Introduction

Allergic diseases have become a major health concern worldwide, with India being no exception¹. Allergic rhinoconjunctivitis and chronic urticaria are common conditions in young children (<12 years) and carry a large burden of disease². Prevalence of AR has been reported to be as high as 40% in children worldwide. In India, ISAAC phase III study, the prevalence of allergic rhinoconjunctivitis in the 6-7 and 13-14 year age-groups was 3.9% and 10.4% respectively³. Whereas, studies have reported the prevalence of acute urticaria to be 1% to 14.5% worldwide but data on the prevalence of chronic urticaria in children is scarce⁴.

Allergic symptoms frequently interfere with a child’s ability to participate in daily activities and disrupt normal sleeping patterns, causing emotional distress and impacting negatively on learning and cognition².

Given the differences between second-generation H₁ antihistamines in terms of pharmacokinetics, general age-related differences among children, a need remains for effective options to treat chronic allergic conditions in young children². Second-generation H₁ antihistamines are treatment of choice for allergic rhinoconjunctivitis and chronic urticaria in children.

According to Allergic Rhinitis and Its Impact on Asthma (ARIA 2008 and 2010) guidelines also, the second generation oral antihistamines are the drugs of first line treatment of periodic allergic rhinitis of mild or moderate/severe clinical course and mild chronic allergic rhinitis with evidence of strength of recommendation A. Antihistamines are also a component of therapy of chronic allergic rhinitis of moderate/severe clinical course as an add-on drug to nasal glucocorticosteroid⁵.

Position paper of EAACI (European Academy of Allergy and Clinical Immunology) on pediatric rhinitis (2018) has recommended use of oral antihistamines as first line therapy for treatment of allergic rhinitis⁶.

Latest joint guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) (2018) clearly stipulate that “modern second generation H₁-antihistamines are to be used as first line treatment of urticaria.” In addition, these guidelines recommend “a trial of up to fourfold dose of modern second generation H₁-antihistamines as second-line in the algorithm of treatment⁷.

Bilastine is a newest, second-generation, highly selective H₁ antihistamine which is a benzimidazole–piperidine derivative. Unlike certain other antihistamines, it is a distinct chemical entity and not derived structurally from other compounds in this class. It was first approved in the European Union in 2010 for the symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria and is now available in approximately 100 countries worldwide⁸. Recently, it has been approved for use in children aged 6 to 11 years. Bilastine has the highest number of desired features for a modern antihistamine according to international ARIA guidelines.

In India, it was approved by CDSCO (Central Drugs Standard Control Organization) in 2019

Unique Features of Bilastine

• Rapid onset of action
• Long duration of action permitting once-daily dosing
• Minimal sedation or cognitive or psychomotor impairment
• No anticholinergic activity
• No cardiac safety concerns
• No clinically relevant pharmacokinetic interactions with food, medication,
• or intestinal proteins
• No interaction with cytochrome P450

Cipla has recently launched an oral liquid formulation of bilastine under the brand name “Billargic oral solution”. Each ml of this solution contains 2.5 mg of bilastine. It is available in strawberry flavour and in an amber coloured pet bottle of 60 ml pack.

Pharmacology

Bilastine, or 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl] piperidin-1-yl] ethyl] phenyl]-2-methylpropionic acid is a novel molecule with a molecular weight of 463.6 daltons.

Pharmacodynamics

Mechanism of Action

Histamine is one of main mediators involved in the pathophysiology of both allergic rhinitis and urticaria. After exposure to an allergen, specific antibodies of the IgE type are produced. These interact with receptors on the surface of basophils and mast cells which in turn releases histamine along with other inflammatory mediators⁹. In allergic rhinitis, the interaction of histamine with H₁ receptors is the primary cause for manifestation of early phase allergic responses that manifest as rhinorrhoea, itch and contraction of bronchial smooth muscles¹⁰. Besides its mediatory activity in the early allergic response, histamine contributes to the late allergic response by stimulating the production of cellular adhesion molecules, class II antigens, and cytokines⁹.

