Indian Journal of Paediatric Dermatology

REVIEW ARTICLE
Year
: 2022  |  Volume : 23  |  Issue : 1  |  Page : 8--23

Antihistamines in children: A dermatological perspective


Sakshi Kohli, Richa Tayal, Tarang Goyal 
 Department of Dermatology, Venereology and Leprosy, Muzaffarnagar Medical College and Hospital, Muzaffarnagar, Uttar Pradesh, India

Correspondence Address:
Tarang Goyal
Department of Dermatology, Venereology and Leprosy, Muzaffarnagar Medical College and Hospital, Muzaffarnagar, Uttar Pradesh
India

Abstract

Antihistamines are widely used drugs in pediatric population. First-generation antihistamines have been in use since last many years, though adequate data on their efficacy and safety in pediatric population is scarce. In contrast, second-generation antihistamines have been studied extensively in children and have a better safety profile with more receptor selectivity and less adverse effects. Pruritus has a significant impact on the quality of life in children and its management is of paramount importance. This article reviews the first and second-generation antihistamines in the light of recent advances in the understanding of their pharmacological properties and safety profile in children. An extensive literature search was done; all clinical trials, randomized double-blinded or single-blinded controlled trials, open-label studies, retrospective studies, reviews, case series, and case reports focusing on the use of antihistamines in pediatric age groups were screened. The selected articles were retrieved; the final manuscript was prepared, analyzed, and presented in a narrative fashion.



How to cite this article:
Kohli S, Tayal R, Goyal T. Antihistamines in children: A dermatological perspective.Indian J Paediatr Dermatol 2022;23:8-23


How to cite this URL:
Kohli S, Tayal R, Goyal T. Antihistamines in children: A dermatological perspective. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 Jan 16 ];23:8-23
Available from: https://www.ijpd.in/text.asp?2022/23/1/8/334663


Full Text



 Introduction



Antihistamines are one of the most commonly used drugs in pediatric dermatology. They are primarily used in children in conditions such as urticaria, angioedema, anaphylaxis, atopic dermatitis (AD), insect bite reactions, and other cutaneous and systemic disorders associated with pruritus. Pediatric population encompasses a wide age group ranging from neonates, infants, toddlers to adolescents.[1] Hence, pediatric drug therapy must be based on specific parameters of that age group and not a blanket approach as there might be different pharmacokinetics at different ages for the same drug.[2]

First-generation antihistamines are still widely used in pediatric population despite numerous adverse effects and lack of adequate data on the efficacy and safety of these drugs in children. This can be attributed to the following facts:

Physicians assume them to be safe since they have been in use since decadesPediatric formulations including syrups and drops are easily available over the counter.

The data on efficacy and safety of second-generation antihistamines, however, are well documented in pediatric population which encourages their routine use in the management of pediatric dermatoses.[3]

This article summarizes the pharmacological characteristics and clinical data on efficacy and safety of commonly used antihistamines in pediatric population. Recent updates on novel uses of antihistamines are also discussed.

 Method of Acquiring Data



An extensive literature search was done using words such as “antihistamines,” “first-generation H1 antihistamines,” “second-generation H1 antihistamines,” “third-generation antihistamines,” “pediatric,” “children” “urticarial,” “atopic dermatitis,” “mastocytosis,” “hydroxyzine,” “cyproheptadine,” “chlorpheniramine,” “promethazine,” “diphenhydramine,” “ketotifen,” “cetirizine,” “levocetirizine,” “loratadine,” “desloratadine,” “fexofenadine,” “bilastine,” “ebastine,” “rupatadine,” “mizolastine.” All clinical trials, randomized double-blinded or single-blinded controlled trials, open-label studies, retrospective studies, reviews, case series, and case reports concerned with the use of antihistamines in pediatric population were screened. The articles which did not have relevant information were excluded. The selected articles were retrieved; the final manuscript was prepared, analyzed, and presented in a narrative fashion.

 Histamine and its Receptors



Histamine is an endogenous biogenic amine formed by the decarboxylation of the amino acid histidine by the enzyme histidine decarboxylase.[4]

By its action on H1 receptors, histamine acts as a potent vasoactive agent, bronchial smooth muscle constrictor, stimulant of nociceptive itch nerves and promotes allergic immune response.[5],[6] It regulates the gastric acid secretion through H2 receptors and plays an important role in neurotransmission and immunomodulation by activation of H3 and H4 receptors, respectively.

