Antihistamines1.

3.4 Antihistamines

antihistamines (common cold) placebo

1Brompheniramine maleatetab, syr

2Chlorpheniramine maleatecap, tab, syr, sterile sol

3Diphenhydramine hydrochloridecap, sterile sol

4Hydroxyzinetab, syr

5Cetirizine hydrochloridetab, syr

6Loratad7inetab, syr

2. atopic dermatitis, pruritus chronic idiopathic urticaria allergic rhinitis search strategies allergic condition conjunctivitis ( topical) asthma () Chlorpheniramine[TI] AND Hypersensitivity[MeSH] AND (Randomized Controlled Trial[ptyp] OR Meta-Analysis[ptyp] OR Review, Academic[ptyp]) NOT Asthma [MeSH] NOT Conjunctivitis[MeSH]3. 1 WHO ATC group R06 Antihistamines for Systemic Use Hydroxyzine ATC code N05BB01 Anxiolytics (N05B ATC group) hydroxyzine antihistamines 1 ATC group ..2547 substituted alkylamines brompheniramine chlorpheniramine tablet capsule syrup sterile solution 1 ( ATC Group)

Generic NamePreparationATC CodeATC Group

Hydroxyzine ()tab 10, 25 mgN05BB01Diphenylmethane derivatives

Carbinoxaminetab 4 mgR06AA08Aminoalkyl ethers

Diphenhydramine ()cap/tab 25 mgR06AA02Aminoalkyl ethers

Cyproheptadinetab/cap 4 mgR06AX02Other antihistamines for systemic use

Desloratadinetab 5 mgR06AX27Other antihistamines for systemic use

Fexofenadinetab 30, 60 mgR06AX26Other antihistamines for systemic use

Ketotifentab 1 mgR06AX17Other antihistamines for systemic use

Loratadine ()tab 10 mgR06AX13Other antihistamines for systemic use

Mebhydrolintab 50 mgR06AX15Other antihistamines for systemic use

Cetirizine ()tab 10 mgR06AE07Piperazine derivatives

Oxatomidetab 30 mgR06AE06Piperazine derivatives

Brompheniramine ()tab/cap 4 mgR06AB01Substituted alkylamines

Chlorpheniramine ()tab/cap 4 mgR06AB04Substituted alkylamines

Dexchlorpheniraminetab 2 mgR06AB02Substituted alkylamines

4. ISafE 2 ISafE US FDA ISafE 0.64 brompheniramine 0.49 fexofenadine, desloratadine cyproheptadine

Fexofenadine administration restriction 0.95 C-max AUC 46 42 2 ISafE FDA ( ISafE ) 50 percentile = 0.64

Generic NameIESIESFreqafafISafE FDAAdult FDA*Ped. FDA*

Loratadine ()0.981.001.000.9811.001.001.000.98yesyes

Cetirizine ()1.001.000.950.9511.001.001.000.95yesyes

Fexofenadine0.951.000.950.9020.950.950.900.81yesyes

Desloratadine0.880.951.000.8411.001.001.000.84yesyes

Hydroxyzine ()0.931.000.850.7931.000.900.900.71yesyes

Diphenhydramine ()0.851.000.900.7731.000.900.900.69yesyes

Chlorpheniramine ()0.831.000.850.7131.000.900.900.64yesyes

Cyproheptadine0.831.000.850.7131.000.900.900.64yesyes

Dexchlorpheniramine0.730.900.950.6231.000.900.900.56yesyes

Ketotifen0.800.850.900.6121.000.950.950.55**nono

Brompheniramine ()0.700.900.850.5431.000.900.900.49yesyes

Oxatomide0.780.900.800.5631.000.900.900.48**nono

Mebhydrolin0.650.800.800.4231.000.900.900.36**n/an/a

Carbinoxamine0.600.800.850.4131.000.900.900.35**n/an/a

* FDA approval status ( Micromedex)** ISafE US FDA ketotifen, oxatomide, mebhydrolin carbinoxamine 0.58, 0.50, 0.38 0.37 50 percentile 0.645. 3 diphen-hydramine, mebhydrolin, oxatomide carbinoxamine WHO/DDD 200, 200, 60 16 . preparation ( 1), frequency ( 2) ..2547 brompheniramine diphenhydra-mine cyproheptadine, ketotifen fexo-fenadine 0.18 4.10 tolerance 7.30 () . . tolerance median cost 2.29 loratadine cetirizine . 3 ( Patient Day)

