BILAFAV M Suspension (Bilastine and Montelukast Sodium Suspension)

Table of Content

Allergic Rhinitis (AR) is one of the most common chronic disorders of the pediatric population. It is defined as a symptomatic disorder of the nose, induced after allergen. The characteristic symptoms of AR are sneezing, rhinorrhea, nasal obstruction, itching and itchy/red/watery eyes. Sneezing, itching, and rhinorrhea are caused due to histamine release while nasal obstruction occurs due to a leukotriene-mediated effect. The treatment of AR can lead to improvements in the specific allergic symptoms, thereby enhancing the overall Quality of Life (QoL).

Oral antihistamines and intranasal corticosteroids are usually given as the first-line therapy for AR, but not all patients with nasal obstruction may respond positively to the treatment. Anti-leukotrienes (LTRAs) are shown to be effective in reducing the symptoms of AR and asthma when used alone or in combination with antihistamine. Thus, combination therapy with antihistamine and anti-leukotriene may have a positive impact on AR, improve day-time and night-time symptoms and the overall QoL, and may offer additional benefits to patients suffering from concomitant asthma.

BILAFAV M Suspension is combination of Bilastine and Montelukast. Bilastine is a second-generation antihistamine medication that binds with high affinity and selectivity to the histamine H1 receptor. Montelukast is a leukotriene receptor antagonist that binds with high affinity and selectivity to the CysLT1 (cysteinyl leukotriene) receptor.

BILAFAV M Suspension is indicated for the treatment of allergic rhinitis in children 6 to 11years of age with a body weight of at least 20 kg.

Dosage:

Children (6 to 11 years of age)

BILAFAV M Suspension: 5 mL once daily or as directed by R.M.P.

The suspension should be taken 1 hour before or 2 hours after intake of food or fruit juice.

For the use of a Registered Medical Practitioner

Black Box Warning

WARNING: SERIOUS NEUROPSYCHIATRIC EVENTS

Serious neuropsychiatric (NP) events have been reported with the use of montelukast. The types of events reported were highly variable, and included, but were not limited to, agitation, aggression, depression, sleep disturbances, suicidal thoughts and behaviour (including suicide). The mechanisms underlying NP events associated with montelukast use are currently not well understood.

Because of the risk of NP events, the benefits of montelukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve the use of montelukast for patients with allergic rhinitis who have an inadequate response or intolerance to an alternative. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing montelukast.

Discuss the benefits and risks of montelukast with patients and caregivers when prescribing montelukast. Advise patients and/or caregivers to be alert for changes in behaviour or new NP symptoms when taking montelukast. If changes in behaviour are observed, or if new NP symptoms or suicidal thoughts and/or behaviour occur, advise patients to discontinue BILAFAV M Suspension and contact a healthcare provider immediately.

 

Qualitative and Quantitative Composition

BILAFAV M Suspension

Each 5 mL Suspension contains:

Bilastine ................................................................................10 mg

Montelukast Sodium IP, equivalent to Montelukast ............. 4 mg

In a flavoured syrup base

Colour: Sunset Yellow

Dosage Form(s) and Strength(s)

Suspension for oral use (Bilastine 10 mg + Montelukast Sodium 4 mg IP, equivalent to Montelukast)

Clinical Particulars

Therapeutic Indications

BILAFAV M Suspension is indicated for the treatment of allergic rhinitis in children 6 to 11 years of age (both inclusive) with a body weight of at least 20 kg.

Posology and Method of Administration

Children (6 to 11 years of age)

BILAFAV M Suspension: 5 mL once daily or as directed by R.M.P.

The suspension should be taken 1 hour before or 2 hours after intake of food or fruit juice.

Contraindications

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

Special Warnings and Precautions for Use

Bilastine

Paediatric Patients

In patients with moderate or severe renal impairment, co-administration of bilastine with P-glycoprotein (P-gp) inhibitors, such as 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.

Montelukast

General

Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus.