 Antihistamines



Antihistamines act as an inverse agonist that binds to the same receptor binding site as histamine and not only antagonize the effects of histamine but also exert the opposite effect by suppressing spontaneous receptor signaling.[7]

 Classification



Conventionally, H1 antihistamines have been classified into 6 chemical groups [Table 1].[8] However, the functional classification is more clinically relevant in today's scenario [Table 2].[9] Functionally, the H1 antihistamines are classified into first-generation (sedating) and second-generation (relatively nonsedating) drugs.{Table 1}{Table 2}

A comparative account of the major differences between the properties of first and second-generation antihistamines is presented in [Table 3].{Table 3}

Some authors have also proposed a new category of third-generation antihistamines with additional properties and less adverse effects, however, till date, there is no consensus with regard to the drugs included in this category.[17]

 First-Generation Antihistamines



Most of the data for the use of first-generation antihistamines in children has been derived by extrapolation of data in adolescent/adult population assuming that efficacy results in adolescents/adults are also valid in children. However, as immune reaction in under 2 years of age is considered to be different than adults, specific efficacy studies are required targeting the pediatric population[18]First-generation antihistamines can significantly influence a child's quality of life and school performance[19] by inducing sedation and cognitive impairment when taken during the day and poor sleep when taken during night[13],[20]Physicians should also be watchful for anticholinergic side effects[21] of first-generation antihistamines such as

Dry mouthUrinary retentionConstipationVisual disturbances (mydriasis, photophobia)TachycardiaDrowsiness, confusion, and agitation (high-dose administration).

Despite the lack of supporting data, hydroxyzine is commonly used for the treatment of pruritus in children with chronic kidney disease (CKD). Since histamine is not the primary mediator of uremic pruritus and patients with CKD are at high risk of having prolonged QT interval, hydroxyzine is not recommended in the treatment of uremic pruritus[22],[23],[24],[25]In 2016, health Canada released a warning that hydroxyzine has been associated with QT interval prolongation and torsade de pointes which may lead to dizziness, palpitation, seizures, and sudden cardiac death in children.[26] Both the Food and Drug Administration (FDA)[27] and European medicines agency[28] have released similar warningsSimilarly, FDA has also released a black box warning regarding the use of phenergan (promethazine) in pediatric patients <2 years of age due to potential risk of fatal respiratory depression. Caution should also be exercised while administering promethazine in children aged 2 years and above.[29]

A brief account of the commonly used first-generation antihistamines is presented in [Table 4], [Table 5], [Table 6].{Table 4}{Table 5}{Table 6}

 Second-Generation Antihistamines



The poor receptor selectivity, high lipophilicity, and inadequate pediatric data of first-generation antihistamines led to a need of relatively safer, nonsedating, and well-documented group of drugs. The second-generation antihistamines were then introduced which offered an improved safety profile and were relatively less sedative.Terfenadine and astemizole were the first of second-generation antihistamines marketed. However, due to reports of QT prolongation and life-threatening ventricular arrhythmias including torsade de pointes, FDA recommended discontinuation of both of these drugs. The risk of ventricular arrhythmia was more in patients who had either exceeded the FDA recommended daily doses or taken concurrently with a drug known to interfere with hepatic CYP3A4 isoenzyme activity or had significant liver dysfunction[16],[42]At present, the rules are very stringent with regard to potential cardiotoxicity and newer antihistamines have to pass strict safety controls before being authorized for introduction into the market[18]Among second-generation antihistamines, cetirizine,[43] desloratadine,[44],[45] fexofenadine,[46] levocetirizine,[47] rupatadine,[48] bilastine,[49] and loratadine[43] have been well studied in children and their safety profile is well established.

A brief account of the commonly used second-generation antihistamines is presented in [Table 7], [Table 8], [Table 9].{Table 7}{Table 8}{Table 9}

Urticaria

Antihistamines are the cornerstone for the treatment of both acute and chronic urticaria.

The latest 2018 EAACI/GA2 LEN/EDF/WAO[15] guidelines recommend the following key points for the management of urticaria:

The second-generation antihistamines should be the first line of treatment for urticariaThe use of first-generation antihistamines is no more recommended for the routine management of urticaria in both adults and childrenAntihistamines should be taken on a regular basis and not as and when neededDifferent second-generation antihistamines should not be used at the same timeFour fold-up dosing of second-generation antihistamines should be preferred before switching to other treatment options (cyclosporine and omalizumab) in case of unresponsive urticaria.

However, in children <12 years of age, there is a paucity of literature regarding up dosing, but nevertheless, considering the safety profile of second-generation antihistamines and various large controlled studies doubling of the recommended dose can be done.[82]

Cetirizine, fexofenadine, bilastine, ebastine, desloratadine, and rupatadine have been studied in urticaria up to fourfold the recommended dose in more than 12 years of age group and their safety has been established.[88],[89],[90],[91],[92],[93],[94],[95],[96],[97]

Atopic dermatitis

The itch in AD is mediated by several mediators other than histamine, such as substance P, IL-31, protease, and gastrin-releasing peptides.[98] Since histamine is not the sole mediator, the usefulness of antihistamines in AD is controversial and debated. The 2019 guidelines on the management of AD in India suggest that a subset of patients of AD with allergic rhinitis and bronchial asthma benefit maximum from antihistamines[99]The sedating properties of first-generation antihistamines have been used by physicians to ameliorate nocturnal itch by inducing sedation. Although they induce sedation but are also known to reduce rapid eye movement (REM) sleep. REM sleep deprivation affects higher cortical functions such as cognition, attention, and memory consolidation.[100] Moreover, their sedative effects persist well into the next day even when taken the night before[19]In a study, atopic children treated with loratadine or placebo demonstrated better learning performance than those treated with diphenhydramine[101]American academy of dermatology recommends against the use of nonsedating antihistamines in the absence of urticaria or rhinoconjunctivitis[102]However, the National Institute of Health and Care Excellence guidelines for treating atopic eczema suggest 1-month trial of nonsedating antihistamines in children with severe itching.[7],[103] As there is no difference in treatment efficacy between sedative and nonsedative antihistamines, it is recommended that a nonsedating antihistamines should be selected.[98]