Generic NameDDDCOCGAmount OAmount GBahtPatient DayBaht/PD

Chlorpheniramine ()120.210.065,422,420875,878,90053,691,442293,767,1070.18*

Hydroxyzine () 300.960.149,947,550150,562,00030,628,32853,503,1830.57*

Cetirizine () 1010.621.396,895,67042,396,120132,162,62249,291,7902.68*

Cyproheptadine120.700.2222,479,50098,955,18837,505,79140,478,2290.93*

Loratadine ()1011.561.858,297,58027,588,606146,958,94635,886,1864.10*

Ketotifen27.681.00186,50011,814,24013,246,5606,000,3702.21

Fexofenadine 1206.960.006,462,900044,981,7843,231,45013.92*

Brompheniramine ()240.730.12968,00018,351,3002,908,7963,219,8830.90

Diphenhydramine ()752.020.301,457,0003,944,2504,126,4151,800,4172.29*

Mebhydrolin1500.001.0704,787,7005,122,8391,595,9003.21

Oxatomide904.380.002,301,500010,080,570767,16713.14

Dexchlorpheniramine60.170.17487,0001,779,000385,220755,3330.51

Desloratadine536.700.00637,970023,413,499637,97036.70*

Carbinoxamine120.110.11402,000262,00073,040221,3330.33

(1) * ISafE (2) 1.04 (3) median cost 2.29 (4) 7.30 (5) 3.54 (6) 7.30 tolerance (7) hydroxyzine fexofenadine 10 mg 60 mg 6. EMCI 4 6.1 . .

6 chlorpheniramine, hydroxyzine, cyproheptadine, cetiri-zine, diphenhydramine loratadine ..2542 1 cyproheptadine . . sedative non-sedative antihistamines

6.2

ISafE EMCI ( ?? ) fexofenadine desloratadine ..2542 fexofenadine . desloratadine ..2547 6.3 6 ketotifen, dexchlorpheniramine, bromphenira-mine, oxatomide, mebhydrolin carbinoxamine 1 ketotifen brom-pheniramine . 4 ..2547 (47) EMCI PP (Propose) ..2542 (42)Generic NameIESafISafECOCGPatient DayBaht/PDEMCI47PP42

Chlorpheniramine ()0.710.900.640.210.06293,767,1070.181.0*

Hydroxyzine ()0.790.900.710.960.1453,503,1830.571.0*

Cyproheptadine0.710.900.640.700.2240,478,2290.931.5*X*

Cetirizine ()0.951.000.9510.621.3949,291,7902.682.8*

Diphenhydramine ()0.770.900.692.020.301,800,4172.293.3*

Loratadine ()0.981.000.9811.561.8535,886,1864.104.2*

Fexofenadine0.900.900.816.960.003,231,45013.9217.2*X??

Desloratadine0.841.000.8436.700.00637,97036.7043.7*X??X

Dexchlorpheniramine0.620.900.560.170.17755,3330.511.0XXX

Ketotifen0.610.950.557.681.006,000,3702.214.0XX

Brompheniramine ()0.540.900.490.730.123,219,8830.901.8XX

Oxatomide0.560.900.484.380.00767,16713.1427.4XXX

Mebhydrolin0.420.900.360.001.071,595,9003.218.9XXX

Carbinoxamine0.410.900.350.110.11221,3330.331.0XXX

*Cyproheptadine ..2542 7.4.2 Prophylactic drugs for migraine Diphenhydramine ..2542 1 Antidotes 7.6 Anti-parkinson drugs 7.10 Antidystonia dystonia 20.4 Antitussives syrupKetotifen ..2542 20.3.2 Non-steroidal respiratory anti-inflammatory drugs 7.7.1 cyproheptadine antihistamines allergy allergic rhinitis urticaria cyproheptadine serotonin receptor vascular headache ..2547 4.7.3.2 Drugs used in the prophylaxis of migraine