Most types of urticaria, including chronic spontaneous urticaria and the majority of inducible urticarias, are mediated primarily by mast cell-derived histamine¹¹. The consequences of histamine release include receptor-mediated smooth muscle cell contraction in the gastrointestinal and respiratory tracts, sensory nerve stimulation, vasodilation, plasma extravasation, and cellular recruitment causing to development of urticarial lesions⁹.

Bilastine is a histamine antagonist with selective peripheral H₁-receptor antagonist affinity. It interferes with histamine action on sensory neurons and small blood vessels, directly downregulating allergic inflammation.

Bilastine displays following pharmacodynamic properties.

It exerts a potent and specific H₁- antihistamine activity. It is non-sedating, long-acting histamine antagonist.

• Superior potency: Bilastine offers potency superior to that of fexofenadine¹².
• High specificity and affinity: The affinity of bilastine for the H₁-receptor is 3 and 6 times higher than that for cetirizine and fexofenadine respectively. It shows high specificity for H₁ receptors. Additionally, it is found to have no significant antagonist activity at a diverse range of 30 other receptors: H₂, H₃, and H₄, 5-HT₂A, bradykinin B₁, leukotriene D₄, N-type voltage-dependent calcium receptors, ?1- and ?2-adrenoceptors, and M₁–M₅ muscarinic receptors. Thus, bilastine does not have anticholinergic side effects like dry mouth, urinary retention and constipation.
• Anti-inflammatory activity: The anti-inflammatory activity of bilastine has been shown by its ability to inhibit the release histamine, IL-4 and TNF-? in human mast cell line cultures.
• Negligible sedation: Bilastine has been shown to have high affinity for the p-gP efflux pump and lowest occupancy on CNS H₁ receptors this effect restricts transit across the blood–brain barrier and limits the potential for sedation¹³.

Pharmacokinetics⁹

Children

Pharmacokinetic (PK) data were obtained in a Phase II study which characterised PK of bilastine through population modelling of data from a limited sampling confirmatory clinical trial in children with allergic rhinoconjunctivitis and urticaria¹⁴.

Children (n=31) were administered with bilastine 10 mg orodispersible tablets once daily.

Pharmacokinetic analysis of plasma concentration data showed that the paediatric dose of bilastine 10 mg once daily results in systemic exposure equivalent to that seen after a 20 mg dose in adults and adolescents, with the mean AUC value being 1,014 ng* x hr/mL for children 6 to 11 years of age. These results were largely below the safety threshold based on data from 80 mg once-daily dose in adults in accordance with the drug safety profile.

The employed extrapolation approach appropriately characterized renal clearance, the primary elimination pathway of bilastine, as well as volume of distribution in children below 12 years and could consequently be used for dose selection in this pediatric patient population. In the specific case of bilastine, the simplicity of its PK behaviour (highly soluble product, linear PK, well known active transport, no metabolism, renal clearance) along with the wide safety margin of the product facilitated the suitability of the selected dose in pediatrics using a reduced trial for confirmation purposes.

These results confirmed the choice of bilastine 10 mg once daily as the appropriate therapeutic dose for the paediatric population in the age range of 6 to 11 years with a body weight of at least 20 kg.

Pharmacokinetics⁹

Adolescents

No pharmacokinetic data are available in adolescents

2 to 17 years of age) as the extrapolation from adult data was deemed appropriate for this product.

In adults, bilastine is rapidly absorbed after oral administration with a time to maximum plasma concentration of around 1.3 hours. No accumulation was observed. The mean value of bilastine oral bioavailability is 61%.

• Rapid onset of action: Its onset of antihistaminic action was found within ~30 minutes post-dose in adults with histamine induced flare reaction¹⁵. In studies with adult patients with allergic rhinitis, bilastine has shown rapid onset of action within 45 minutes which was faster than fexofenadine (1hour)¹⁶.