Patients should be advised to have appropriate rescue medication available. Therapy with montelukast can be continued during acute exacerbations of asthma.

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast should not be abruptly substituted for inhaled or oral corticosteroids. Montelukast should not be used as monotherapy for the treatment and management of exercise-induced bronchospasm. Patients who have exacerbations of asthma after exercise should continue to use their usual regimen of inhaled β-agonists as prophylaxis and have available for rescue a short-acting inhaled β-agonist.

NP (Neuropsychiatric) Events

Serious NP events have been reported with the use of montelukast. These postmarketing reports have been highly variable and included, but were not limited to, agitation, aggressive behaviour or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behaviour (including suicide), tic, and tremor. NP events have been reported in adult, adolescent and paediatric patients with and without a previous history of psychiatric disorder. NP events have been reported mostly during montelukast treatment, but some were reported after montelukast discontinuation. Animal studies showed that montelukast distributes into the brain in rats; however, the mechanisms underlying montelukast-associated NP events are currently not well understood. Based upon the available data, it is difficult to identify risk factors for or quantify the risk of NP events with montelukast use.

Because of the risk of NP events, the benefits of montelukast may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve the use of montelukast for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise-induced bronchoconstriction, consider the benefits and risks before prescribing montelukast.

Discuss the benefits and risks of montelukast use with patients and caregivers when prescribing montelukast. Advise patients and/or caregivers to be alert for changes in behaviour or for new NP symptoms when taking montelukast. If changes in behaviour are observed, or if new NP symptoms or suicidal thoughts and/or behaviour occur, advise patients to discontinue montelukast and contact a healthcare provider immediately. In many cases, symptoms resolved after stopping montelukast therapy; however, in some cases symptoms persisted after discontinuation of montelukast. Therefore, continue to monitor and provide supportive care until symptoms resolve. Re-evaluate the benefits and risks of restarting treatment with montelukast if such events occur.

Acute Asthma

Patients should be advised never to use oral montelukast to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled beta-agonist should be used. Patients should seek their doctors' advice as soon as possible if they need more inhalations of short-acting beta-agonists than usual.

Concomitant Corticosteroid Use

Montelukast should not be substituted abruptly for inhaled or oral corticosteroids.

There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.

Eosinophilic Conditions

In rare cases, patients on therapy with anti-asthma agents, including montelukast, may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, physicians should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

Aspirin Sensitivity

Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).

Although montelukast is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients.

Drug Interactions

Bilastine

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

Interaction with Food: Food significantly reduces the oral bioavailability of bilastine by 20–30%.

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 area under the plasma concentration curve (AUC) 2-fold and Cmax 2- to 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 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 interaction 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.

Montelukast

Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl oestradiol/norethindrone 35/1), terfenadine, digoxin, and warfarin.

The AUC for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolised by cytochrome P450 (CYP) 3A4, 2C8 and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8 and 2C9, such as phenytoin, phenobarbital and rifampicin.

In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug–drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolised by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolised by this enzyme (e.g. paclitaxel, rosiglitazone, and repaglinide).

In vitro studies have shown that montelukast is a substrate of CYP 2C8 and, to a less significant extent, of 2C9, and 3A4. In a clinical drug–drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon co-administration with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be aware of the potential for an increase in adverse reactions.

Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g. trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

Use in Special Populations

Pregnant Women

Bilastine

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.

Montelukast

Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.

Available data from published prospective and retrospective cohort studies with montelukast use in pregnant women evaluating major birth defects have not established a drug-associated risk. Available studies have methodologic limitations, including small sample size, retrospective data collection (in some cases), and inconsistent comparator groups.

As a precautionary measure, it is preferable to avoid the use of the bilastine plus montelukast combination suspension during pregnancy.

Lactating Women

Bilastine

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 breastfeeding or 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.

Montelukast

Studies in rats have shown that montelukast is excreted in milk. It is unknown whether montelukast and/or metabolites are excreted in human milk.