7.2 fexofenadine fexofenadine active metabolite terfenadine

ISafE . ..2542 DUE . . chronic idiopathic urticaria cetirizine fexofenadine 28 cetirizine (symptom free) 51.9% 4.4% fexofenadine (partial improvement) 36.5% 42.2% (no improvement) 11.5% 53.3% seasonal allergic rhinitis cetirizine fexofenadine 33 fexofenadine seasonal allergic rhinitis fexofenadine adverse effect loratadine

1 3 fexofenadine ( 3) cetirizine fexofenadine 12,107,166 ..2547 7.3 desloratadine

desloratadine active metabolite loratadine relative potency 10-20 loratadine ISafE SMP 2546 ..25477.4 ketotifen antihistamines allergy asthma allergic rhinitis urticaria US FDA approval probably effective good

allergic rhinitis cetirizine

ketotifen ISafE ..2547 ketotifen prophylaxis therapy asthma

7.5 brompheniramine ..2542 brompheniramine chlorpheniramine chlorpheniramine drowsiness

ISafE brompheniramine maleate extended release formulation ISafE ..2547 Micromedex 8. antihistamines 8.1 antihistamines antihistamines (common cold) anticholinergic effect sedative effect

second generation antihistamines cetirizine loratadine anticholinergic activity sedative effect 11 chlorpheniramine 2 severity score 0 (no symptoms) 3 4 (severe symptoms) antihistamines 0.25 (95% CI 0.10 to 0.40) 0.15 (95% CI 0 to 0.30) 0.30 (95% CI 0.15 to 0.45) many systematic reviews (search date 2003, 32 RCTs, 8228 adults and children with naturally acquired colds, 702 with experimentally induced colds) antihistamines overall symptoms 1-10 antihistamines 998/1825 55 892/1667 54 (RR 0.99, 95% CI 0.93 to 1.05; at 35 days) BMJ Clinical Evidence Common cold (new), Search date May 2004 Bruce Arroll decongestant Actifed( (triprolidine + pseudoephedrine) Clarinase( (loratadine + pseudoephe-drine) common cold Piriton( (chlorpheniramine) Clarityne( (loratadine) common cold antihistamines sedative non-sedative antihistamines 54 antihistamines antihistamines

. antihistamines routine

. non-sedating antihistamines sedating antihistamines

paradoxical excitability

50

8.2 antihistamines asthma BNF (British National Formulary) 48 September 2004 respiratory system Antihistamines are of no value in the treatment of bronchial asthma. GINA (Global Initiatives for Asthma) guidelines 2004 antihistamines ( ketotifen) asthma review antihistamines cetirizine asthma asthma atopic dermatitis Further well-controlled trials involving larger samples are needed.

8.3 antihistamines BNF Chlorpheniramine maleate

Indications: symptomatic relief of allergy such as hay fever, urticaria; emergency treatment of anaphylactic reactions

Dose: by mouth, 4mg every 46 hours, max. 24mg daily; child under 1 year not recommended, 12 years 1mg twice daily; 25 years 1mg every 46 hours, max. 6mg daily; 612 years 2mg every 46 hours, max. 12mg daily By subcutaneous or intramuscular injection or by intravenous injection over 1 minute, 1020mg; max. 40mg in 24 hours; infant 1 month1 year 250micrograms/kg; child 112 years 200micrograms/kg or 15 years 2.55mg, 612 years 510mg Brompheniramine maleate