The onset of action of bilastine 20 mg was faster than that of fexofenadine and the inhibitory effect on TNSS was relatively greater than that of fexofenadine¹⁵.

At therapeutic doses bilastine is 84–90% bound to plasma proteins. In vitro and in vivo studies have shown that bilastine is a substrate of p-gp and OATP. Bilastine does not appear to be a substrate of the transporter BCRP (BREAST cancer resistance proteins) or renal transporters OCT2, OAT1 and OAT3.

Based on in vitro studies, bilastine is not expected to inhibit the following transporters in the systemic circulation: P-gp, MRP2, BCRP, BSEP, OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and NTCP, since only mild inhibition was detected for P-gp, OATP2B1 and OCT1, with an estimated IC₅₀ ≥ 300 ?M, much higher than the calculated clinical plasma Cmax and, therefore, these interactions will not be clinically relevant. However, based on these results, inhibition by bilastine of transporters present in the intestinal mucosa, e.g. P-gp, cannot be excluded.

• Prolonged duration of action: Prolonged drug- H₁ receptor residence time correlates with duration of antagonism. Bilastine has 100-fold higher residence time compared to first generation antihistamines¹⁷. It has longer residence time of 73 mins compared to fexofenadine (60 mins) and diphenhydramine (0.41 min).

It shows 60-70% H1 receptor antagonism 24 hours post dose, even after decrease in plasma concentration below pharmacologically active concentration.

Bilastine has been found to have longer duration of action of 26 hours compared to fexofenadine⁹.

Bilastine was significantly more active than fexofenadine between 22 and 26 h after dosing suggesting a longer duration of action¹⁸.

• Low potential for drug interaction: Bilastine does not interact significantly, either as an inhibitor or as an inducer, with the CYP enzyme system in vitro and it does not undergo significant metabolism in humans. Thus it has low potential for drug interaction⁴. Additionally, bilastine does not alter cardiac safety on co-administration with CYP450 or p-gP inhibitors⁹.

In a mass-balance study performed in healthy volunteers, after administration of a single dose of 20 mg 14C-Bilastine, almost 95% of the administered dose was recovered in urine (28.3%) and faeces (66.5%) as unchanged bilastine, confirming that bilastine is not significantly metabolised in humans. The mean elimination half-life calculated in healthy volunteers was 14.5 hours.

Bilastine presents linear pharmacokinetics in the dose range studied (5–220 mg), with a low interindividual variability.

Indications, Dosage and Administration

Indications¹⁹

Bilastine oral solution is indicated for symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria in children aged 6 to 11 years with a body weight of at least 20 kg.

Dosage¹⁹

The recommended dose in children 6 to 11 years of age with a body weight of at least 20 kg is 10 mg bilastine (4 mL of oral solution) once daily.

Use of bilastine in children under 6 years of age and under 20 kg is limited due to the lack of sufficient clinical evidence.

Special Population¹⁹

Renal Impairment

The safety and efficacy of bilastine in renally impaired children have not been established.

Studies conducted in adults in special risk groups (renally impaired patients) indicate that it is not necessary to adjust the dose of bilastine in adults.

Hepatic Impairment

The safety and efficacy of bilastine in hepatically impaired children have not been established.

There is no clinical experience in adult patients with hepatic impairment. However, since bilastine is not metabolized and is eliminated as unchanged in urine and faeces, hepatic impairment is not expected to increase systemic exposure above the safety margin in adult patients. Therefore, no dosage adjustment is required in adult patients with hepatic impairment.

Method of Administration¹⁹

The liquid oral solution should be taken one hour before or two hours after intake of food or fruit juice.

Duration of treatment¹⁹

For allergic rhino-conjunctivitis the treatment should be limited to the period of exposure to allergens. For seasonal allergic rhinitis treatment can be discontinued after the symptoms have resolved and can be reinitiated upon their reappearance. In perennial allergic rhinitis, continued treatment may be proposed to the patients during the allergen exposure periods. For urticaria the duration of treatment depends on the type, duration and course of the complaints.

