Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Menarini International Operations Luxembourg S.A., 1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg
Pharmacotherapeutic group: Antihistamines for systemic use, other antihistamines for systemic use
ATC code: R06AX29
Bilastine is a non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist affinity and no affinity for muscarinic receptors.
Bilastine inhibited histamine-induced wheal and flare skin reactions for 24 hours following single doses.
In clinical trials performed in adult and adolescent patients 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 two clinical trials performed in patients 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 clinically relevant prolongation of QTc interval or any other cardiovascular effect has been observed in the clinical trials performed with Bilastine, even at doses of 200 mg daily (10 times the clinical dose) for 7 days in 9 subjects, or even when coadministered with P-gp inhibitors, such as ketoconazole (24 subjects) and erythromycin (24 subjects). Additionally a thorough QT study including 30 volunteers has been performed.
In controlled clinical trials at the recommended dose of 20 mg once daily, the CNS safety profile of bilastine was similar to placebo and the incidence of somnolence was not statistically different from placebo. 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.
Elderly patients (≥65 years) included in phase II and III studies showed no difference in efficacy or safety with respect to younger patients. A post-authorization study in 146 elderly patients showed no differences in the safety profile with respect to the adult population.
Adolescents (12 years to 17 years) were included in the clinical development. 128 adolescents received bilastine during the clinical studies (81 in double blind studies in allergic rhino-conjunctivitis). A further 116 adolescent subjects were randomised to active comparators or placebo. 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 with a body weight of at least 20 kg is equivalent to the exposure in adults with 20 mg bilastine (see section 5.2). The extrapolation from adult and adolescent data is deemed appropriate for this product as the pathophysiology of allergic rhino-conjunctivitis and urticaria is the same for all age groups.
In a 12-week controlled clinical trial with children aged 2-11 years (total 509 children, 260 treated with bilastine 10 mg: 58 at age 2 to <6 years, 105 at age 6 to <9 years and 97 at 9 to <12 years and 249 treated with placebo: 58 at age 2 to <6 years, 95 at age 6 to <9 years and 96 at 9 to <12 years), at the recommended paediatric dose of 10 mg once daily, the safety profile of bilastine (n=260) was similar to placebo (n=249), with adverse drug reactions seen in 5.8% and 8.0% of patients taking bilastine 10 mg and placebo, respectively. 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 these children aged 2 to 11 years, no significant differences in QTc were observed following 10 mg bilastine daily compared with placebo. Quality of Life questionnaires specific for children with allergic rhinoconjunctivitis or chronic urticaria showed a general increase in scores over 12 weeks with no statistically significant difference between the bilastine and placebo arms. The total population of 509 children encompassed: 479 subjects with allergic rhinoconjunctivitis and 30 subjects diagnosed of 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 European Medicines Agency has waived the obligation to submit the results of studies with bilastine in all subsets of the paediatric population below 2 years of age (see section 4.2 for information on paediatric use).
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%.
In vitro and in vivo studies have shown that bilastine is a substrate of P-gp (see section 4.5 “Interaction with ketoconazole, erythromycin and diltiazem”) and OATP (see section 4.5 “Interaction with grapefruit juice”). Bilastine does not appear to be a substrate of the transporter BCRP 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 µM, 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.
At therapeutic doses bilastine is 84-90% bound to plasma proteins.
Bilastine did not induce or inhibit activity of CYP450 isoenzymes in in vitro studies.
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 metabolized in humans. The mean elimination half-life calculated in healthy volunteers was 14.5 h.
Bilastine presents linear pharmacokinetics in the dose range studied (5 to 220 mg), with a low interindividual variability.
In a study in subjects with renal impairment the mean (SD) AUC0-∞ increased from 737.4 (± 260.8) ngxhr/ml in subjects without impairment (GFR: >80 ml/min/1.73 m²) to: 967.4 (± 140.2) ngxhr/ml in subjects with mild impairment (GFR: 50-80 ml/min/1.73 m²), 1384.2 (± 263.23) ngxhr/ml in subjects with moderate impairment (GFR: 30 - <50 ml/min/1.73 m²), and 1708.5 (± 699.0) ngxhr/ml in subjects with severe impairment (GFR: <30 ml/min/1.73 m²). Mean (SD) half-life of bilastine was 9.3 h (± 2.8) in subjects without impairment, 15.1 h (± 7.7) in subjects with mild impairment, 10.5 h (± 2.3) in subjects with moderate impairment and 18.4 h (± 11.4) in subjects with severe impairment. Urinary excretion of bilastine was essentially complete after 48-72 h in all subjects. These pharmacokinetic changes are not expected to have a clinically relevant influence on the safety of bilastine, since bilastine plasma levels in patients with renal impairment are still within the safety range of bilastine.
There are no pharmacokinetic data in subjects with hepatic impairment. Bilastine is not metabolized in human. Since the results of the renal impairment study indicate renal elimination to be a major contributor in the elimination, biliary excretion is expected to be only marginally involved in the elimination of bilastine. Changes in liver function are not expected to have a clinically relevant influence on bilastine pharmacokinetics.
Only limited pharmacokinetic data are available in subjects older than 65 years. No statistically significant differences have been observed with regard to PK of bilastine in elderly aged over 65 years compared to adult population aged between 18 and 35 years.
No pharmacokinetic data are available in adolescents (12 years to 17 years) as the extrapolation from adult data was deemed appropriate for this product.
Pharmacokinetic data in children were obtained in a Phase II pharmacokinetic study including 31 children aged 4 to 11 years with allergic rhinoconjunctivitis or chronic urticaria, administered once daily with bilastine 10 mg orodispersible tablet. Pharmacokinetic analysis of plasma concentration data showed that the pediatric dose of bilastine 10 mg once daily results in systemic exposure equivalent to that seen after a 20 mg dose in adults and adolescents, being the mean AUC value 1014 ng* x hr/mL for children 6 to 11 years. These results were largely below the safety threshold based on data from 80 mg once daily dose in adults in accordance to the drug safety profile. These results confirmed the choice of bilastine 10 mg p.o. once daily as the appropriate therapeutic dose for the paediatric population in the age range 6 to 11 years with a body weight of at least 20 kg.
Non-clinical data with bilastine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproduction toxicity studies effects of bilastine on the foetus (pre-and post-implantation loss in rats and incomplete ossification of cranial bones, sternebrae and limbs in rabbits) were only observed at maternal toxic doses. The exposure levels at the NOAELs are sufficiently in excess (>30 fold) to the human exposure at the recommended therapeutic dose.
In a lactation study, bilastine was identified in the milk of nursing rats administered a single oral dose (20 mg/kg). Concentrations of bilastine in milk were about half of those in maternal plasma. The relevance of those results for humans is unknown.
In a fertility study in rats, bilastine administered orally up to 1000 mg/kg/day did not induce any effect on female and male reproductive organs. Mating, fertility and pregnancy indices were not affected.
As seen in a distribution study in rats with determination of drug concentrations by autoradiography, bilastine does not accumulate in the CNS.
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