4.1. Therapeutic indications

Symptomatic treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria.

Ilaxten is indicated in adults and adolescents (12 years of age and over).

4.2. Posology and method of administration

Posology

Adults and adolescents (12 years of age and over)

20 mg bilastine (1 tablet) once daily for the relief of symptoms of allergic rhinoconjunctivitis (SAR and PAR) and urticaria.

The tablet should be taken one hour before or two hours after intake of food or fruit juice (see section 4.5).

Duration of treatment

For allergic rhino-conjunctivitis the treatment should be limited to the period of exposure to allergens. For seasonal allergic rhinitis treatment could be discontinued after the symptoms have resolved and 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.

Special populations

Elderly

No dosage adjustments are required in elderly patients (see sections 5.1 and 5.2).

Renal impairment

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 (see section 5.2).

Hepatic impairment

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 (see section 5.2).

Paediatric population

- Children 6 to 11 years of age with a body weight of at least 20 kg

Bilastine 10 mg orodispersible tablets and bilastine 2.5 mg/mL oral solution are appropriate for administration to this population.

- Children under 6 years of age and under 20 kg

Currently available data are described in section 4.4, 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. Therefore bilastine should not be used in this age group.

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

Method of administration

Oral use.

The tablet is to be swallowed with water. It is recommended to take the daily dose in one single intake.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Paediatric population

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 coadministration of bilastine with P-glycoprotein inhibitors, such as 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, coadministration of bilastine and P-glycoprotein inhibitors should be avoided in patients with moderate or severe renal impairment.

Cases of Electrocardiogram QT prolonged have been reported in patients using bilastine (see sections 4.8, 4.9 and 5.1). Medicinal products that cause QT/QTC prolongation are suspected to increase the risk of Torsade de pointes.

Therefore, caution should be exercised when administering bilastine to patients who are at increased risk of experiencing QT/QTC-prolongation. This includes patients with a history of cardiac arrhythmias; patients with hypokalemia, hypomagnesaemia, hypocalcemia; patients with known prolongation of the QT interval or significant bradycardia; patients with concomitant use of other medicinal products associated with QT/QTC-prolongation.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium free'.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults and are summarised below.

Interaction with food: Food significantly reduces the oral bioavailability of bilastine by 30%.

Interaction with 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 (see section 5.2). 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.

Interaction with 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 interaction with intestinal efflux transporters, since bilastine is substrate for P-gp and not metabolised (see section 5.2). These changes do not appear to affect the safety profile 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.

Interaction with 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 (see section 5.2), and does not appear to affect the safety profile of bilastine.

Interaction with 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.

Interaction with lorazepam: Concomitant intake of bilastine 20 mg o.d. and lorazepam 3 mg o.d. for 8 days did not potentiate the depressant CNS effects of lorazepam.

Paediatric population

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 are no clinical data in children to state whether changes to the AUC or Cmax due to interactions affect the safety profile of bilastine.

4.6. Fertility, pregnancy and lactation

Pregnancy: There are no or limited amount of data from the use of bilastine in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Ilaxten during pregnancy.

Breast-feeding: The excretion of bilastine in milk has not been studied in humans. Available pharmacokinetic data in animals have shown excretion of bilastine in milk (see section 5.3). A decision on whether to continue/discontinue breast-feeding or to discontinue/abstain from Ilaxten therapy must be made taking into account the benefit of breast-feeding for the child and the benefit of bilastine therapy for the mother.

Fertility: There are no or limited amount of clinical data. A study in rats did not indicate any negative effect on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

A study performed in adults to assess the effects of bilastine on the ability to drive demonstrated that treatment with 20 mg did not affect the driving performance. However, as the individual response to the medicinal product may vary, patients should be advised not to drive or use machines until they have established their own response to bilastine.

4.8. Undesirable effects

Summary of safety profile in adults and adolescent patients

The incidence of adverse events in adult and adolescent patients suffering from allergic rhinoconjunctivitis or chronic idiopathic urticaria treated with 20 mg bilastine in clinical trials was comparable with the incidence in patients receiving placebo (12.7% versus 12.8%).

The phase II and III clinical trials performed during the clinical development included 2525 adult and adolescent patients treated with different doses of bilastine, of which 1697 received bilastine 20 mg. In these trials 1362 patients received placebo. The ADRs most commonly reported by patients receiving 20 mg bilastine for the indication of allergic rhinoconjunctivitis or chronic idiopathic urticaria were headache, somnolence, dizziness, and fatigue. These adverse events occurred with a comparable frequency in patients receiving placebo.

