For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only
Qualitative and Quantitative Composition
Each mL contains:
Bilastine ………….…2.5mg
In a flavoured syrup base
Dosage Form and Strength
Liquid Oral Solution, 2.5mg/mL
Clinical Particulars
Therapeutic Indications
Symptomatic treatment of allergic rhinoconjunctivitis (seasonal and perennial) and urticaria.Bilastine is indicated in children aged 6 to 11years with a body weight of at least 20kg.
Posology and Method of Administration
Children 6 to 11 Years of Age with a Body Weight of at least 20kg
10 mgbilastine (4 ml of oral solution) once daily for the relief of symptoms of allergic rhinoconjunctivitis (Seasonal allergic rhinitis and perennial allergic rhinitis) and urticaria.
Route of Administration
To be taken orally.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Special Warnings and Precautions for Use
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 Interactions
Interaction studies have only been performed in adults and are summarised below.
Food
Food significantly reduces the oral bioavailability of bilastine 20mg tablets by 30% and that of bilastine 2.5mg/ml oral solution by 20%
Grapefruit Juice
Concomitant intake of bilastine 20 mg and grapefruit juice decreased bilastine bioavailability by 30%. This effect may also apply to other fruit juices. The degree of bioavailability decrease may vary between producers and fruits. The mechanism for this interaction is an inhibition of OATP1A2, an uptake transporter, for which bilastine is a substrate.Medicinal products that are substrates or inhibitors of OATP1A2, such as ritonavir or rifampicin, may likewise have the potential to decrease plasma concentrations of bilastine.
Ketoconazole or Erythromycin
Concomitant intake of bilastine 20 mg o.d. and ketoconazole 400 mg o.d. or erythromycin 500 mg t.i.d. increased bilastine AUC 2-fold and Cmax 2-3 fold. These changes can be explained by its interaction with intestinal efflux transporters, since bilastine is a substrate for P-gp and not metabolised.These changes do not appear to affect the safety profiles of bilastine and ketoconazole or erythromycin, respectively. Other medicinal products that are substrates or inhibitors of P-gp, such as cyclosporine, may likewise have the potential to increase plasma concentrations of bilastine.
Diltiazem
Concomitant intake of bilastine 20 mg o.d. and diltiazem 60 mg o.d. increased Cmax of bilastine by 50%. This effect can be explained by interaction with intestinal efflux transporters and does not appear to affect the safety profile of bilastine.
Alcohol
The psychomotor performance after concomitant intake of alcohol and 20 mg bilastine o.d. was similar to that observed after intake of alcohol and placebo.
Lorazepam
Concomitant intake of bilastine 20 mg o.d. and lorazepam 3 mg o.d. for 8 days did not potentiate the depressant central nervous system (CNS) effects of lorazepam.
Paediatric Patients
No interaction studies have been performed in children with bilastine oral solution. 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 are no clinical data in children to state whether changes to the AUC or Cmax due to interactions affect the safety profile of bilastine.
Use in Special Populations
Paediatric Patients
Children Under 6 Years of Age and Under 20 kg
The safety and efficacy of bilastine in children under 6 years of age and under 20kg have not yet been established.
Renal Impairment
The safety and efficacy of bilastine in renally impaired children have not been established. Studies conducted in adults in special risk group (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 both adult and paediatric patients with hepatic impairment. However, since bilastine is not metabolized and is eliminated as unchanged in urine and feces, hepatic impairment is not expected to increase systemic exposure above the safety margin in adult patients. Therefore, no dose adjustment is required in adult patients with hepatic impairment.
Undesirable Effects
Summary of Safety Profile in Paediatric Patients
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.
The percentage of children (2 to 11 years of age) who reported AEs after treatment with bilastine 10 mg for allergic rhinoconjunctivitis or chronic idiopathic urticaria in a 12-week controlled clinical trial was comparable with patients receiving placebo (68.5% versus 67.5%).
The related AEs most commonly reported by 291 children (2 to 11 years of age) receiving bilastine (orodispersible tablet formulation) 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 249 patients receiving placebo.
Tabulated Summary of AEs in Paediatric Patients
AEs at least possibly related to bilastine and reported in more than 0.1% of children (2 to 11 years of age) receiving bilastine during the clinical development are tabulated below.
