is also used with a decongestant such as pseudoephedrine hydrochloride.

For doses in children or in patients with renal impairment, see below.

Administration in children. Fexofenadine hydrochloride is used in children for the treatment of seasonal allergic rhinitis in an oral dose of 30 mg twice daily in the UK it is licensed for use in children aged 6 to 11 years whereas in the USA it may be used in children as young as 2 years.

In the USA, fexofenadine is also licensed for use in paediatric chronic idiopathic urticaria. The dose in children aged 6 months to less than 2 years is 15 mg twice daily older children may be given 30 mg twice daily.

For suggested doses in children with renal impairment see below.

Administration in renal impairment. US licensed product information recommends that initial oral doses of fexofenadine hydrochloride in adults with renal impairment should be reduced to 60 mg once daily. In children with renal impairment, the initial dose should be reduced to 30 mg once daily in patients aged 2 to 11 years, and to 15 mg once daily in children aged 6 months to less than 2 years.

UK product information advises that fexofenadine should be given with caution to patients with renal impairment however, it also states that dose adjustment is not considered to be necessary in such patients.

Preparations

The United States Pharmacopeia 31, 2008: Fexofenadine Hydrochloride and Pseudoephedrine Hydrochloride Extended-Release Tablets Fexofenadine Hydrochloride Capsules Fexofenadine Hydrochloride Tablets.

Proprietary Preparations

Argentina: Alerfedine Allegra Fexofen †

Australia: Fexotabs Telfast Xergic

Austria: Telfast

Belgium: Telfast

Brazil: Allegra Altiva

Canada: Allegra

Chile: Aerodan Alexia Allegra Fenax

Czech Republic: Afexil Ewofex Telfast

Denmark: Telfast

Finland: Telfast

France: Telfast

Germany: Telfast

Hong Kong: Telfast

Hungary: Altiva Telfast

India: Alernexf Allegra Fexigra Fexofen Fexova Odifex

Indonesia: Telfast

Ireland: Telfast

Israel: Telfast

Italy: Kalicet † Telfast

Malaysia: Telfast

Mexico: Allegra

The Netherlands: Telfast

Norway: Telfast

New Zealand: Telfast Xergic

Philippines: Telfast

Poland: Telfast

Portugal: Telfast

Russia: Fexadin Telfast

South Africa: Telfast

Singapore: Telfast

Spain: Telfast

Sweden: Telfast

Switzerland: Telfast

Thailand: Fenafex Telfast

Turkey: Fexadyne Fexofen Telfast

UK: Telfast

USA: Allegra

Venezuela: Allegra Fexidine Fexoril Rinolast

Multi-ingredient

Argentina: Alerfedine D Allegra-D

Australia:: Telfast Decongestant

Brazil: Allegra-D

Canada: Allegra-D

Chile: Alexia D Allegra-D

Hong Kong: Telfast-D

Indonesia: Telfast Plus

Malaysia: Altiva-D Telfast-D

Mexico: Allegra-D

New Zealand: Telfast Decongestant †

Singapore: Telfast-D

USA: Allegra-D

Venezuela: Allegra-D Rinolast D

(British Approved Name, rINN)

Drug Nomenclature

Pharmacopoeias. In Japan.

Diphenhydramine Citrate

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008 (Diphenhydramine Citrate). Store in airtight containers. Protect from light.

Diphenhydramine Di(acefyllinate)

Note. The name Etanautine has been applied both to diphenhydramine monoacefyllinate and to ethylbenzhydramine, an antimuscarinic formerly used in the symptomatic treatment of parkinsonism.

Diphenhydramine Hydrochloride

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In China, Europe, Japan, and US. Japan also includes Diphenhydramine Tarmate.

European Pharmacopoeia, 6th ed. (Diphenhydramine Hydrochloride). A white or almost white, crystalline powder. Very soluble in water freely soluble in alcohol. A 5% solution in water has a pH of 4.0 to 6.0. Protect from light.

The United States Pharmacopeia 31, 2008 (Diphenhydramine Hydrochloride). A white, odourless, crystalline powder. It slowly darkens on exposure to light. Soluble 1 in 1 of water, 1 in 2 of alcohol and of chloroform, and 1 in 50 of acetone very slightly soluble in ether and in benzene. Its solutions are neutral to litmus. Store in airtight containers. Protect from light.