Cutaneous mastocytosis

Nonsedating H1 antihistamines have been recommended for the treatment of pruritus, flushing, urticaria, and tachycardia associated with mastocytosis in children. If necessary, sedating H1 antihistamines may be added on demand depending on severity of disease.[104],[105]

Cetirizine, mizolastine, desloratadine, fexofenadine, and levocetirizine have been shown to have anti-inflammatory and mast cell stabilizing properties.[2],[106],[107],[108]

Others

Antihistamines are useful as an adjunctive therapy in anaphylaxis, insect bite reactions and in the management of various other cutaneous and systemic disorders associated with pruritus.

Over dosage

First-generation antihistamines have frequently been associated with intoxication both accidental and intentional which can be life threatening particularly in children. Diphenhydramine has even been used as an agent of infanticide in the past.[109] The symptoms of intoxication vary from CNS depression in adults to paradoxical stimulation in the form of excitation, hallucinations, convulsions, and death in children.[3]

In the year 2020, FDA has issued a warning that taking higher than recommended doses of the common over-the-counter allergy medicine diphenhydramine (Benadryl) can lead to serious heart problems, seizures, coma, and even death. FDA recommends to keep these medicines out of reach from children to prevent accidental poisonings and misuse, especially when they are home more often due to COVID-19 pandemic.[110]

Second-generation antihistamines are relatively safer and have less side effects in therapeutic as well as overdose. Even with extremely high serum concentration observed in in vitro studies, second-generation antihistamines do not produce significant toxicity.

 What's New in Antihistamines?



Antihistamines as an adjunctive treatment in Acne

H1 receptors have been identified on the sebaceous glands, and a possible role of histamine in the production of sebum has been implicated.[111],[112]

Antihistamines have been found to play an adjuvant role in the management of acne by the following mechanisms:

They reduce itching associated with acne by inhibiting the release of inflammatory mediators[113]They have a synergistic effect with retinoids:

Retinoids reduce sebum in general with little effect on squalene while antihistamines are known to reduce squalene levels[111],[114]Antihistamines reduce the associated adverse effects of retinoids such as itching and acne outbreaks.[115]

Antihistamines which have been studied to be effective as an adjunctive treatment in acne include loratadine,[116] levocetirizine,[113] and desloratadine.[112],[114],[115]

Modulation of antibiotic efficacy by antihistamines

Various authors have hypothesized the following mechanisms by which the antihistamines may enhance the effect of antibacterial drugs:

Inhibition of bacterial efflux pumpsInhibition of biofilm formationAlteration of biological membrane permeability because of surfactant like properties of antihistamines[117],[118]Counteracting the effect of histamine produced under stress condition by some bacteria such as Lactobacillus reuteri and Escherichia coli.[119],[120]

El-Banna et al.[116] and Bruer et al.[119] have described the modulation of antibiotic efficacy by antihistamines in their in vitro studies on Klebsiella pneumonia and Escherichia coli.

Mepyramine,[119] promethazine,[116] diphenhydramine, and cetirizine[116] have been shown to increase the efficacy of some antibiotics.

These effects of modulation of antibiotic efficacy are seen primarily with first-generation antihistamines owing to their nonselective receptor binding. The second-generation antihistamines are more specific for H1 receptor and hence do not show these properties to that extent.

The authors have proposed that combined use of antihistamines and antibacterials might be a potential option to treat infectious diseases in the future and to reduce the absolute amount of antibacterials used therapeutically, although in vitro findings n eed to be confirmed in vivo.[116],[119]

 Paradox with Antihistamines Treatment



Antihistamine-induced urticaria

Antihistamines are the first-line treatment for urticaria. However, paradoxically, there are reports of antihistamine-induced urticaria. Hypothesis such as haptenization of metabolites, abnormal routes of metabolism, antibody production, complement activation, cross reactivity between metabolites of various drugs, type 1 and type 4 hypersensitivity reactions has been proposed to explain this paradox.

If urticaria lesions tend to persist or worsen despite H1 antihistamine treatment, physician should keep in mind the possibility of this paradoxical effect of antihistamines. Various antihistamines which have been reported to induce urticaria are fexofenadine, loratadine, cetirizine, ebastine, and hydroxyzine.[121],[122],[123],[124],[125]

Antihistamine-induced paradoxical excitation and seizures

The major drawback of first-generation antihistamines is their sedative potential, however, in children, they are paradoxically known to cause excitation, irritability and can precipitate seizures, especially in known epileptics or cases of febrile convulsions.[98],[121],[126] It is hypothesized that first-generation antihistamines may reduce the seizure threshold by blocking the histamine activity in central nervous system.[127]

Third-generation antihistamines

Consensus group on new generation antihistamines (COGNA)[17] in support with British society of allergy and clinical immunology have made recommendations for a drug to classify as third-generation antihistamine, it should have the following properties:

Anti-inflammatory effectsHigh therapeutic indexLack of cardiac toxicityMinimal drug interactionsLack of CNS effectsAdditional effect other than being an H1 blocker.