Contraindications¹⁹

Bilastine oral solution is contraindicated in patients who have hypersensitivity to the active substance or to any of the excipients.

Clinical Efficacy

Adolescents (12 to 17 years of age) were included in the clinical development. 128 adolescents received bilastine during the clinical Studies (81 in double-blind studies in allergic rhinoconjunctivitis). A further 116 adolescent subjects were randomised to active comparators or placebo.

In clinical trials performed in adult and adolescents (12-17 years) with allergic rhinoconjunctivitis (seasonal and perennial), bilastine 20 mg administered once daily for 14-28 days, was effective in relieving symptoms such as sneezing, nasal discharge, nasal itching, nasal congestion, ocular itching, tearing and ocular redness. Bilastine effectively controlled symptoms for 24 hours.

In clinical trials performed in adults with chronic idiopathic urticaria, bilastine 20 mg, administered once daily for 28 days, was effective in relieving the itching intensity and the number and size of wheals, as well as the patients discomfort due to urticaria. Patients improved their sleep conditions and their quality of life.

No differences in efficacy and safety between adults and adolescents were seen.

According to guidelines, the proved efficacy in adults and adolescents can be extrapolated to children, having demonstrated that the systemic exposure with 10 mg bilastine in children from 6 to 11 years of age with a body weight of at least 20 kg is equivalent to the exposure in adults with 20 mg bilastine. As the pathophysiology of allergic rhinoconjunctivitis and urticaria is the same for all age groups, the extrapolation from adult and adolescent data is deemed appropriate for this product¹⁹.

Safety and Tolerability

Warnings and Precautions¹⁹

Efficacy and safety of bilastine in children under 2 years of age have not been established and there is little clinical experience in children aged 2 to 5 years; therefore, bilastine should not be used in these age groups.

In patients with moderate or severe renal impairment co-administration of bilastine with P-glycoprotein (p-gp) inhibitors, e.g. ketoconazole, erythromycin, cyclosporine, ritonavir or diltiazem, may increase plasmatic levels of bilastine and, therefore, increase the risk of adverse effects of bilastine. Therefore, co-administration of bilastine and P-gp inhibitors should be avoided in patients with moderate or severe renal impairment.

Drug Interactions¹⁹

Interaction studies have only been performed in adults. As there is no clinical experience regarding the interaction of bilastine with other medicinal products, food or fruit juices in children, the results obtained in adult interactions studies should be at present taken into consideration when prescribing bilastine to children. There is no clinical data in children to state whether changes to the AUC or Cmax due to interactions affect the safety profile of bilastine.

Safety in Children and Adolescents

A phase III, multicentre, double blind, controlled study was carried out in children aged 2 to 11 years with allergic rhinoconjunctivitis and chronic urticaria to assess the safety and tolerability of bilastine².

The total population of 509 children encompassed: 479 subjects with allergic rhinoconjunctivitis and 30 subjects diagnosed with chronic urticaria. 260 children received bilastine, 252 (96.9%) for allergic rhinoconjunctivitis and 8 (3.1%) for chronic urticaria. In analogy, 249 children received placebo, 227 (91.2%) for allergic rhinoconjunctivitis and 22 (8.8%) for chronic urticaria.

The safety profile of once daily bilastine 10 mg orodispersible tablet (n = 260) was similar to placebo (n = 249). The percentage of children (2 to 11 years of age) who reported AEs (Adverse Effects) after treatment was comparable with patients receiving placebo (68.5% versus 67.5%).

The related AEs most commonly (frequency (≥1/100 to <1/10)) reported by 291 children receiving bilastine during clinical trials (^#260 children exposed in the clinical safety study, 31 children exposed in the pharmacokinetic study) were headache, allergic conjunctivitis, rhinitis and abdominal pain.