Tabulated summary of adverse reactions in adult and adolescent patients

ADRs at least possibly related to bilastine and reported in more than 0.1% of the patients receiving 20 mg bilastine during the clinical development (N = 1697) 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

20 mg

N = 1697

All Bilastine

Doses

N = 2525

Placebo

N = 1362

Frequency

Adverse reaction

Infections and infestations

Uncommon

Oral herpes

2 (0.12%)

2 (0.08%)

0 (0.0%)

Metabolism and nutrition disorders

Uncommon

Increased appetite

10 (0.59%)

11 (0.44%)

7 (0.51%)

Psychiatric disorders

Uncommon

Anxiety

6 (0.35%)

8 (0.32%)

0 (0.0%)

Insomnia

2 (0.12%)

4 (0.16%)

0 (0.0%)

Nervous system disorders

Common

Somnolence

52 (3.06%)

82 (3.25%)

39 (2.86%)

Headache

68 (4.01%)

90 (3.56%)

46 (3.38%)

Uncommon

Dizziness

14 (0.83%)

23 (0.91%)

8 (0.59%)

Ear and labyrinth disorders

Uncommon

Tinnitus

2 (0.12%)

2 (0.08%)

0 (0.0%)

Vertigo

3 (0.18%)

3 (0.12%)

0 (0.0%)

Cardiac disorders

Uncommon

Right bundle branch block

4 (0.24%)

5 (0.20%)

3 (0.22%)

Sinus arrhythmia

5 (0.30%)

5 (0.20%)

1 (0.07%)

Electrocardiogram QT prolonged*

9 (0.53%)

10 (0.40%)

5 (0.37%)

Other ECG abnormalities

7 (0.41%)

11 (0.44%)

2 (0.15%)

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea

2 (0.12%)

2 (0.08%)

0 (0.0%)

Nasal discomfort

2 (0.12%)

2 (0.08%)

0 (0.0%)

Nasal dryness

3 (0.18%)

6 (0.24%)

4 (0.29%)

Gastrointestinal disorders

Uncommon

Upper abdominal pain

11 (0.65%)

14 (0.55%)

6 (0.44%)

Abdominal pain

5 (0.30%)

5 (0.20%)

4 (0.29%)

Nausea

7 (0.41%)

10 (0.40%)

14 (1.03%)

Stomach discomfort

3 (0.18%)

4 (0.16%)

0 (0.0%)

Diarrhoea

4 (0.24%)

6 (0.24%)

3 (0.22%)

Dry mouth

2 (0.12%)

6 (0.24%)

5 (0.37%)

Dyspepsia

2 (0.12%)

4 (0.16%)

4 (0.29%)

Gastritis

4 (0.24%)

4 (0.16%)

0 (0.0%)

Skin and subcutaneous tissue disorders

Uncommon

Pruritus

2 (0.12%)

4 (0.16%)

2 (0.15%)

General disorders and administration site conditions

Uncommon

Fatigue

14 (0.83%)

19 (0.75%)

18 (1.32%)

Thirst

3 (0.18%)

4 (0.16%)

1 (0.07%)

Improved pre-existing condition

2 (0.12%)

2 (0.08%)

1 (0.07%)

Pyrexia

2 (0.12%)

3 (0.12%)

1 (0.07%)

Asthenia

3 (0.18%)

4 (0.16%)

5 (0.37%)

Investigations

Uncommon

Increased gamma-glutamyltransferase

7 (0.41%)

8 (0.32%)

2 (0.15%)

Alanine aminotransferase increased

5 (0.30%)

5 (0.20%)

3 (0.22%)

Aspartate aminotransferase increased

3 (0.18%)

3 (0.12%)

3 (0.22%)

Blood creatinine increased

2 (0.12%)

2 (0.08%)

0 (0.0%)

Blood triglicerides increased

2 (0.12%)

2 (0.08%)

3 (0.22%)

Increased weight

8 (0.47%)

12 (0.48%)

2 (0.15%)

*Electrocardiogram QT prolonged have also been reported post marketing.

Frequency not known (cannot be estimated from the available data): Palpitations, tachycardia, hypersensitivity reactions (such as anaphylaxis, angioedema, dyspnoea, rash, localised oedema/local swelling, and erythema), and vomiting have been observed during the post-marketing period.

Description of selected adverse reactions in adult and adolescent patients

Somnolence, headache, dizziness and fatigue were observed either in patients treated with bilastine 20 mg or with placebo. The frequency reported was 3.06 % vs. 2.86% for somnolence; 4.01% vs. 3.38% for headache; 0.83% vs. 0.59% for dizziness, and 0.83% vs. 1.32% for fatigue.

The information collected during the post-marketing surveillance has confirmed the safety profile observed during the clinical development.

Summary of safety profile in paediatric population

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

The percentage of children (2-11 years) which reported adverse events (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 (2-11 years) 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 adverse reactions in paediatric population

AEs at least possibly related to bilastine and reported in more than 0.1% of children (2-11 years) 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

Adverse Reaction

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 adverse reactions in paediatric population

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% vs. 1.2% for headache; 1.0% vs. 1.2% for abdominal pain; 1.4% vs. 2.0% for allergic conjunctivitis, and 1.0% vs. 1.2% for rhinitis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Information regarding acute overdose of bilastine is retrieved from the experience of clinical trials conducted during the development and the post-marketing 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 adverse events was two times higher than with placebo. The adverse reactions most frequently reported were dizziness, headache and nausea. No serious adverse events and no significant prolongation in the QTc interval were reported. The information collected in the post-marketing surveillance is consistent with that reported in clinical trials.

Critical evaluation of bilastine's multiple dose (100 mg x 4 days) effect on ventricular repolarization by a “thorough QT/QTc cross-over study” involving 30 healthy adult volunteers did not show significant QTc prolongation.

There are no data for overdose in children.

In the event of overdose symptomatic and supportive treatment is recommended.

There is no known specific antidote to bilastine.