A decision on whether to continue/discontinue breastfeeding or to discontinue/abstain from the bilastine plus montelukast combination therapy must be made taking into account the benefit of breastfeeding for the child and the benefit of the therapy for the mother.

Fertility

There are no or limited amount of clinical data regarding effect on fertility. A study in rats did not indicate any negative effect on fertility with bilastine.

Paediatric Patients

Bilastine

In patients with moderate or severe renal impairment, co-administration of bilastine with P-gp inhibitors, such as 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.

Montelukast

The effectiveness of montelukast for the treatment of seasonal allergic rhinitis in paediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in paediatric patients 6 months to 14 years of age have been established and is supported by extrapolation from the demonstrated effectiveness in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations.

The safety of montelukast 4 mg and 5 mg chewable tablets in paediatric patients 2 to 14 years of age with allergic rhinitis is supported by data from studies conducted in paediatric patients 2 to 14 years of age with asthma. A safety study in paediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile. The safety of montelukast 4 mg oral granules in paediatric patients as young as 6 months of age with perennial allergic rhinitis is supported by extrapolation from safety data obtained from studies conducted in paediatric patients 6 months to 23 months of age with asthma and from pharmacokinetic data comparing systemic exposures in patients 6 months to 23 months of age to systemic exposures in adults.

The safety and effectiveness in paediatric patients below the age of 12 months with asthma, 6 months with perennial allergic rhinitis, and 6 years with exercise-induced bronchoconstriction have not been established.

FDC of Bilastine 10mg + Montelukast 4 mg per 5 ml suspension for the treatment of allergic rhinitis in Children aged 6 to 11 years (both inclusive) with a body weight of at least 20 kg the safety and efficacy in children has been established.

Geriatric Patients

Bilastine

No dosage adjustments are required in elderly patients.

Montelukast

No dosage adjustment is necessary for the elderly. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly.

Patients with Renal Impairment

Bilastine

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

Montelukast

Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is necessary for patients with renal insufficiency.

Patients with Hepatic Impairment

Bilastine

The safety and efficacy of bilastine in hepatically impaired children have not been established. Studies conducted in adults in special risk groups (hepatically impaired patients) indicate that it is not necessary to adjust the dose of bilastine in adults.

Montelukast

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is necessary for patients with mild-to-moderate hepatic impairment. There are no data on patients with severe hepatic impairment.

Effects on Ability to Drive and Use Machines

Bilastine

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.

Montelukast

Montelukast has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.

Undesirable Effects

Bilastine

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 postmarketing surveillance has confirmed clinical trial findings.

The percentage of children (2 to 11 years of age) who 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 the percentage in the group receiving placebo (68.5% vs 67.5%).

The related AEs most commonly reported by 291 children (2 to 11 years of age) receiving bilastine 10 mg (orodispersible tablet formulation) during clinical trials (260 children exposed in the clinical safety study, and 31 children exposed in the pharmacokinetic study) were headache, allergic conjunctivitis, rhinitis and abdominal pain. These related AEs occurred with a comparable frequency in 249 patients receiving placebo.

Tabulated Summary of AEs in Paedriatic 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 were assigned as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); and, 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

AE

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 in children treated with either 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.

Summary of Safety Profile in Adult and Adolescent Patients

The incidence of adverse events in 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% vs 12.8%).

The Phase II and III clinical trials performed during the clinical development included 2,525 patients treated with different doses of bilastine, of whom 1,697 received bilastine 20 mg. In these trials, 1,362 patients received placebo. The AEs 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 AEs occurred with a comparable frequency in patients receiving placebo.

Tabulated Summary of AEs in Adult and Adolescent Patients

AEs, 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=1,697), are tabulated below.