Till date, no antihistamine drug has fulfilled all these criteria. Rico et al. have analyzed ebastine in light of COGNA recommendation and have suggested that it could be a step forward toward the quest for third-generation antihistamines.[77] Rupatadine also has additional anti-inflammatory effects and platelet-activating factor antagonistic activity apart from being an H1 blocker, however, due to CYP p450 metabolism, it has a potential for drug interactions.[84]

There still seems to be a long way before a novel antihistamine is developed that fulfills all the COGNA recommendations and be classified as a third-generation antihistamine in true sense.

 Conclusion



Antihistamines are an important therapeutic class of drugs in children. Since pediatric population encompasses a wide age group, drug therapy in children should be evidence based.

In our department, the first choice of antihistamine in children is always a second-generation drug. Since the therapeutic efficacy of the various second-generation antihistamines is almost comparable, so the choice of drug in an otherwise healthy pediatric patient is dictated by other factors such as financial considerations, academic activities, and school performance. In situations where even mild sedative potential of drugs is undesirable such as school-going children, during examinations where learning performance might get affected, we prefer drugs as fexofenadine and bilastine.

Our preferred antihistamines for various age groups (not in order of preference)

In a pediatric patient with no associated systemic medical conditions,

6 months to 2 years: cetirizine, levocetirizine, desloratadine, fexofenadine2 years to 6 years: cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine>6 years: cetirizine, levocetirizine, desloratadine, fexofenadine, loratadine, bilastine.

In children with associated systemic medical conditions:Children with renal impairment:

6 months to 6 years: desloratadine, fexofenadine (however, dose adjustment required in severe renal impairment)6 years: bilastine

Children with hepatic impairment:

6 months to 6 years: levocetirizine, fexofenadine>6 years: levocetirizine, fexofenadine, bilastine.

Children with cardiac impairment:

6 months to 2 years: cetirizine, fexofenadine>2 years: cetirizine, fexofenadine, loratadine.