These related adverse events occurred with a comparable frequency in children receiving either bilastine 10 mg or placebo. The frequency reported was 2.1% versus 1.2% for headache; 1.0% versus 1.2% for abdominal pain; 1.4% versus 2.0% for allergic conjunctivitis, and 1.0% versus 1.2% for rhinitis.

• Minimal Sedation: Both bilastine 10 mg and placebo showed a slight decrease in somnolence and sedation scores on the Paediatric Sleep Questionnaire during this study, with no statistically significant differences between treatment groups.

In controlled clinical trials conducted in adult patients, similar CNS safety profile was observed. Bilastine at doses of up to 40 mg q.d. did not affect psychomotor performance in clinical trials and did not affect driving performance in a standard driving test. In another study, no sleepiness, vigilance or impaired performance on complex tasks related to flying up to 6 hours at 8000 ft cabin altitude was reported after treatment with bilastine 20 mg.^20,21

• Cardiac safe: In these children aged 2 to 11 years, no significant differences in QTc were observed following 10 mg bilastine daily compared with placebo. Similar results have been observed in clinical trials in adults as well. Clinically relevant prolongation of QTc interval or any other cardiovascular effect has not been observed even at therapeutic and sub-therapeutic doses of (20 mg to 200 mg daily) (10 times the clinical dose). Bilastine is the only commercially available AH that has been tested using the stringent ICH E/14 criteria⁶. Bilastine 10 mg was found to have a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria.

During the clinical development, the frequency, type and severity of adverse reactions in adolescents (12 to 17 years of age) were the same as observed in adults. The information collected in this population (adolescents) during the postmarketing surveillance has confirmed clinical trial findings.

No weight gain has been observed in any of the studied population.

Overdose¹⁹

There is no data for overdose in children.

Information regarding acute overdose of bilastine is retrieved from the experience of clinical trials conducted during the development and the postmarketing surveillance. In clinical trials, after administration of bilastine at doses 10 to 11 times the therapeutic dose (220 mg as single dose; or 200 mg/day for 7 days) to 26 adult healthy volunteers, frequency of treatment-emergent AEs was two times higher than with placebo.

The AEs most frequently reported were dizziness, headache and nausea. No serious AEs and no significant prolongation in the QTc interval were reported. The information collected in the postmarketing surveillance was consistent with that reported in clinical trials.

Critical evaluation of bilastine's multiple-dose (100 mg x 4 days) effect on ventricular repolarisation by a ‘thorough QT/QTc crossover study’ involving 30 healthy adult volunteers did not show significant QTc prolongation. In the event of overdose, symptomatic and supportive treatment is recommended.

There is no known specific antidote to bilastine.

Highlights

Bilastine is a modern, second generation antihistamine available in 100 countries worldwide and recently approved for use in children between 6 to 11 years of age. It has the highest number of properties of an ideal antihistamine (with highest score of 10) as recommended by ARIA guidelines which are as follows:

A distinct chemical entity and is not structurally derived from any other currently available antihistamines.

Highly selective at the H1 receptor. It has affinity 3 times and 6 times more than cetirizine and fexofenadine respectively and has no affinity to 30 other receptors.

Anti-inflammatory properties in addition to antihistaminic properties.

Rapid onset of action within 30 minutes to 45 minutes.

Longer residence time at H1 receptors (73 minutes vs 60 minutes for fexofenadine) translating into prolonged duration of action for at-least 26 hours.

Low potential for drug interactions

No dosage adjustments required for patients with renal and hepatic impairment.

Effective in reducing the nasal as well as eye symptoms of allergic rhinitis and in relieving itching intensity and number of size of wheals*

Good safety and tolerability profile across all age groups in children.

Negligible CNS H₁ receptor occupancy, thus minimally sedating.

Cardiac safe and the only commercially available AH that has been tested using the stringent ICH E/14 criteria.

*Extrapolated from adult and adolescent clinical data as similar disease pathology as well as equivalent systemic exposure observed in all age groups.

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