Frequencies were 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); and, 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=1,697

All Bilastine Doses

N=2,525

Placebo

N=1,362

Frequency

AE

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%)

10 (0.59%)

10 (0.59%)

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 (ALT) increased

5 (0.30%)

5 (0.20%)

3 (0.22%)

 

Aspartate aminotransferase (AST) increased

3 (0.18%)

3 (0.12%)

3 (0.22%)

 

Blood creatinine increased

2 (0.12%)

2 (0.08%)

0 (0.0%)

 

Blood triglycerides increased

2 (0.12%)

2 (0.08%)

3 (0.22%)

 

Increased weight

8 (0.47%)

12 (0.48%)

2 (0.15%)

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

Description of Selected AEs in Adult and Adolescent Patients

Somnolence, headache, dizziness and fatigue were observed in patients treated with either 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 postmarketing surveillance has confirmed the safety profile observed during the clinical development.

Montelukast

NP (Neuropsychiatric) Events:

Clinical Trials Experience

In the following description of clinical trials experience, AEs are listed regardless of causality assessment:

Adults and Adolescents, 15 Years of Age and Older, with Seasonal Allergic Rhinitis

Montelukast has been evaluated for safety in 2,199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following reaction was reported with montelukast with a frequency of ³1% and at an incidence greater than placebo: upper respiratory infection in 1.9% of patients receiving montelukast vs 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.

Paediatric Patients, 2 to 14 Years of Age, with Seasonal Allergic Rhinitis Montelukast has been evaluated in 280 paediatric patients, 2 to 14 years of age, in a 2-week, multicentre, double-blind, placebo-controlled, parallel-group safety study. Montelukast administered once daily in the evening had a safety profile similar to that of placebo. In this study, the following reactions occurred with a frequency of ³2% and at an incidence greater than placebo: headache, otitis media, pharyngitis, and upper respiratory infection.

Adults and Adolescents, 15 Years of Age and Older, with Perennial Allergic Rhinitis

Montelukast has been evaluated for safety in 3,357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1,632 received Montelukast in two 6-week clinical studies. Montelukast administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following reactions were reported with montelukast with a frequency of ³1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.

Paediatric Patients, 6 Months to 14 Years of Age, with Perennial Allergic Rhinitis The safety of montelukast in patients 2 to 14 years of age with perennial allergic rhinitis is supported by the safety in patients 2 to 14 years of age with seasonal allergic rhinitis. The safety in patients 6 to 23 months of age is supported by data from pharmacokinetic and safety and efficacy studies in asthma in this paediatric population and from adult pharmacokinetic studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of montelukast. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

BLOOD AND LYMPHATIC SYSTEM DISORDERS: increased bleeding tendency, thrombocytopaenia.

IMMUNE SYSTEM DISORDERS: hypersensitivity reactions, including anaphylaxis, and hepatic eosinophilic infiltration.

PSYCHIATRIC DISORDERS: including, but not limited to, agitation, aggressive behaviour or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thinking and behaviour (including suicide), tic, and tremor.

NERVOUS SYSTEM DISORDERS: drowsiness, paraesthesia/hypoesthesia, seizures.

CARDIAC DISORDERS: palpitations.

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: epistaxis, pulmonary eosinophilia.

GASTROINTESTINAL DISORDERS: diarrhoea, dyspepsia, nausea, pancreatitis, vomiting.

HEPATOBILIARY DISORDERS: Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with montelukast. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: angio-oedema, bruising, erythema multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria.

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: arthralgia, myalgia, including muscle cramps.

RENAL AND URINARY DISORDERS: enuresis in children.

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: oedema.

Patients with asthma on therapy with montelukast may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These reactions have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

The most frequently reported adverse drug reactions (ADRs) based on clinical trials and/or spontaneous reports from treatment with FDC of Bilastine 10 mg + Montelukast 4 mg Suspension are Headache, Nausea, Fever, Dizziness, Abdominal pain.

Reporting of Suspected Adverse Reactions

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 to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Bilastine

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 a single dose; or 200 mg/day for 7 days) to 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 adverse events and no significant prolongation in the QTc interval were reported. The information collected in the postmarketing surveillance is consistent with that reported in clinical trials.