Incompatibility. Diphenhydramine hydrochloride has been reported to be incompatible with amphotericin B, cefmetazole sodium, cefalotin sodium, hydrocortisone sodium succinate, some soluble barbiturates, some contrast media, and solutions of alkalis or strong acids.

Adverse Effects and Precautions

As for the sedating antihistamines in general.

Abuse. Reports of the abuse of diphenhydramine hydrochloride.

Extrapyramidal disorders. Reports of dystonic extrapyramidal reactions to diphenhydramine.

Overdosage. In an evaluation of 136 cases, one fatal, of intoxication with diphenhydramine, the plasma concentration was correlated with frequency or extent of symptoms. The most common symptom was impaired consciousness psychosis, seizures, antimuscarinic symptoms such as mydriasis, tachycardia, and tachyarrhythmias, and respiratory failure were also observed. The positive association between dose and frequency and severity of symptoms was confirmed in a more recent study it was also found that severe symptoms were more likely to occur when 1 g or more of diphenhydramine had been taken.

There have been reports’ of rhabdomyolysis as an effect of oral diphenhydramine overdosage. The liberal application of a lotion containing diphenhydramine produced acute delirium with visual and auditory hallucinations in a 9-year-old boy and similar effects were seen in 3 children with varicella-zoster infection following the topical application of diphenhydramine (2 of these children also received oral diphenhydramine).

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

Pregnancy. A pregnant woman who was receiving diphenhydramine hydrochloride 150 mg daily for a pruritic rash gave birth to an infant who developed diarrhoea and generalised tremulous-ness 5 days later. The delay in appearance of withdrawal symptoms was considered to be due to reduced activity of glucuronyl conjugating enzymes in the first few days of life. For discussion of the use of antihistamines in pregnancy, including a suggestion of a relationship between inguinal hernia or genito-urinary malformations and diphenhydramine exposure. See also under Interactions, below, for a report of perinatal death possibly associated with temazepam and diphenhydramine.

Interactions

As for the sedating antihistamines in general. Diphenhydramine inhibits the cytochrome P450 isoenzyme CYP2D6 that is partly responsible for the metabolism of some beta blockers including metoprolol and the antidepressantvenlafaxine.

Benzodiazepines. There has been a report suggesting that a reduction in temazepam metabolism caused by diphenhydramine may have contributed to perinatal death after ingestion of these drugs by the mother.

Pharmacokinetics

Diphenhydramine hydrochloride is well absorbed from the gastrointestinal tract, although high first-pass metabolism appears to affect systemic availability. Peak plasma concentrations are achieved about 1 to 4 hours after oral doses. Diphenhydramine is widely distributed throughout the body including the CNS. It crosses the placenta and has been detected in breast milk. Diphenhydramine is highly bound to plasma proteins. Metabolism is extensive. Diphenhydramine is excreted mainly in the urine as metabolites little is excreted as unchanged drug. The elimination half-life has been reported to range from 2.4 to 9.3 hours.

Uses and Administration

Diphenhydramine, a monoethanolamine derivative, is a sedating antihistamine with antimuscarinic and pronounced sedative properties. It is used for the symptomatic relief of allergic conditions including urticaria and angioedema, rhinitis and conjunctivitis, and in pruritic skin disorders. It is also used for its antiemetic properties in the treatment of nausea and vomiting, particularly in the prevention and treatment of motion sickness (when it should be given at least 30 minutes before travelling), and in the treatment of vertigo of various causes. Diphenhydramine is used for its antimuscarin-ic properties in the control of parkin sonism and drug-induced extrapyramidal disorders (although the possibility that diphenhydramine itself may cause extrapyramidal symptoms should be remembered). Diphenhydramine has pronounced central sedative properties and may be used as a hypnotic in the short-term management of insomnia. It is a common ingredient of compound preparations for symptomatic treatment of coughs and the common cold. However, such preparations should be used with caution in children, and generally avoided in those under 2 years of age. It may also be given in combination preparations containing analgesics, particularly paracetamol. Diphenhydramine may be used parenterally as an adjunct in the emergency treatment of anaphylactic shock or when oral therapy is not feasible.

For most indications, diphenhydramine hydrochloride is given in usual oral doses of 25 to 50 mg three or four times daily. The dose for children is 6.25 to 25 mg three or four times daily, or a total daily dose of 5 mg/kg may be given in divided doses. The maximum dose in adults and children is about 300 mg daily. A dose of 20 to 50 mg may be used as ahypnotic in adults and children over 12 years old.