Indications: symptomatic relief of allergy such as hay fever, urticaria

Dose: 4-8 mg 3-4 times daily; CHILD up to 3 years 0.4-1 mg/kg daily in 4 divided doses, 3-6 years 2 mg 3-4 times daily, 6-12 years 2-4 mg 3-4 times daily Diphenhydramine hydrochloride

Indications: to aid relief of temporary sleep disturbance in adults

Note Sedating antihistamines, such as diphenhydramine, are used as the cough suppressant component of many compound cough preparations on sale to the public; all tend to cause drowsiness which may reflect their main mode of action. Diphenhydramine 16 Antidotes . cap, sterile sol. dystonia Hydroxyzine

Indications: pruritus, anxiety (short-term) Dose: pruritus, initially 25 mg at night increased if necessary to 25 mg 3-4 times daily; CHILD 6 months-6 years initially 5-15 mg daily increased if necessary to 50 mg daily in divided doses; over 6 years initially 15-25 mg daily increased if necessary to 50-100 mg daily in divided doses

Anxiety (adults only), 50-100 mg 4 times daily Cetirizine hydrochloride

Indications: symptomatic relief of allergy such as hay fever, urticaria

Dose: adult and child over 6 years, 10 mg daily or 5 mg twice daily; child 26 years, hayfever, 5 mg daily or 2.5 mg twice daily Loratadine

Indications: symptomatic relief of allergy such as hay fever, urticaria

Dose: adult and child over 6 years 10mg daily; child 25 years 5mg daily9. antihistamines

2544-2545 antihistamines / Cetirizine Loratadine/Fexofenadine

Micromedex Healthcare Series Vol. 123, 2004

Clinical Pharmacology 2004 CD ROM

prolong QT interval

Handa S, Dogra S, Kumar B.,Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria. J Dermatolog Treat. 2004 Jan;15(1):55-7.

Day JH, Briscoe MP, Rafeiro E, Hewlett D Jr, Chapman D, Kramer B.Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.Allergy Asthma Proc. 2004 Jan-Feb;25(1):59-68.

BMJ Clinical Evidence. Seasonal allergic rhinitis. Search date September 2003. Aziz Sheikh, Sukhmeet Singh Panesar, and Sangeeta Dhami.

Aziz Sheikh, et al. Seasonal allergic rhinitis. Clin Evid 2003; 10:621-633

Safety Monitoring Period

Micromedex Drugdex Drugevaluation 2004

Lai DS, Lue KH, Hsieh JC, Lin KL, Lee HS. The comparison of the efficacy and safety of cetirizine, oxatomide, ketotifen, and a placebo for the treatment of childhood perennial allergic rhinitis.Ann Allergy Asthma Immunol. 2002 Dec;89(6):589-98.

Clinical Pharmacology 2004 CD ROM

Textbook of Therapeutics, Drugs and Disease Management, 6th Edition, Eric T.Herfindal, Dick R.Gourley Editor. 1996, P.1253-54

D'Agostino RB Sr, Weintraub M, Russell HK, et al. The effectiveness of antihistamines in reducing the severity of runny nose and sneezing: a meta-analysis. Clin Pharmacol Ther 1998;64:579596.

De Sutter AIM, Lemiengre M, Campbell H, et al. Antihistamines for the common cold. In: The Cochrane Library, Issue 2, 2004.

chlorpheniramine cetirizine

Nelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol. 2003 Oct;112(4 Suppl):S96-100.

Wilson AM. Are antihistamines useful in managing asthma? Curr Opin Allergy Clin Immunol. 2002 Feb;2(1):53-9.

Warner JO; ETAC Study Group. Early Treatment of the Atopic Child. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up.J Allergy Clin Immunol. 2001 Dec;108(6):929-37.

Fumagalli F, Baiardini I, Pasquali M, Compalati E, Guerra L, Massacane P, Canonica GW. Antihistamines: do they work? Further well-controlled trials involving larger samples are needed. Allergy. 2004 Aug;59 Suppl 78:74-7.

BNF (British National Formulary) 48 September 2004, with permission.