Critical evaluation of bilastine's multiple-dose effect (100 mg ´ 4 days) on ventricular repolarisation by a thorough QT/QTc crossover study involving 30 healthy 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.

Montelukast

In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately 1 week without clinically important adverse experiences.

There have been reports of acute overdose in postmarketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1,000 mg (approximately 61 mg/kg in a 42-month-old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences accounted for in the majority of overdose reports.

Symptoms of Overdose

The most frequently occurring AEs were consistent with the safety profile of montelukast and included abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity.

Management of Overdose

No specific information is available on the treatment of overdose with montelukast. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. It is not known whether montelukast is dialysable by peritoneal or haemodialysis.

In the event of over dosage with BILFAV M Suspension, patients should be treated symptomatically with supportive measures

Pharmacological Properties

Mechanism of Action

Bilastine

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.

Montelukast

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. CysLT (cysteinyl leukotriene: LTC4, LTD4, LTE4) receptors have been correlated with the pathophysiology of asthma and allergic rhinitis. In allergic rhinitis, CysLT receptors are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.

Pharmacodynamic Properties

Bilastine

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.

Clinical Safety

In a 12-week controlled clinical trial with 509 children 2 to 11 years of age (260 treated with the recommended paediatric dose of bilastine 10 mg once daily: 58 at age 2 to <6 years, 105 at age 6 to <9 years, and 97 at age 9 to <12 years; 249 treated with placebo: 58 at age 2 to <6 years, 95 at age 6 to <9 years, and 96 at age 9 to <12 years), 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 in the trial, 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. Of the 260 children who received bilastine, 252 (96.9%) got it for allergic rhinoconjunctivitis and 8 (3.1%) for chronic urticaria. Of the 249 children who received placebo, 227 (91.2%) got it for allergic rhinoconjunctivitis and 22 (8.8%) for chronic urticaria.

Montelukast

Pharmacotherapeutic group: Leukotriene receptor antagonist. ATC-code: R03D C03.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta-agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late-phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.

In studies in adults, montelukast 10 mg once daily, compared with placebo, demonstrated significant improvements in morning forced expiratory volume in 1 second (FEV1; 10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR; 24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total beta-agonist use (–26.1% vs –4.6% change from baseline).

Improvement in patient-reported daytime and night-time asthma symptoms scores was significantly better with montelukast than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclomethasone plus montelukast vs beclometasone, respectively, for FEV1: 5.43% vs 1.04%; beta-agonist use: –8.70% vs 2.64%). Compared with inhaled beclomethasone (200 μg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclomethasone provided a greater average treatment effect (% change from baseline for montelukast vs beclomethasone, respectively, for FEV1: 7.49% vs 13.3%; beta-agonist use: –28.28% vs –43.89%). However, compared with beclomethasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g. 50% of patients treated with beclomethasone achieved an improvement in FEV1 of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult and adolescent asthmatic patients, 15 years of age and older, with concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhoea, sneezing, nasal itching) and the Night-time Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and night-time awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not a primary objective in this study.

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1: 8.71% vs 4.16% change from baseline; AM PEFR: 27.9 L/min vs 17.8 L/min change from baseline) and decreased ‘as-needed’ beta-agonist use (–11.7% vs +8.2% change from baseline).

Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1: 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1: 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short-term study in paediatric patients (maximal fall in FEV1: 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1: 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV1: 8.55% vs –1.74% change from baseline; and decrease in total beta-agonist use: –27.78% vs 2.09% change from baseline).

BILAFAV M Suspension (FDC of Bilastine 10 mg + Montelukast 4 mg Suspension)

Title of Study:

A Phase III, Prospective, Randomized, Double Blind, Active-Controlled, Comparative, Parallel Group and Multicentric Clinical Study to Evaluate the Efficacy, Safety and Tolerability of FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension Versus FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension in patients with allergic rhinitis.