When oral therapy is not feasible, diphenhydramine hydrochloride may be given by deep intramuscular injection or by intravenous injection using concentrations of 1% or 5%. Usual doses are 10 to 50 mg, although doses of 100 mg have been given. No more than 400 mg should be given in 24 hours. Children may be given 5 mg/kg daily in divided doses to a maximum of 300 mg in 24 hours. Diphenhydramine hydrochloride is applied topically, usually in preparations containing 1 to 2% although, as with other antihistamines, there is a risk of sensitisation.

Diphenhydramine citrate is given orally in a dose of 76 mg at night in combination preparations for its hypnotic action. Diphenhydramine di(acefyllinate) is given as an antiemetic for the prevention and treatment of motion sickness. The usual oral dose is 90 to 135 mg, which may be repeated if necessary at intervals of at least 6 hours, to a maximum of 540 mg daily. Other diphenhydramine salts that have been used include the polistirex, the salicylate, and the tannate by mouth, the methylbromide rectally, and the metilsulfate applied topically.

Dimenhydrinate is diphenhydramine teoclate and mefenidramium metilsulfate is diphenhydramine methyl sulfomethylate.

Preparations

BP 2008: Diphenhydramine Oral Solution

The United States Pharmacopeia 31, 2008: Acetaminophen and Diphenhydramine Citrate Tablets; Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Hydrochloride Tablets; Diphenhydramine and Pseudoephedrine Capsules; Diphenhydramine Hydrochloride Capsules; Diphenhydramine Hydrochloride Elixir; Diphenhydramine Hydrochloride Injection

Proprietary Preparations

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

Argentina: Benadryl Antialergico¤; Benadryl; Caladryl D; Drepatil¤; Fabolergic; Histaler; Klonadryl; Mudantos H; Australia: Benadryl¤; Nytol¤; Unisom; Austria: Calmaben; Dermodrin; Dibondrin; Histaxin; Noctor; Prurex¤; Sleepia; Belgium: Azaron; Benylin Antihistaminicum; Diphamine; Nuicalm; Nustasium; R Calm; Brazil: Difenidrin; Canada: Aller-Aide; Allerdryl; Allergy Caplets; Allergy Elixir; Allergy Formula¤; Allernix; Benadryl; Calmex; Children‘s Allergy Formula; Clear Caladryl Spray¤; Dormex; Dormiphen; Insomnal; Jack & Jill Bedtime; Nytol; Simply Sleep; Sleep Aid; Sleep-Eze D; Sominex; Unisom-C¤; Unisom; Chile: Jaquedryl; Pasifen¤; Somol; Czech Republic: Benadryl N; Psilo-Balsam; Finland: Benylan¤; France: Benylin¤; Butix; Nautamine; Germany: Benadryl N¤; Betadorm D; Dibadorm N¤; Dolestan; Dormigoa N¤; Dormutil N; Emesan; Halbmond; Hevert-Dorm; Logomed Allergie-Gel¤; Logomed Beruhigungs-Tabletten¤; Logomed Juckreiz¤; Lupovalin¤; Medapur¤; Moradorm-A¤; Moradorm; nervo OPT N; Nytol¤; Pellisal-Gel¤; Pellit Insektenstich, Pellit Sonnenallergie¤; Pheramin N¤; ratioAllerg¤; S.8; Sedativum-Hevert; Sediat; Sedopretten; Sedovegan Novo¤; Sekundal-D¤; Sleepia; Vivinox Sleep stark; Greece: Benadryl; Hong Kong: Benadryl; Calox; Hydramine Cream; Unisom; India: Benadryl; Cofryl; Dimiril¤; Israel: Nytol; Italy: Allergan; Allergina¤; Benadryl¤; Nytol¤; Mexico: Bionaril¤; Difedram¤; Difenhistat¤; Drafen; Histadryl; Indumir; Nytol; Sontedril¤; Tzoali¤; Ulcoid; Unisom; Netherlands: Benylin-Difenhydraminehydrochloride¤; New Zealand: Unisom; Portugal: Benaderma; Codilergi; Russia: Psilo-Balsam (Псило-Бальзам); South Africa: Benadryl¤; Betasleep; Dihydral¤; Nytol¤; Sleepeze-PM; Singapore: Benocten; Paxidorm; Spain: Benadryl; Dormplus¤; Neosayomol; Nytol; Sonodor; Sweden: Benylan¤; Desentol; Switzerland: Bedorma; Benadryl¤; Benocten; Benylin Paediatric¤; Comprimes somniferes “S”; Comprimes somniferes formule 533¤; Dobacen¤; Neo-Synodorm¤; Sleepia; Thailand: Benadryl; United Arab Emirates: Amydramine II; United Kingdom: Adult Chesty Cough; Aller-Eze¤; Child Chesty Cough; Dreemon; Histergan; Mandalyn Paediatric; Medinex¤; Nightcalm; Nytol; Paxidorm; Sleep Aid; Sleepeaze; Sleepia¤; United States: 40 Winks; Aler-Dryl; Allerdryl¤; AllerMax; Altaryl Childrens Allergy; Banophen Allergy; Belix¤; Ben-Allergin¤; Ben-Tann; Bena-D¤; Benadryl Childrens Allergy; Benadryl Itch; Benadryl; Benahist¤; Benoject¤; Bydramine Cough¤; Compoz Night-time Sleep Aid; Dermamycin; Dihydrex¤; Diphen AF; Diphen Cough¤; Diphenhist; Dormarex 2¤; Dormin; DPH¤; Dytan; Dytuss; Genahist; Hydramyn¤; Hyrexin¤; Maximum Strength Sleepinal; Maximum Strength Unisom SleepGels; Miles Nervine; MouthKote P/R¤; Nidryl¤; Nordryl¤; Nytol; Phendry¤; Scot-Tussin Allergy; Siladryl; Silphen; Simply Sleep; Sleep-Ettes D; Sleep-eze 3¤; Sleepwell 2-nite; Snooze Fast; Sominex; Triaminic Cough & Runny Nose; Tusstat; Twilite; Uni-Bent Cough¤; Wehdryl¤; Venezuela: Benadryl; Di-Fedril; Ystal;