As many novel antihistamines have now been introduced with additional properties and improved safety profile, it is imperative to raise concerns precluding the routine use of first-generation antihistamines in children. Further research with newer antihistamines focusing on specific pediatric age groups is warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Setyawati NK, Pusvitasari LW, Rusyati LM, Gotama D. Antihistamine in pediatrics dermatology. Int J Res Med Sci 2020;9:1602-7.
2de Benedictis FM, de Benedictis D, Canonica GW. New oral H1 antihistamines in children: Facts and unmeet needs. Allergy 2008;63:1395-404.
3Church MK, Maurer M, Simons FE, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, et al. Risk of first-generation H(1)-antihistamines: A GA(2)LEN position paper. Allergy 2010;65:459-66.
4Tiligada E, Ennis M. Histamine pharmacology: From Sir Henry Dale to the 21st century. Br J Pharmacol 2020;177:469-89.
5Simons FE, editor. H1-antihistamines in children. In: Histamine and H1 Antihistamines in Allergic Disease. 2nd ed. New York: Marcel Dekker, Inc.; 2002. p. 437-64.
6Sicari V, Zabbo CP. Diphenhydramine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526010/. [Last updated on 2020 Jul 13].
7Parisi GF, Leonardi S, Ciprandi G, Corsico A, Licari A, Miraglia Del Giudice M, et al. Antihistamines in children and adolescents: A practical update. Allergol Immunopathol (Madr) 2020;48:753-62.
8Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-17.
9Tripathi KD. Essentials of Medical Pharmacology. 8th ed. New Delhi: JAYPEE Brothers Medical Publishers; 2019.
10Simons FE, Simons KJ. H1 antihistamines: Current status and future directions. World Allergy Organ J 2008;1:145-55.
11Mittal PA, Godse KV, Patil SP. Second-generation antihistamines. Indian J Drugs Dermatol 2016;2:3-12.
12Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Saf 2001;24:119-47.
13Simons FE, Simons KJ. Histamine and H1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol 2011;128:1139-50.e4.
14Fein MN, Fischer DA, O'Keefe AW, Sussman GL. CSACI position statement: Newer generation H1-antihistamines are safer than first-generation H1-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria. Allergy Asthma Clin Immunol 2019;15:61.
15Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy 2018;73:1393-414.
16Tatarkiewicz J, Rzodkiewicz P, Żochowska M, Staniszewska A, Bujalska-Zadrożny M. New antihistamines – Perspectives in the treatment of some allergic and inflammatory disorders. Arch Med Sci 2019;15:537-53.
17Holgate ST, Canonica GW, Simons FE, Taglialatela M, Tharp M, Timmerman H, et al. Consensus Group on New-Generation Antihistamines (CONGA): Present status and recommendations. Clin Exp Allergy 2003;33:1305-24.
18Del Cuvillo A, Sastre J, Montoro J, Jáuregui I, Ferrer M, Dávila I, et al. Use of antihistamines in pediatrics. J Investig Allergol Clin Immunol 2007;17 Suppl 2:28-40.
19Kay GG. The effects of antihistamines on cognition and performance. J Allergy Clin Immunol 2000;105:S622-7.
20Church MK, Church DS. Pharmacology of antihistamines. Indian J Dermatol 2013;58:219-24.
21Yanai K. Anticholinergic activity of antihistamines. Clin Neurophysiol 2012;123:633-4.
22Combs SA, Teixeira JP, Germain MJ. Pruritus in kidney disease. Semin Nephrol 2015;35:383-91.
23Mettang T, Kremer AE. Uremic pruritus. Kidney Int 2015;87:685-91.
24Manenti L, Tansinda P, Vaglio A. Uraemic pruritus: Clinical characteristics, pathophysiology and treatment. Drugs 2009;69:251-63.
25Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med 2013;368:1625-34.
26Government of Canada HC. ATARAX (hydroxyzine) – Risk of QT Prolongation and Torsade de Pointes; 2016. Available from: https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/58758a-eng.php. [Last accessed on 2021 Jun 14].
27FDA Safety Information-Vistaril (hydroxyzine pamoate) Capsules and Oral Suspension. NY: Pfizer; May, 2014. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/011459s048%2C011795s025lbl.pdf. [Last accessed on 2021 Jun 14].
28Hydroxyzine. European Medicines Agency; 2018. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/hydroxyzine. [Last accessed on 2021 Jun 14].
29FDA drug Safety Information of Promethazine HCl Tablets and Suppositories. Wyeth Pharmaceuticals. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf. [Last accessed on 2021 Jun 20].
30Malamed SF. Sedation: A Guide to Patient Management. 6th ed. St. Louis, Missouri: Elsevier; 2017.
31Paton DM, Webster DR. Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet 1985;10:477-97.
32FDA Drug Safety Information of Cyproheptadine Hydrochloride Tablets USP. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/087056s045lbl.pdf. [Last accessed on 2021 Jun 21].
33Gunja N, Collins M, Graudins A. A comparison of the pharmacokinetics of oral and sublingual cyproheptadine. J Toxicol Clin Toxicol 2004;42:79-83.
34Pathirana S, Jayawardena S, Meeves S, Thompson GA. Brompheniramine and chlorpheniramine pharmacokinetics following single-dose oral administration in children aged 2 to 17 years. J Clin Pharmacol 2018;58:494-503.
35Rumore MM. Clinical pharmacokinetics of chlorpheniramine. Drug Intell Clin Pharm 1984;18:701-7.