Study Objectives:

Primary Objective:

Evaluation of the efficacy of FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension versus FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension in patients with allergic rhinitis.

Secondary Objective:

Evaluation of the safety and tolerability of FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension versus FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension in patients with allergic rhinitis.

Methodology:

This was a phase III, prospective, randomized, double blind, active-controlled, comparative, parallel group and Multicentric clinical study.

This study was done on male and female patients aged between 6 to 11 years (both inclusive), with a history of allergic rhinitis, a positive skin prick test to at least one relevant allergen and active symptoms of allergic rhinitis at study entry, elevated serum IgE levels (>100 IU/mL) at screening or baseline visit and total nasal symptom score (TNSS) ≥4 at screening or baseline visit.

A total of 229 patients were screened and 212 patients were randomized by computer generated block randomization program to 14 days treatment of either of the study arm i.e., FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension (Arm A) or FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension (Arm B) in 1:1 proportion. Total patients randomized/enrolled were 106 in FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension arm and 106 in FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension arm. All sites had approval from the respective Institutional Ethics Committees prior to the study initiation.

Randomized patients were given blinded study medication i.e., either FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension or FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension and instructed to administer 5 mL of oral suspension once a day orally one hour before or two hours after meals around same time every day for 2 weeks (14 days). The treatment continued for the 14 days with interim follow-up on day 7±2 (Visit 2) from the start of treatment. The end of study visit was conducted on day 14±2 (Visit 3).

Patient’s Informed assent form (IAF), demographic data and medical history were taken on screening or baseline visit only. Vital signs and physical examination were done at all visits.

Haematological Tests (Haemoglobin, Total RBC count, Platelet’s count, Total WBC count, Differential WBC count) were performed at screening or baseline visit (Visit 1) and end of the study visit (Visit 3). Biochemical Tests (Total bilirubin, SGOT, SGPT, BUN and Serum creatinine) were performed at screening or baseline visit (Visit 1) and end of the study visit (Visit 3). Serum IgE was performed at screening or baseline visit only. Physical examination, vitals and concomitant medications were assessed at all the visits till the end of the study. Adverse events were recorded from visit 2 to end of the study visit. Body weight and BMI were recorded at screening or baseline visit only. 12 Lead ECG was performed at screening or baseline visit (Visit 1) and end of the study visit (Visit 3). Routine urine analysis was performed at screening or baseline visit (Visit 1) and end of the study visit (Visit 3).

Total symptom score (sum of total nasal symptom score and total non-nasal symptom score) was recorded at screening or baseline visit (Visit 1), Visit 2 and end of the study visit (Visit 3).

Diary was issued to patient at screening or baseline or randomization visit to record each administration or missed drug administration for compliance assessment. Also, Patients / caretakers or parents were instructed to record the daily symptom scoring on patient diary. Study drug dispensing was done at randomization visit / visit 1 and visit 2. Patients were trained for diary filling and study drug administration.

The data was collected on paper CRFs. The data analysis was performed for predefined parameters to correspond with the primary efficacy, secondary efficacy and safety endpoints.

Study Assessments:

Primary Efficacy Endpoint:

  • The change in Total Symptom Score at the end of study as compared to baseline.

Secondary Efficacy Endpoints:

  • The change in Total nasal symptom score (TNSS) at the end of study as compared to baseline.
  • The change in Total non-nasal symptom score (TNNSS) at the end of study as compared to baseline.

Safety End Points:

  • The assessment of safety of patients .
  • The assessment of tolerability of investigational product was based on incidence of AEs and SAEs and changes in laboratory values.

Summary:

Efficacy Results

FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension shows similar efficacy profile compared to FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension in the improvement of Total Symptom Score (TSS), Total Nasal Symptom Score (TNSS) and Total Non-Nasal Symptom Score (TNNSS).

