Composition:

Each tablet contains 20 mg of bilastine.

Inactive ingredients: Microcrystalline cellulose (Avicel PH102), sodium starch glycolate, colloidal silicon dioxide (Aerosil 200), magnesium stearate.

Pharmacodynamic:

Pharmacotherapeutic group: Antihistamines for systemic use.

Contrahistadin, bilastine, is a non-sedating, long-acting histamine antagonist with selective peripheral HI 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 rhino-conjunctivitis (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 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 wheels, as well as the patient’s 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 and erythromycin.

In controlled clinical trials at the recommended dose of 20 mg once daily, the CNS safety profile of bilastine was similar to the placebo and the incidence of somnolence was not statistically different from the 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) showed no difference in efficacy or safety concerning younger patients.

Pediatric population:

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

Pharmacokinetic:

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 Pgp and OATP.

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 IC, > 300 much higher than the calculated clinical plasma C-max 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.

Biotransformation:

Bilastine did not induce or inhibit the activity of CYP450 isoenzymes in invitro studies.

Elimination:

In a mass balance study performed in healthy volunteers, after administration of a single dose of 20 mg C-bilastine, almost 95% of the administered dose was recovered in urine (28.3%) and feces (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.

Linearity:

Bilastine presents linear pharmacokinetics in the dose range studied (5 to 220 mg), with low inter-individual variability.

Renal impairment:

In a study in subjects with renal impairment, the mean (SD) AUCmax increased from 737.4 (1260.8) ngxhr/ml in subjects without impairment (GFR: > 80 ml/min/1.73 m2) to: 967.4 (1140.2) mg.hr/ml in subjects with mild impairment (GFR: 50-80 ml/min/1.73 m2), 1384.2 (1263.23) mg.hr/ml in subjects with moderate impairment (GFR: 30 - <50 ml/min/1.73 m2), and 1708.5 (1699.0) mg.hr/ml in subjects with severe impairment (GFR: < 30 ml/min/1.73 m2). The mean (SD) half-life of bilastine was 9.3 h (12.8) in subjects without impairment, 15.1 h (17.7) in subjects with mild impairment, 10.5 h (12.3) in subjects with moderate impairment, and 18.4 h (1 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.

Hepatic impairment:

There are no pharmacokinetic data in subjects with hepatic impairment.

Bilastine is not metabolized in humans.

Since the results of the renal impairment study indicate renal elimination to be a major contributor to 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.

Elderly:

Only limited pharmacokinetic data are available in subjects older than 65 years.

No, statistically significant differences have been observed concerning the PK of bilastine in the elderly aged over 65 years compared to the adult population aged between 18 and 35 years.

Pediatric population:

No pharmacokinetic data are available in adolescents (12 years to 17 years) as the extrapolation from adult data was deemed appropriate for this product.

Therapeutic Indications:

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

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

Dosage and Administration:

Posology:

Adults and adolescents (12 years of age and over):

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

The tablet should be taken one hour before or two hours after the intake of food or fruit juice.

Special populations:

Elderly:

No dosage adjustments are required in elderly patients.

Renal impairment:

No dosage adjustment is required in patients with renal impairment.

Hepatic impairment:

There is no clinical experience in patients with hepatic impairment.

Since bilastine is not metabolized and renal clearance is its major elimination route, hepatic impairment is not expected to increase systemic exposure above the safety margin.

Therefore, no dosage adjustment is required in patients with hepatic impairment.

Pediatric population:

There is no relevant use of Contrahistadin in children aged 0 to 2 years for the indications of allergic rhino-conjunctivitis and urticaria.

The safety and efficacy in children below 12 years have not yet been established.

Duration of treatment:

For allergic rhinitis, 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 re-initiated 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.

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.

Overdose:

Information regarding acute overdose of bilastine is retrieved from the experience of clinical trials conducted during the development and the post-marketing surveillance.

After administration of bilastine at doses, 10 to 11 times the therapeutic dose (220 mg as a single dose; or 200 mg/day for 7 days) to healthy volunteer 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.

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

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

There is no known specific antidote to bilastine.

Drug-Drug Interaction:

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 the 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.

Interaction with ketoconazole or erythromycin:Concomitant intake of bilastine and ketoconazole or erythromycin increased bilastine AUC 2-fold and C-max 2-3 fold.

These changes can be explained by interaction with intestinal efflux transporters since bilastine is a substrate for P-gp and is not metabolized.

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 and diltiazem 60 mg increased C-max 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.

Interaction with alcohol: The psychomotor performance after concomitant intake of alcohol and 20 mg bilastine was similar to that observed after intake of alcohol and placebo.

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

Pediatric population:

Interaction studies have only been performed in adults.

The extent of interaction with other medicinal products and other forms of interaction is expected to be similar in the pediatric population from 12 to 17 years of age.

Precautions:

Pediatric population:

The efficacy and safety of bilastine in children under 12 years of age have not been established.

In patients with moderate or severe renal impairment co-administration 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 reactions of bilastine. Therefore, co-administration of bilastine and P-glycoprotein inhibitors should be avoided in patients with moderate or severe renal impairment.

Fertility, pregnancy, and lactation:

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

Breastfeeding: The excretion of bilastine in milk has not been studied in humans.

The decision on whether to discontinue/abstain from bilastine therapy must be made taking into account the benefit of breastfeeding for the child and the benefit of bilastine therapy for the mother.

Fertility: There is no or limited amount of clinical data for the safety profile of bilastine.

Interaction with alcohol: The psychomotor performance after concomitant intake of alcohol and 20 mg bilastine was similar to that observed after intake of alcohol and placebo.

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

Pediatric population:

Interaction studies have only been performed in adults.

The extent of interaction with other medicinal products and other forms of interaction is expected to be similar in the pediatric population from 12 to 17 years of age.

Effects on the ability to drive and use machines:

A study performed to assess the effects of bilastine on the ability to drive demonstrated that treatment with 20 mg did not affect driving performance. However, patients should be informed that very rarely some people experience drowsiness, which may affect their ability to drive or use machines.

Contraindications:

Hypersensitivity to the active substance or any of the excipients listed.

Adverse Reactions:

Tabulated summary of adverse reactions

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 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.

Frequency not known (cannot be estimated from the available data): Palpitations and tachycardia have been observed during the post-marketing period.

Description of selected adverse reactions

The most frequently reported adverse reactions were two common (somnolence and headache) and two uncommon (dizziness and fatigue). Almost all the adverse reactions, including those in the above table, were observed either in patients treated with bilastine 20 mg or with a placebo with a similar incidence.

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

Pediatric population

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

Presentation & Storage:

Contrahistadin tablets are supplied in a carton box containing 1, 2, 3 (AL/A1) strip(s) of 10 tablets + inner insert.

Special precautions for storage:

Store at a temperature not exceeding 30 °C, in a dry place.