36Southard BT, Al Khalili Y. Promethazine. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544361/. [Last accessed on 2020 Jul 10].
37Gelotte CK, Zimmerman BA, Thompson GA. Single-dose pharmacokinetic study of diphenhydramine HCl in children and adolescents. Clin Pharmacol Drug Dev 2018;7:400-7.
38FDA Drug Safety Information of Diphenhydramine Hydrochloride Injection USP. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/091526lbl.pdf. [Last accessed on 2021 Jun 23].
39Grant SM, Goa KL, Fitton A, Sorkin EM. Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Drugs 1990;40:412-48.
40Sokol KC, Amar NK, Starkey J, Grant JA. Ketotifen in the management of chronic urticaria: Resurrection of an old drug. Ann Allergy Asthma Immunol 2013;111:433-6.
41Markham A, Goa KL. Ketotifen. Clin Immunother 1996;5:400-11.
42Woosley R, Darrow WR. Analysis of potential adverse drug reactions – A case of mistaken identity. Am J Cardiol 1994;74:208-9.
43Nayak AS, Berger WE, LaForce CF, Urdaneta ER, Patel MK, Franklin KB, et al. Randomized, placebo-controlled study of cetirizine and loratadine in children with seasonal allergic rhinitis. Allergy Asthma Proc 2017;38:222-30.
44Gupta S, Khalilieh S, Kantesaria B, Banfield C. Pharmacokinetics of desloratadine in children between 2 and 11 years of age. Br J Clin Pharmacol 2007;63:534-40.
45Gupta SK, Kantesaria B, Banfield C, Wang Z. Desloratadine dose selection in children aged 6 months to 2 years: Comparison of population pharmacokinetics between children and adults. Br J Clin Pharmacol 2007;64:174-84.
46Meltzer EO, Scheinmann P, Rosado Pinto JE, Bachert C, Hedlin G, Wahn U, et al. Safety and efficacy of oral fexofenadine in children with seasonal allergic rhinitis – A pooled analysis of three studies. Pediatr Allergy Immunol 2004;15:253-60.
47Pampura AN, Papadopoulos NG, Spičák V, Kurzawa R. Evidence for clinical safety, efficacy, and parent and physician perceptions of levocetirizine for the treatment of children with allergic disease. Int Arch Allergy Immunol 2011;155:367-78.
48Potter P, Mitha E, Barkai L, Mezei G, Santamaría E, Izquierdo I, et al. Rupatadine is effective in the treatment of chronic spontaneous urticaria in children aged 2-11 years. Pediatr Allergy Immunol 2016;27:55-61.
49Novák Z, Yáñez A, Kiss I, Kuna P, Tortajada-Girbés M, Valiente R, et al. Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases. Pediatr Allergy Immunol 2016;27:493-8.
50Watson WT, Simons KJ, Chen XY, Simons FE. Cetirizine: A pharmacokinetic and pharmacodynamic evaluation in children with seasonal allergic rhinitis. J Allergy Clin Immunol 1989;84:457-64.
51Desager JP, Dab I, Horsmans Y, Harvengt C. A pharmacokinetic evaluation of the second-generation H1-receptor antagonist cetirizine in very young children. Clin Pharmacol Ther 1993;53:431-5.
52Spicák V, Dab I, Hulhoven R, Desager JP, Klánová M, de Longueville M, et al. Pharmacokinetics and pharmacodynamics of cetirizine in infants and toddlers. Clin Pharmacol Ther 1997;61:325-30.
53Horsmans Y, Desager JP, Hulhoven R, Harvengt C. Single-dose pharmacokinetics of cetirizine in patients with chronic liver disease. J Clin Pharmacol 1993;33:929-32.
54Campoli-Richards DM, Buckley MM, Fitton A. Cetirizine. A review of its pharmacological properties and clinical potential in allergic rhinitis, pollen-induced asthma, and chronic urticaria. Drugs 1990;40:762-81.
55Wood SG, John BA, Chasseaud LF, Yeh J, Chung M. The metabolism and pharmacokinetics of 14C-cetirizine in humans. Ann Allergy 1987;59:31-4.
56Papadopoulos NG, Zuberbier T. The safety and tolerability profile of bilastine for chronic urticaria in children. Clin Transl Allergy 2019;9:55.
57Belloni Fortina A, Fontana E. Update on antihistamine treatment for chronic urticaria in children. Curr Treat Options Allergy 2014;1:287-98.
58FDA Drug Safety of Cetirizine Hydrochloride Tablets and Syrup for Oral Use. USA: Pfizer. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/19835s15,%2020346s8lbl.pdf. [Last accessed on 2021 Jun 21].
59FDA Drug Safety of Levocetirizine Dihydrochloride. UCB Biopharma. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022064s038,022157s020lbl.pdf. [Last accessed on 2021 Jun 23].
60Cranswick N, Turzíkova J, Fuchs M, Hulhoven R. Levocetirizine in 1-2 year old children: Pharmacokinetic and pharmacodynamic profile. Int J Clin Pharmacol Ther 2005;43:172-7.
61Yumibe N, Huie K, Chen KJ, Clement RP, Cayen MN. Identification of human liver cytochrome P450s involved in the microsomal metabolism of the antihistaminic drug loratadine. Int Arch Allergy Immunol 1995;107:420.
62Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Cayen MN, et al. Loratadine administered concomitantly with erythromycin: Pharmacokinetic and electrocardiographic evaluations. Clin Pharmacol Ther 1995;58:269-78.
63Slater JW, Zechnich AD, Haxby DG. Second-generation antihistamines: A comparative review. Drugs 1999;57:31-47.
64Haria M, Fitton A, Peters DH. Loratadine. A reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs 1994;48:617-37.
65FDA Drug Safety Information of Loratadine Tablets, Syrup and Rapidly Disintegrating Tablets. USA: Schering Corporation. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20641s7lbl.pdf. [Last accessed on 2021 Jun 22].
66Ellis AK, Day JH. Second- and third-generation antihistamines in the treatment of urticaria. Dermatol Ther 2000;13:327-36.