Safety Results

For evaluation of safety, frequency of suspected, unanticipated adverse drug reactions reported possibly related to the investigational product up to end of study from start of the treatment was considered. Safety and tolerability of the test and reference products were assessed depending on the outcome from this clinical study. There were events and evidence of adverse reaction observed but were non-significant. Total 17 adverse events (AEs) were reported in 17 patients. 08 AEs were reported in FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension arm and 09 AEs were reported in FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension arm. All the adverse events were mild in nature. No SAE was reported during the study.

Conclusion

FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension shows similar efficacy profile compared to FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension in the improvement of TSS (TNSS+TNNSS) in patients with allergic rhinitis. FDC of Bilastine 10 mg + Montelukast 4 mg Oral Suspension observed to be comparable safety profile with FDC of Levocetirizine 2.5 mg + Montelukast 4 mg Oral Suspension. There were no deaths or hospitalizations in both the treatment groups

Pharmacokinetic Properties

Bilastine

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

Food significantly reduces the oral bioavailability of bilastine 2.5 mg/mL oral solution by 20%.

In vitro and in vivo studies have shown that bilastine is a substrate of P-gp and OATP .

At therapeutic doses, bilastine is 84 to 90% bound to plasma proteins.

Metabolism

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

Excretion

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 metabolised in humans. The mean elimination half-life calculated in healthy volunteers was 14.5 hours.

Linearity

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

Patients with Renal Impairment

In a study in subjects with renal impairment, the mean (SD) AUC0-infinity increased from 737.4 (± 260.8) ng ´ hr/mL in subjects without impairment (glomerular filtration rate : >80 mL/min/1.73 m2) to: 967.4 (± 140.2) ng ´ hr/mL in subjects with mild impairment (GFR: 50 to 80 mL/min/1.73 m2), 1,384.2 (± 263.23) ng ´ hr/mL in subjects with moderate impairment (GFR: 30 to <50 mL/min/1.73 m2), and 1,708.5 (± 699.0) ng ´ hr/mL in subjects with severe impairment (GFR: <30 mL/min/1.73 m2). Mean (SD) half-life of bilastine was 9.3 hours (± 2.8) in subjects without impairment, 15.1 hours (± 7.7) in subjects with mild impairment, 10.5 hours (± 2.3) in subjects with moderate impairment, and 18.4 hours (± 11.4) in subjects with severe impairment. Urinary excretion of bilastine was essentially complete after 48to 72 hours 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.

Patients with Hepatic Impairment

There are no pharmacokinetic data in subjects with hepatic impairment. Bilastine is not metabolised 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.

Paediatric Patients

Pharmacokinetic data in children were obtained in a Phase II pharmacokinetic study, including 31 children in the age range of 4 to 11 years with allergic rhinoconjunctivitis or chronic urticaria, administered bilastine 10 mg orodispersible tablet once daily. This formulation has been shown to be bioequivalent to bilastine 2.5 mg/mL oral solution. Pharmacokinetic analysis of the plasma concentration data showed that the paediatric 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 of 1,014 ng*hr/mL for children 6 to 11 years of age. 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 of 6 to 11 years with a body weight of at least 20 kg.

Montelukast

Absorption

Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.

For the 5 mg chewable tablet, the Cmax is achieved 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.

After administration of the 4 mg chewable tablet to paediatric patients 2 to 5 years of age in the fasted state, Cmax is achieved 2 hours after administration. The mean Cmax is 66% higher while mean Cmin is lower than in adults receiving a 10 mg tablet.

The 4 mg granule formulation is bioequivalent to the 4 mg chewable tablet when administered to adults in the fasted state. In paediatric patients 6 months to 2 years of age, Cmax is achieved 2 hours after administration of the 4 mg granules formulation. The Cmax is nearly 2-fold greater than in adults receiving a 10 mg tablet. The co-administration of applesauce or a high-fat standard meal with the granule formulation did not have a clinically meaningful effect on the pharmacokinetics of montelukast as determined by AUC (1,225.7 vs 1,223.1 ng.hr/mL with and without applesauce, respectively, and 1,191.8 vs 1,148.5 ng.hr/mL with and without a high-fat standard meal, respectively).