Frequencies are assigned as follows:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Rare, very rare and reactions with unknown frequency have not been included in the table.
|
System Organ Class |
Bilastine 10 mg (n=291)# |
Placebo (n=249) |
|
|
Frequency |
AEs |
||
|
Infections and infestations |
|||
|
Common |
Rhinitis |
3 (1.0%) |
3 (1.2%) |
|
Nervous system disorders |
|||
|
Common |
Headache |
6 (2.1%) |
3 (1.2%) |
|
Uncommon |
Dizziness |
1 (0.3%) |
0 (0.0%) |
|
Loss of consciousness |
1 (0.3%) |
0 (0.0%) |
|
|
Eye disorders |
|||
|
Common |
Allergic conjunctivitis |
4 (1.4%) |
5 (2.0%) |
|
Uncommon |
Eye irritation |
1 (0.3%) |
0 (0.0%) |
|
Gastrointestinal disorders |
|||
|
Common |
Abdominal pain/Upper abdominal pain |
3 (1.0 %) |
3 (1.2 %) |
|
Uncommon |
Diarrhoea |
2 (0.7 %) |
0 (0.0 %) |
|
Nausea |
1 (0.3 %) |
0 (0.0 %) |
|
|
Lip swelling |
1 (0.3 %) |
0 (0.0 %) |
|
|
Skin and subcutaneous tissue disorders |
|||
|
Uncommon |
Eczema |
1 (0.3 %) |
0 (0.0 %) |
|
Urticaria |
2 (0.7 %) |
2 (0.8 %) |
|
|
General disorders and administration site conditions |
|||
|
Uncommon |
Fatigue |
2 (0.7%) |
0 (0.0%) |
# 260 children exposed in the clinical safety study, 31 children exposed in the pharmacokinetic study
Description of Selected AEs in Paediatric Patients
Headache, abdominal pain, allergic conjunctivitis and rhinitis were observed either in children treated with bilastine 10 mg or with 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.
Reporting of Suspected Side Effects
If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report on 1800 267 7779 (Cipla number). By reporting sideeffects, you can help provide more information on the safety of this product.
Overdose
There are 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.
Pharmacological Properties
Mechanism of Action
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
Pharmacodynamic Properties
It exerts a potent and specific H1‑antihistamine activity. It has high specificity for H1‑receptors. It is a non-sedating, long-acting histamine antagonist with selective peripheral H1-receptor antagonist affinity and no affinity for muscarinic receptors. The affinity for the H1-receptor is 3 and 6 times higher than for cetirizine and fexofenadine. Additional in vitro trials demonstrated that bilastine had no significant antagonist activity at a diverse range of other receptors: H2, H3, and H4, 5-HT2A, bradykinin B1, leukotriene D4, N-type voltage-dependent calcium receptors, α1- and β2-adrenoceptors, and M1–M5 muscarinic receptors
Clinical Efficacy
The efficacy of bilastine has been studied in adults and adolescents. 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. The extrapolation from adult and adolescent data is deemed appropriate for this product as the pathophysiology of allergic rhinoconjunctivitis and urticaria is the same for all age groups
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 co-administered 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 of age) included in Phase II and III studies showed no difference in efficacy or safety with respect to younger patients. A post-authorisation study in 146 elderly patients showed no differences in the safety profile with respect to the adult population.
Clinical Safety
In a 12-week controlled clinical trial with children aged 2 to 11 years (total of 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 AEs 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 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.
Paediatric Population
The European Medicines Agency has waived the obligation to submit the results of studies with Bilastine in all subsets of the paediatric population below 2years of age.
Pharmacokinetic Properties
Absorption
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%.
Distribution
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 μM, much higher than the calculated clinical plasma Cmaxand, 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.
Metabolism
Bilastine did not induce or inhibit activity of CYP450 isoenzymes in in vitro studies.
Elimination
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.
Linearity
Bilastine presents linear pharmacokinetics in the dose range studied (5–220 mg), with a low interindividual variability.
Pharmaceutical Particulars
Incompatibilities
Not applicable.
Shelf-Life
See on pack.
Packaging Information
60 ml amber colour pet bottle
Storage and Handling Instructions
Store below 30◦Cin a dark and dry place
Details of the Manufacturer
Manufactured by
Synokem Pharmaceuticals Ltd.
Plot No. 35-36, Sector-6A, Integrated Industrial Estate (SIDCUL), Ranipur,
(BHEL), Haridwar-249403 (Uttarakhand)
Marketed by
Cipla Ltd.
Registered Office:
Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel,
Mumbai – 400 013, India
Details of Permission or License Number with Date
MF/SND/19/000014 dated 10-12-2019
Date of Revision
16-12-2019