Safety considerations in the management of allergic diseases: focus on antihistamines

Abstract

Objective:

To conduct a systematic review of evidence supporting the safety profiles of frequently used oral H₁-antihistamines (AHs) for the treatment of patients with histamine-release related allergic diseases, e.g. allergic rhinitis and urticaria, and to compare them to the safety profiles of other medications, mostly topical corticosteroids and leukotriene antagonists (LTRA).

Research design and methods:

Systematic search of the published literature (PubMed) and of the regulatory authorities databases (EMA and FDA) for oral AHs.

Results:

Similarly to histamine, antihistamines (AHs) have organ-specific efficacy and adverse effects. The peripheral H₁-receptor (PrH1R) stimulation leads to allergic symptoms while the brain H₁-receptor (BrH1R) blockade leads to somnolence, fatigue, increased appetite, decreased cognitive functions (impaired memory and learning), seizures, aggressive behaviour, etc. First-generation oral AHs (FGAHs) inhibit the effects of histamine not only peripherally but also in the brain, and additionally have potent antimuscarinic, anti-α-adrenergic and antiserotonin effects leading to symptoms such as visual disturbances (mydriasis, photophobia, and diplopia), dry mouth, tachycardia, constipation, urinary retention, agitation, and confusion. The somnolence caused by FGAHs interferes with the natural circadian sleep–wake cycle and therefore FGAHs are not suitable to be used as sleeping pills. Second-generation oral AHs (SGAHs) have proven better safety and tolerability profiles, much lower proportional impairment ratios, with at least similar if not better efficacy, than their predecessors. Only SGAHs, and especially those with a proven long-term (e.g., ≥12 months) clinical safety, should be prescribed for young children. Evidence exist that intranasally applied medications, like intranasal antihistamines, have the potential to reach the brain and cause somnolence.

Conclusions:

Second-generation oral antihistamines are the preferred first-line treatment option for allergic rhinitis and urticaria. Patients taking SGAHs report relatively little and mild adverse events even after long-term continuous treatments. An antihistamine should ideally possess high selectivity for the H₁-receptor, high PrH1R occupancy and low to no BrH1R occupancy.

Keywords::

• Antihistamine
• H₁-receptor occupancy peripheral and brain
• Immunotherapy
• Intranasal steroid
• Leukotriene receptor antagonist

Transparency

Declaration of funding

UCB Farchim SA, Switzerland provided financial editorial support for the writing and formatting of this manuscript, as well as for the creation of the visual elements used in it.

Declaration of financial/other relationships:

K.Y. has received funds from Sanofi-Aventis, Boehringer-Ingelheim, Kyowa-Kirin, and Mitsubishi Tanabe, for the continuous education of antihistamine use for medical doctors, pharmacists and the public in Japan, and for PET studies performed in Tohoku University, Japan. He has received research funding from GSK for examining the sedating properties of histamine H₁-receptor occupancy by antihistamines. He has served on the Speakers’ Bureau for Sanofi-Aventis, GSK, MSD, Boehringer-Ingelheim, Kyowa-Kirin, Mitsubishi Tanabe, Dainippon-Sumitomo, Torii, and Eisai for lectures in Japan. B.R. has served on Speakers’ bureaus for Takeda/Nycomed, Teva, UCB and Chiesi. A.N.P. has served on Speaker’s bureaus for UCB, MSD and EGIS. R.B. is an employee of UCB Farchim SA, Switzerland. K.C. and E.P. declare no conflict of interest.

Acknowledgements

The authors would like to thank Marleen Oppermann, from Cologne, Germany, for her editorial assistance.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed any relevant financial relationships.