67FDA Drug Safety Information of Desloratadine Tablets, RediTabs and Oral Solution. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021165s014lbl.pdf. [Last accessed on 2021 Jun 23].
68Simons FE, Bergman JN, Watson WT, Simons KJ. The clinical pharmacology of fexofenadine in children. J Allergy Clin Immunol 1996;98:1062-4.
69FDA Drug Safety Information of Fexofenadine Hydrochloride Capsules and Tablets. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20786se8-014,20872se8-011,20625se8-012_allegra_lbl.pdf. [Last accessed on 2021 Jun 23].
70Bosma R, van den Bor J, Vischer HF, Labeaga L, Leurs R. The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H1 receptor. Eur J Pharmacol 2018;838:107-11.
71Church MK, Tiongco-Recto M, Ridolo E, Novák Z. Bilastine: A lifetime companion for the treatment of allergies. Curr Med Res Opin 2020;36:445-54.
72Dávila I, del Cuvillo A, Mullol J, Jáuregui I, Bartra J, Ferrer M, et al. Use of second generation H1 antihistamines in special situations. J Investig Allergol Clin Immunol 2013;23 Suppl 1:1-16.
73Hurst M, Spencer CM. Ebastine: An update of its use in allergic disorders. Drugs 2000;59:981-1006.
74Simons FE, Watson WT, Simons KJ. Pharmacokinetics and pharmacodynamics of ebastine in children. J Pediatr 1993;122:641-6.
75Goyal V, Gupta A, Gupta O, Lal D, Gill M. Comparative efficacy and safety of Ebastine 20 mg, Ebastine 10 mg and Levocetirizine 5 mg in acute urticaria. J Clin Diagn Res 2017;11:WC06-9.
76Pecoraro L, Paiola G, Pietrobelli A. Ebastine overdose in a child. Clin Case Rep 2017;5:403-5.
77Rico S, Antonijoan R, Barbanoj M. Ebastine in the light of CONGA recommendations for the development of third-generation antihistamines. J Asthma Allergy 2009;2:73-92.
78Roberts DJ, Gispert J. The non-cardiac systemic side-effects of antihistamines: Ebastine. Clin Exp Allergy 1999;29 Suppl 3:151-5.
79Yamaguchi T, Hashizume T, Matsuda M, Sakashita M, Fujii T, Sekine Y, et al. Pharmacokinetics of the H1-receptor antagonist ebastine and its active metabolite carebastine in healthy subjects. Arzneimittelforschung 1994;44:59-64.
80Roberts DJ, Llenas J. Some observations on the cardiotoxic and drug interaction profiles of second generation antihistamines as measured in the guinea pig. Arzneimittelforschung 1996;46:832-3.
81Wiseman LR, Faulds D. Ebastine. a review of its pharmacological properties and clinical efficacy in the treatment of allergic disorders. Drugs 1996;51:260-77.
82Caffarelli C, Paravati F, El Hachem M, Duse M, Bergamini M, Simeone G, et al. Management of chronic urticaria in children: A clinical guideline. Ital J Pediatr 2019;45:101.
83Santamaría E, Izquierdo I, Valle M, Vermeulen J, Potter P. Rupatadine oral solution for 2-5-year-old children with allergic rhinitis: A safety, open-label, prospective study. J Asthma Allergy 2018;11:225-31.
84Shamizadeh S, Brockow K, Ring J. Rupatadine: Efficacy and safety of a non-sedating antihistamine with PAF-antagonist effects. Allergo J Int 2014;23:87-95.
85Simons FE, Simons KJ. Clinical pharmacology of new histamine H1 receptor antagonists. Clin Pharmacokinet 1999;36:329-52.
86Lebrun-Vignes B, Diquet B, Chosidow O. Clinical pharmacokinetics of mizolastine. Clin Pharmacokinet 2001;40:501-7.
87Gandhi J, Godse K, Godse G. Bilastine: A novel antihistamine. Indian J Drugs Dermatol 2018;4:3-6.
88Sánchez J, Zakzuk J, Cardona R. Prediction of the efficacy of antihistamines in chronic spontaneous urticaria based on initial suppression of the histamine- induced wheal. J Investig Allergol Clin Immunol 2016;26:177-84.
89Staevska M, Popov TA, Kralimarkova T, Lazarova C, Kraeva S, Popova D, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010;125:676-82.
90Siebenhaar F, Degener F, Zuberbier T, Martus P, Maurer M. High-dose desloratadine decreases wheal volume and improves cold provocation thresholds compared with standard-dose treatment in patients with acquired cold urticaria: A randomized, placebo-controlled, crossover study. J Allergy Clin Immunol 2009;123:672-9.
91Abajian M, Curto-Barredo L, Krause K, Santamaria E, Izquierdo I, Church MK, et al. Rupatadine 20 mg and 40 mg are effective in reducing the symptoms of chronic cold urticaria. Acta Derm Venereol 2016;96:56-9.
92Finn AF Jr., Kaplan AP, Fretwell R, Qu R, Long J. A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999;104:1071-8.
93Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000;84:517-22.
94Church MK, Maurer M. H(1)-antihistamines and urticaria: How can we predict the best drug for our patient? Clin Exp Allergy 2012;42:1423-9.
95Weller K, Viehmann K, Bräutigam M, Krause K, Siebenhaar F, Zuberbier T, et al. Management of chronic spontaneous urticaria in real life-in accordance with the guidelines? A cross-sectional physician-based survey study. J Eur Acad Dermatol Venereol 2013;27:43-50.
96Okubo Y, Shigoka Y, Yamazaki M, Tsuboi R. Double dose of cetirizine hydrochloride is effective for patients with urticaria resistant: A prospective, randomized, non-blinded, comparative clinical study and assessment of quality of life. J Dermatolog Treat 2013;24:153-60.
