Bilastine

證據等級: L5

預測適應症: 10 個

Bilastine: From Allergic Rhinitis to Cold Urticaria

One-Sentence Summary

Bilastine is a second-generation, non-sedating H1-antihistamine with established international approval for allergic rhinitis/rhinoconjunctivitis, but currently not registered in Singapore. The TxGNN model identifies Cold Urticaria as the highest-confidence, mechanistically plausible new indication (rank #7, score 90.15%), supported by 2 completed clinical trials and 1 RCT-level publication; the closely related indication Allergic Urticaria (rank #9) is additionally backed by 6 clinical trials and 20 publications, reaching L1 evidence level.

Quick Overview

Item	Content
Original Indication	Allergic rhinitis / rhinoconjunctivitis (international approval; not registered in Singapore)
Predicted New Indication	Cold Urticaria
TxGNN Prediction Score	90.15% (Cold Urticaria, overall rank #7)
Evidence Level	L2 (Cold Urticaria) · L1 (Allergic Urticaria)
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Note on TxGNN ranking: The six highest-scoring TxGNN predictions (ranks #1–#6: duodenal obstruction, duodenal ulcer, duodenogastric reflux, gastric ulcer, linitis plastica, duodenitis) all carry a Hold recommendation due to mechanistic implausibility — H1 receptor blockade has no established role in upper GI structural or acid-mediated pathology. These are assessed as knowledge-graph false positives. The meaningful predictions begin at rank #7 (Cold Urticaria).

Why is This Prediction Reasonable?

Detailed mechanism of action data was not captured in this Evidence Pack. Based on well-established pharmacological knowledge, Bilastine is a highly selective H1-receptor inverse agonist: it binds to H1 receptors and stabilises them in an inactive state, blocking histamine-mediated downstream signalling. Key pharmacological characteristics include non-CNS penetration (non-sedating profile), absence of significant CYP450 metabolism (low drug-drug interaction potential), rapid onset of action (~1 hour), and prolonged effect duration (~24 hours). These properties distinguish it from older first-generation antihistamines and place it among the most selective second-generation agents.

Cold Urticaria (cold contact urticaria, CCU) is a physical urticaria subtype in which cold stimulus directly activates mast cells, triggering degranulation and histamine release. The resulting wheal-and-flare reaction is histamine-mediated via H1 receptors — making H1-antihistamines the recommended first-line treatment in international guidelines (EAACI/GA²LEN/EDF/WAO). Bilastine's high H1 selectivity is mechanistically well-matched to this pathophysiology. Published clinical evidence further shows that dose escalation to 40–80 mg (2–4× standard dose) yields dose-dependent improvements in cold stimulation thresholds, addressing the common clinical scenario where standard doses provide insufficient control in CCU patients.

The same H1-mediated mechanism applies to Allergic Urticaria, where allergen exposure — rather than cold — triggers mast cell activation. Bilastine has been evaluated in large pivotal Phase 3 RCTs for this indication and achieved EU regulatory approval. The convergence of strong mechanistic alignment and high-quality clinical evidence across both urticaria subtypes makes this one of the most well-supported predictions in the dataset. By contrast, C1 inhibitor deficiency (rank #8, hereditary angioedema) is bradykinin-mediated rather than histamine-mediated; antihistamines are ineffective for acute HAE attacks and that prediction should be disregarded entirely.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01271075	Phase 2/3	Completed	20	Double-blind triple crossover RCT in cold contact urticaria: Bilastine 20/40/80 mg vs placebo; primary endpoints were critical stimulation time threshold (CSTT) and critical temperature threshold (CTT); direct mechanistic and efficacy assessment
NCT00421109	Phase 3	Completed	522	Pivotal RCT: Bilastine 20 mg QD vs levocetirizine 5 mg QD vs placebo for chronic idiopathic urticaria; key trial supporting EU marketing authorisation
NCT01940393	Phase 4	Completed	150	Comparative study of 5 antihistamines in urticaria (including cold urticaria subgroup) in a Latin American tropical population; pharmacokinetic and pharmacodynamic comparison
NCT01081574	Phase 1/2	Completed	36	Multicentre adaptive PK study in children aged 2–<12 years with allergic rhinoconjunctivitis or chronic urticaria; established paediatric dosing regimen
NCT07042828	Phase 1	Completed	42	Full replicate crossover bioequivalence study for generic bilastine tablet formulation under fasting conditions; confirms manufacturing equivalence
NCT00419783	Phase 1	Completed	30	QTc cardiac safety study: bilastine 20 mg and 100 mg (5× standard) vs moxifloxacin 400 mg and placebo over 4 days; cardiac safety confirmed at therapeutic doses
NCT04967092	Phase 2	Unknown	58	Double-blind RCT for Xiao-Feng Powder (Chinese herbal formula) in chronic urticaria; bilastine used as active control only — not the investigational agent; status uncertain
NCT02576041	Phase 4	Completed	19	CNS safety: assessment of bilastine's effects on attention and reaction time using an F1 high-speed simulator in rhinitis/urticaria patients; confirms non-sedating profile