Multi-ingredient Preparations

Australia: Benacine¤; Benadryl Cough Medicine for Children¤; Benadryl for the Family – Dry; Benadryl for the Family Original; Benatuss¤; Benyphed¤; Bidramine¤; Chemists Own Difenacol¤; Delixir¤; Ergodryl¤; Gold Cross Cough Medicine¤; Paedamin; Panadol Night¤; Sedu Caps D¤; Senetuss¤; Austria: Aleot; Asthma Efeum; Benadryl mit Codein¤; Benadryl¤; Benadryl; Caladryl¤; Cathejell; Coldistan; Coldistan; Luuf-Nasenspray; Multodrin; Nisicur; Rhinodrin; Rhinoperd comp; Seltoc; Somnium; Sunsan-Heillotion¤; Tussoretardin; Umadren¤; Canada: Ambenyl¤; Balminil Codeine Night-Time+Expectorant; Balminil Night-Time; Benadryl Allergy/Sinus Headache; Benadryl Decongestant¤; Benylin for Allergies¤; Buckley’s Bedtime; Bye Bye Bite¤; Calamine Antihistamine; Calmasol¤; Calmylin No 4; Calmylin Original with Codeine; Calmylin; Contac Cold & Fever; Contac Cough Cold and Flu Day & Night; Contac Cough, Cold & Flu Nighttime¤; Contac Day & Night Sinus/Allergy¤; Cough Syrup with Codeine; Cough Syrup; Dermarest Plus; DM Cough Syrup¤; DM Plus; Ergodryl; Mandrax¤; Pulmorex DM; Sinutab Extra Strength Daytime/Nightime; Sinutab Nightime; Suppress; Trialyn DM; Tylenol Allergy Sinus (Nighttime); Tylenol Allergy-D; Tylenol Flu (Nighttime Relief); Germany: Anaesthecomp N; Asth-Med¤; Asthmastop¤; Befelka-Asthma N¤; Benadryl mit Codein¤; Benadryl N mit Codein¤; Betadorm-A¤; Betadorm-N¤; Betadorm¤; Biokanol N¤; Cathejell¤; Codyl cum expectorans¤; Dabylen¤; Dexa-Bronchisan¤; Diabenyl-Rhinex¤; Diabenyl¤; Dolestan forte comp¤; DoloVisano¤; Emesan forte¤; Euvegal comp¤; Grippostad¤; Keldrin¤; Kontagripp-RR¤; Kontagripp¤; Lomapect¤; Makatussin forte¤; Novo-Dolestan¤; Older¤; Palacril¤; Pectischoll¤; Pellit dermal Wund- und Heilsalbe¤; Plantival plus¤; Praesidin¤; Psilo-Balsam N¤; Reisedragee Eu Rho¤; Reisegold¤; Ribbeck¤; Sagittacin¤; Solamin¤; Spondylon B¤; Spondylon¤; Stada Reise-Dragees¤; Supertendin 3000¤; Tussoretard¤; Valeriana comp novum; Valeriana forte N¤; VisanoCor N; Vivinox-Schlafdragees¤; Vivisun¤; Zincum val plus¤; Spain: Aerospray Antialergico¤; Aletor Compositum¤; Anafilaxol B¤; Anafilaxol¤; Benadryl Expectorante¤; Benylin A P¤; Bisolvon Compositum; Caladryl; Caladryl; Coduretas¤; Curapic¤; Dexabronchisan¤; Diptol Antihist¤; Disnetam¤; Duponil¤; Isdinex; Maboterpen¤; Nasal Rovi¤; Paidoterin Descongestivo NF; Pulmofasa Antihist¤; Rhinocap; Rino Vitna¤; Rinocusi Descong¤; Rinosular¤; Syner Atom¤; Tabletas Quimpe; Talco Antihistam Calber¤; Talquis Cusi¤; Yafin¤; Switzerland: Barbamin¤; Bellagotin; Beny-Caps a la codeine¤; Benylin a la codeine N; Benylin¤; Broncho-Rivo¤; Broncho-Rivo; Caladryl¤; Cathejell¤; Demoderhin¤; Demostan¤; Detensor; Dobacen plus¤; Dolopyrine¤; Expectorant Cough Syrup¤; Expectoryn Paediatric¤; Expectoryn¤; Histacyl Compositum; Histacyl Cutane¤; Histacylettes; Lunadon; Makatussin Comp; Motolon¤; Neo Makatussin N¤; Nina cum Diphenhydramino¤; Parapic; Pectramin; Pellit¤; Pharmalyn¤; Radix¤; Rhinitin¤; Rivolyn¤; Sedovalin¤; Somnium; Spasmo-Barbamin¤; Spasmo-Barbamine compositum¤; Toquilone compositum; Tossamine plus; United Kingdom: Benadryl Skin Allergy Relief; Benylin 4 Flu¤; Benylin 4 Flu; Benylin Chesty Coughs Original; Benylin Childrens Night Coughs; Benylin Cough & Congestion; Benylin Day & Night; Benylin Decongestant¤; Benylin Dry Coughs Original; Benylin Mentholated Linctus¤; Benylin with Codeine¤; Boots Nightime Cough Syrup 1 Year Plus; Bronalin Expectorant¤; Bronalin Junior¤; Caladryl¤; Cold Relief Night-Time¤; Cough Nurse; Covonia Night-Time; Dolvan; Dozol; Ecdylin¤; Flurex Bedtime¤; Flurex Hot Lemon¤; Guanor¤; Histalix; Lemsip Expectorant¤; Lotussin¤; Mandalyn Expectorant; Medised Infant; Meltus Junior Night Time; Meltus Night Time; Night Cold Comfort¤; Nirolex Night Cold & Flu; Noradran; Owbridges for Children¤; Panadol Night; Propain; Tixycolds; Tixylix Catarrh¤; Tixyplus; Uniflu with Gregovite C; United States: Actifed Allergy; Actifed Sinus Nighttime; Advil PM; Anti-Itch; Arthritis Foundation Nighttime¤; Aspirin Free Anacin PM; Banophen Decongestant; Bayer Select Maximum Strength Night Time Pain Relief; Benadryl Allergy/Cold; Benadryl Allergy/Congestion; Benadryl Allergy/Sinus Headache; Benadryl Cold Nighttime Formula; Benadryl Cold/Flu¤; Benadryl Decongestant; Benadryl Itch; Benadryl Plus¤; Benylin Decongestant¤; Bite & Itch Lotion; Bufferin AF Nite Time; Cala-gen¤; Clearly Cala-gel¤; Cold Control; Contac Day & Night Allergy Sinus; Contac Night Cold & Flu Caplets¤; Dermarest Plus; Dermarest; Di-Delamine; Dytan-CS; Dytan-D; Dytan-HC; Emergent-Ez; Endal-HD; Excedrin PM; Extra Strength Doans PM; Hydro DP; Ivarest; Legatrin PM; Midol PM; MouthKote O/R; MouthKote P/R¤; Night-Time Effervescent Cold¤; Nighttime Pamprin; Sominex Pain Relief; Sting-Eze; Theracof Plus; Tylenol Allergy Complete NightTime; Tylenol Allergy Sinus Day & Night; Tylenol Flu Maximum Strength; Tylenol Flu NightTime; Tylenol PM Extra Strength; Tylenol Severe Allergy; Tylenol Sore Throat Nighttime; Unisom with Pain Relief; Ziradry