97Guillén-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, Guillén-Grima F, Ferrer M. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: A systematic review and meta-analysis. Br J Dermatol 2016;175:1153-65.
98Katoh N, Ohya Y, Ikeda M, Ebihara T, Katayama I, Saeki H, et al. Japanese guidelines for atopic dermatitis 2020. Allergol Int 2020;69:356-69.
99Rajagopalan M, De A, Godse K, Krupa Shankar DS, Zawar V, Sharma N, et al. Guidelines on management of atopic dermatitis in India: An evidence-based review and an expert consensus. Indian J Dermatol 2019;64:166-81.
100Nami M. Medication induced poor sleep and neuro-cognitive consequences in allergic rhinitis: A brief review. Internet J Fam Pract 2011;9:1
101Vuurman EF, van Veggel LM, Uiterwijk MM, Leutner D, O'Hanlon JF. Seasonal allergic rhinitis and antihistamine effects on children's learning. Ann Allergy 1993;71:121-6.
102Eichenfield LF, Ahluwalia J, Waldman A, Borok J, Udkoff J, Boguniewicz M. Current guidelines for the evaluation and management of atopic dermatitis: A comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines. J Allergy Clin Immunol 2017;139:S49-57.
103National Institute for Health and Care Excellence. Atopic Eczema in Under 12s: Diagnosis and Management. London: National Institute for Health and Care Excellence (NICE); 2021.
104Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: Practical recommendations. Am J Clin Dermatol 2011;12:259-70.
105Cardet JC, Akin C, Lee MJ. Mastocytosis: Update on pharmacotherapy and future directions. Expert Opin Pharmacother 2013;14:2033-45.
106Levi-Schaffer F, Eliashar R. Mast cell stabilizing properties of antihistamines. J Invest Dermatol 2009;129:2549-51.
107Agrawal DK. Anti-inflammatory properties of desloratadine. Clin Exp Allergy 2004;34:1342-8.
108Baroody FM, Naclerio RM. Antiallergic effects of H1-receptor antagonists. Allergy 2000;55 Suppl 64:17-27.
109Baker AM, Johnson DG, Levisky JA, Hearn WL, Moore KA, Levine B, et al. Fatal diphenhydramine intoxication in infants. J Forensic Sci 2003;48:425-8.
110Benadryl (diphenhydramine): Drug Safety Communication – Serious Problems with High Doses of the Allergy Medicine. FDA; September 24, 2020. Available from: https://www.fda.gov/safety/medical-productsafety-information/benadryl-diphenhydramine-drug-safety-communication-serious-problems-high-doses-allergy-medicine. [Last accessed on 2021 Jun 23].
111Pelle E, McCarthy J, Seltmann H, Huang X, Mammone T, Zouboulis CC, et al. Identification of histamine receptors and reduction of squalene levels by an antihistamine in sebocytes. J Invest Dermatol 2008;128:1280-5.
112Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, et al. Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: A randomized, controlled comparative study. J Eur Acad Dermatol Venereol 2014;28:1654-60.
113Pandey D, Agrawal S. Efficacy of isotretinoin and antihistamine versus isotretinoin alone in the treatment of moderate to severe acne: A randomised control trial. Kathmandu Univ Med J (KUMJ) 2019;17:14-9.
114Dhaher SA, Jasim ZM. The adjunctive effect of desloratadine on the combined azithromycin and isotretinoin in the treatment of severe acne: Randomized clinical trial. J Dermatol Dermatol Surg 2018;22:21-5.
115Van TN, Thi LD, Trong HN, Van TC, Minh TT, Minh PP, et al. Efficacy of oral isotretinoin in combination with desloratadine in the treatment of common vulgaris acne in vietnamese patients. Open Access Maced J Med Sci 2019;7:217-20.
116El-Banna TE, Sonbol FI, El-Aziz AA, Al-Fakharany OM. Modulation of antibiotic efficacy against Klebsiella pneumoniae by antihistaminic drugs. J Med Microbiol Diagn 2016;5:225.
117Attwood D, Florence AT. Physicochemical Principles of Pharmacy: In Manufacture, Formulation and Clinical Use. 6th ed. London: Pharmaceutical Press; 2016.
118Hagmar P, Pierrou S, Nielsen P, Nordén B, Kubista M. Ionic strength dependence of the binding of methylene blue to chromatin and calf thymus DNA. J Biomol Struct Dyn 1992;9:667-79.
119Bruer GG, Hagedorn P, Kietzmann M, Tohamy AF, Filor V, Schultz E, et al. Histamine H1 receptor antagonists enhance the efficacy of antibacterials against Escherichia coli. BMC Vet Res 2019;15:55.
120Thomas CM, Hong T, van Pijkeren JP, Hemarajata P, Trinh DV, Hu W, et al. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One 2012;7:e31951.
121Adya KA, Inamadar AC, Palit A. Paradoxes in dermatology. Indian Dermatol Online J 2013;4:133-42.
122Lee SW, Byun JY, Choi YW, Myung KB, Choi HY. Fexofenadine-induced urticaria. Ann Dermatol 2011;23:S329-32.
123Inomata N, Tatewaki S, Ikezawa Z. Multiple H1-antihistamine-induced urticaria. J Dermatol 2009;36:224-7.
124González de Olano D, Roán Roán J, de la Hoz Caballer B, Cuevas Agustín M, Hinojosa Macías M. Urticaria induced by antihistamines. J Investig Allergol Clin Immunol 2006;16:144-6.
125Rodríguez del Río P, González-Gutiérrez ML, Sánchez-López J, Nuñez-Acevedo B, Bartolomé Alvarez JM, Martínez-Cócera C. Urticaria caused by antihistamines: Report of 5 cases. J Investig Allergol Clin Immunol 2009;19:317-20.
126Zolaly MA. Histamine H1 antagonists and clinical characteristics of febrile seizures. Int J Gen Med 2012;5:277-81.
127Yamashita Y, Isagai T, Seki Y, Ohya T, Nagamitsu S, Matsuishi T. West syndrome associated with administration of a histamine H1 antagonist, oxatomide. Kurume Med J 2004;51:273-5.