Maxstine Tablets

bilastine

Each film coated tablet contains:

Bilastine 20 mg

Excipients q.s.

Tablet

Bilastine 20mg

4.1 Therapeutic Indication

For symptomatic treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria in adults.

4.2 Posology and method of administration

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

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.

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.

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.

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

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 the formulation

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

4.5 Drugs interactions

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. 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. 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, 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 Use in special populations

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. As a precautionary measure, it is preferable to avoid the use of Maxstine 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. A decision on whether to continue/discontinue breast-feeding or to discontinue/abstain from Maxstine 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

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

The ADRs most commonly reported by patients (N = 2525) during the clinical development 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.

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)

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 listed below.

Infections and infestations

Uncommon - Oral herpes.

Metabolism and nutrition disorders

Uncommon - Increased appetite.

Psychiatric disorders

Uncommon - Anxiety, Insomnia

Nervous system disorders

Common - Somnolence, Headache.

Uncommon- Dizziness.

Ear and labyrinth disorders

Uncommon - Tinnitus, Vertigo.

Cardiac disorders

Uncommon - Right bundle branch block, Sinus arrhythmia, Electrocardiogram QT prolonged.

Respiratory disorders

Uncommon - Dyspnoea, Nasal discomfort, Nasal dryness.

Gastrointestinal disorders

Uncommon - Nausea, Stomach, Discomfort Abdominal pain, Diarrhoea Dry

Mouth, Dyspepsia, Gastritis.

Skin and subcutaneous tissue disorders

Uncommon - Pruritus.

General disorders

Uncommon - Fatigue, Thirst, Pyrexia, Asthenia.

Investigations

Uncommon - Increased gammaglutamyltransferase, increased ALT and AST, increased Blood creatinine, increased Blood TG, Increased weight.

Frequency not known (cannot be estimated from the available data)

Palpitations, Tachycardia, Hypersensitivity reactions (e.g. Anaphylaxis, Angioedema, Rash, Oedema/local swelling and Erythema) and vomiting have been observed during the post-marketing period.

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 email to : medico@zuventus.com 

By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

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 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.

5.1 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.

5.2 Pharmacodynamic properties

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 chronic idiopathic urticaria patients, Bilastine 20 mg once daily for 28 days was effective in relieving the itching intensity and the number and size of wheals, 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 (24 subjects) and erythromycin (24 subjects). Additionally, a thorough QT study including 30 volunteers has been performed.

In clinical trials at 20 mg once daily dose, 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.

5.3 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 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.

Biotransformation

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

Elimination

In a mass balance study performed in healthy adult 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.

6.1 Animal toxicology or pharmacology

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 postimplantation 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.

Bilastine (Figure 1) is a novel, benzimidazole–piperidine derivative that is a highly selective second-generation H1 antihistamine.

Molecular formula : C₂₈H₃₇N₃O₃

Molecular weight : 463.622 g/mol

8.1 Incompatibilities

No incompatibility study have been found.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions

Store at a temperature not exceeding 30°C. Protect from light.

Keep out of reach of children.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. In particular, please discuss with your doctor if you are taking any of the following medicines :

• Ketoconazole (an antifungal medicine)

• Erythromycin (an antibiotic)

• Diltiazem (to treat angina)

• Cyclosporine (to reduce the activity of your immune system, thus avoiding transplant rejection or reducing disease activity in autoimmune and allergic disorders, such as psoriasis, atopic dermatitis or rheumatoid arthritis)

• Ritonavir (to treat AIDS)

• Rifampicin (an antibiotic)

Maxstine with food, drink and alcohol

These tablets should not be taken with food or with grapefruit juice or other fruit juices, as this will decrease the effect of Bilastine. To avoid this, you can :

• Take the tablet and wait for one hour before taking food or fruit juice or

• If you have taken food or fruit juice, wait for two hours before taking the tablet.

Bilastine, at the recommended dose (20 mg), does not increase the drowsiness produced by Alcohol.