Literature Evidence

PMID	Year	Type	Journal	Key Findings
35593100	2022	Systematic Review + Meta-Analysis	Am J Rhinology & Allergy	Meta-analysis of RCTs: bilastine significantly reduces total nasal/ocular symptom scores in allergic rhinitis and wheal/flare scores in chronic urticaria vs placebo
36380619	2023	Systematic Review + Meta-Analysis	Int Archives Allergy Immunol	Meta-analysis specific to chronic urticaria: bilastine superior to placebo in reducing wheal size and erythema; evidence-based reference for clinical use
23742030	2013	RCT / Dose-escalation study	Allergy	Up-dosing bilastine (20→40→80 mg) in cold contact urticaria: dose-dependent improvement in CSTT and CTT; first clinical evidence for dose escalation in CCU
33030434	2021	Systematic Review	J Investig Allergol Clin Immunol	Systematic review of antihistamine up-dosing (up to 4× licensed dose) in chronic spontaneous urticaria; supports guideline recommendation for dose escalation including bilastine
22686617	2012	Drug Review	Drugs	Comprehensive review of bilastine Phase 3 RCT data; summarises efficacy vs placebo and levocetirizine in seasonal allergic rhinitis and chronic urticaria
26844221	2016	Consensus Statement	Asia Pacific Allergy	Asia-Pacific regional consensus on bilastine for allergic rhinitis and chronic urticaria; directly relevant to Singapore patient population and prescribing context
36382168	2022	Drug Review / Guideline	Australian Prescriber	Regulatory prescribing summary issued in the Asia-Pacific context for bilastine in allergic rhinoconjunctivitis and urticaria
28210286	2017	Practice Guideline / Review	Drugs in Context	Clinical decision guide covering bilastine use in co-morbid patients, concomitant medications, and special populations; based on Medical Information Department queries
34850647	2022	Pediatric Review	Immunotherapy	Bilastine paediatric development summary (2–<12 years); EMA-authorised pharmacokinetic modelling and Phase 3 trial in children with rhinoconjunctivitis and urticaria
38742145	2024	Delphi Expert Consensus	Drugs in Context	International Delphi study from EU/Asia experts defining bilastine's positioning among second-generation antihistamines for rhinitis and urticaria across age groups

Singapore Market Information

Bilastine is not currently registered in Singapore. There are no recorded product authorizations (0 licenses).

For reference, bilastine holds regulatory approval in the following major jurisdictions:

Region	Brand Name	Approved Indications
European Union (EMA)	Bilaxten / Ilaxten	Allergic rhinoconjunctivitis, urticaria (adults, adolescents, children ≥2 years)
Japan (PMDA)	Bilanoa	Allergic rhinitis, urticaria
South Korea (MFDS)	Bilaxten	Allergic rhinitis, urticaria
Australia (TGA)	Bilaxten	Allergic rhinoconjunctivitis, urticaria

The absence of Singapore registration represents a directly addressable regulatory gap for a drug with a well-established international safety and efficacy profile.

Safety Considerations

No Singapore-specific package insert data is available as bilastine is unregistered locally. Based on international clinical development data:

Sedation: Does not penetrate the blood-brain barrier at therapeutic doses; no psychomotor impairment at 20 mg (confirmed by driving simulator study NCT02576041)
Cardiac safety: No clinically significant QTc prolongation at 20 mg standard dose; minor effects observed only at supratherapeutic doses (100 mg) in combination with the P-gp/CYP3A4 inhibitor ketoconazole
Drug interactions: No significant CYP450 metabolism; low inherent DDI risk; however, concomitant use with P-glycoprotein inhibitors (e.g., ketoconazole, erythromycin) can increase bilastine plasma exposure — caution advised
Food interaction: Bioavailability reduced when taken with food or grapefruit juice; should be taken on an empty stomach

Please refer to the EU Summary of Product Characteristics (EU SmPC) or Japanese prescribing information for the complete, authoritative safety profile.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Bilastine's H1-selective inverse agonism is directly mechanistically matched to histamine-driven urticaria. Allergic Urticaria is supported by a pivotal Phase 3 RCT (n=522, L1 evidence) and two meta-analyses; Cold Urticaria by a dedicated Phase 2/3 crossover RCT and a dose-escalation publication (L2 evidence). The drug is approved in the EU, Japan, Australia, and South Korea. Singapore's current absence of any bilastine registration is a clear market gap for a mature, well-characterised antihistamine with a favourable safety profile.

To proceed, the following is needed:

Initiate an HSA Singapore registration application using the EU SmPC or Japanese package insert as reference dossier (abridged approval pathway may apply)
Obtain and review the full EU SmPC for safety label localisation and YMYL compliance
Confirm that both allergic urticaria and cold urticaria are captured within the proposed Singapore label, or plan for separate indication extension
Clarify the regulatory position on dose escalation (40–80 mg) for cold urticaria — whether a separate dosing section is required in the local label
Review the P-gp interaction warning in the context of commonly co-prescribed drugs in Singapore (e.g., macrolide antibiotics)
Prepare a pharmacovigilance plan aligned with HSA post-market surveillance requirements
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.