Drug Approvals

(British Approved Name Modified, US Adopted Name, rINN)

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Clemastine Fumarate). A white or almost white, crystalline powder. Very slightly soluble in water sparingly soluble in alcohol (70%) slightly soluble in alcohol (50%) and in methyl alcohol. A 10% suspension in water has a pH of 3.2 to 4.2.

The United States Pharmacopeia 31, 2008 (Clemastine Fumarate). A colourless to faintly yellow, odourless, crystalline powder. Very slightly soluble in water very slightly soluble in chloroform slightly soluble in methyl alcohol. pH of a 10% suspension in water is between 3.2 to 4.2. Store in airtight containers at a temperature not exceeding 25°. Protect from light.

Adverse Effects and Precautions

As for the sedating antihistamines in general.

Breast feeding. The American Academy of Pediatrics considers that clemastine should be given with caution to breast-feeding mothers, since it has been associated with adverse effects in the infant. Drowsiness, irritability, a high-pitched cry, neck stiffness, and refusal to feed in a 10-week-old breast-fed baby occurred 12 hours after her mother started treatment with clemastine. Clemastine was detected in the mother’s breast milk. The baby recovered and was feeding normally on the day after the drug was stopped.

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

Interactions

As for the sedating antihistamines in general.

Pharmacokinetics

Clemastine fumarate is rapidly and almost completely absorbed from the gastrointestinal tract peak plasma concentrations are achieved in 2 to 4 hours. Unchanged drug and metabolites are excreted principally in the urine. An elimination half-life of about 21 hours has been reported. Clemastine is distributed into breast milk.

Uses and Administration

Clemastine fumarate, a monoethanolamine derivative, is a sedating antihistamine with antimuscarinic and moderate sedative properties. It has been reported to have a duration of action of about 10 to 12 hours. It is used for the symptomatic relief of allergic conditions including urticaria and angioedema, rhinitis and conjunctivitis, and in pruritic skin disorders.

Clemastine is given as the fumarate although doses are expressed in terms of the base. Clemastine fumarate 1.34 mg is equivalent to about 1 mg of clemastine base. The usual oral dose is 1 mg twice daily. Up to 6 mg daily has been given, particularly for urticaria and angioedema. Children aged 1 to 3 years may be given 250 to 500 micrograms twice daily those aged 3 to 6 years, 500 micrograms twice daily and those aged 6 to 12 years, 0.5 to 1 mg twice daily. Clemastine fumarate may be given by intramuscular or slow intravenous injection in a total daily dose equivalent to 4 mg of clemastine for acute allergic reactions for prophylaxis 2 mg is given by intravenous injection. The dose for children is 25 micrograms/kg daily in two divided doses by intramuscular injection. Clemastine fumarate has also been used topically, although as with other antihistamines, there is a risk of sensitisation.

Preparations

British Pharmacopoeia 2008: Clemastine Oral Solution Clemastine Tablets

The United States Pharmacopeia 31, 2008: Clemastine Fumarate Tablets.

Proprietary Preparations

Austria: Tavegyl

Brazil: Agasten

Canada: Tavist

Czech Republic: Tavegyl

Denmark: Tavegyl

Germany: Tavegil

India: Clamist

Indonesia: Tavegyl

Italy: Tavegil

Mexico: Tavist

The Netherlands: Tavegil

Philippines: Marsthine Tavegyl Tavist

Portugal: Tavegyl Tavist

Russia: Tavegyl

South Africa: Tavegyl

Spain: Tavegil

Sweden: Tavegyl

Switzerland: Tavegyl

Turkey: Tavegyl

UK: Tavegil

USA: Contac 12 Hour Allergy; Dayhist-I; Tavist Allergy.

Multi-ingredient

Brazil: Emistin

Germany: Corto-Tavegil †

Mexico: Tavist-D

Spain: Dexa Tavegil