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours’ post-dose were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children.

CYP 2C8 is the major enzyme in the metabolism of montelukast. Additionally, CYP 3A4 and 2C9 may have a minor contribution although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects who received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.

Excretion

The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.

Special Populations

PATIENTS WITH RENAL/HEPATIC IMPAIRMENT

Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment.

No dosage adjustment is necessary for the elderly or mild-to-moderate hepatic insufficiency. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score >9). With high doses of montelukast (20- and 60-fold the recommended adult dose), a decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

BILAFAV M Suspension (FDC of Bilastine 10 mg + Montelukast 4 mg Suspension)

Title of Study:

An open label, randomized, balanced, two treatment, two sequence, two period, cross-over, single-dose oral bioequivalence study of 05 mL containing Bilastine 10mg + Montelukast 4mg oral suspension (T: test product) with 4 mL of Bilastine 2.5 mg/ml Solution and 4 ml of Montelukast Sodium 5 mg/5ml suspension (R: reference product) in normal healthy, adult male subjects under Fasting condition..

Objectives:

To compare the rate and extent of absorption of Bilastine and Montelukast from fixed dose combination of 5mL containing Bilastine 10mg + Montelukast 4mg oral suspension (T) and 4mL of Bilastine 2.5mg/ml Solution and 4 mL Montelukast suspension 5mg/5ml (R) in healthy, adult, human male subjects under fasting conditions.

To monitor the safety and tolerability of a single dose of fixed dose combination of Bilastine 10mg + Montelukast 4mg oral suspension in healthy, adult, human male subjects under fasting conditions. 

Methodology:

Clinical personnel explained all study related procedures, duration, dates and timings, information on the study treatments and confidentiality of the subjects’ data clearly to the subjects during the informed consent procedure. Subjects who signed the consent form and showed their willingness to participate in the study were enrolled. Subjects who were eligible when assessed against the inclusion and exclusion criteria and who were found to be healthy on physical examination with laboratory investigation values within reference limits were considered for admission to the study. Subjects whose pre-study laboratory values were outside the reference range were also considered for participation provided these values were considered clinically non-significant by the investigator. The eligible subjects reported to the study site on 1 Aug 2020 for period 01 and on 8 Aug 2020 for period 02. Treatments were allocated to subjects per the randomization schedule generated using statistical techniques with SAS® (SAS Institute Inc., USA) version 9.4. Blood samples were drawn before dosing (0.00 hour) and up to 48.00 hours after dosing in each period. 

Plasma concentrations of Bilastine and montelukast were analyzed using a validated LC-MS/MS method. Statistical analysis was performed to assess bioequivalence between the pharmacokinetic parameters of test and reference formulations using SAS® (SAS Institute Inc., USA) version 9.4.

Safety Assessment:

All subjects who had received at least one dose of investigational product were included in the safety evaluation. Safety assessment was based on clinical laboratory evaluation, chest X-ray (P/A view), ECG recordings, clinical examination along with vital signs (axillary temperature, radial pulse rate, sitting blood pressure and respiratory rate) measurement and post-study clinical laboratory safety evaluation. Laboratory assessments (hematology, biochemistry, serology and urine analysis), chest X-ray (P/A view) and ECG recordings were done at the time of screening. Clinical examination along with vital signs (axillary temperature, radial pulse rate, sitting blood pressure, respiratory rate) were undertaken at the time of screening, during check-in and before check-out of each period. Vital signs (axillary temperature, radial pulse rate and sitting blood pressure) were recorded within 2.50 hours prior to dosing in each period. Vital signs (sitting blood pressure and radial pulse rate) were measured and recorded at 2.00, 6.00 and 11.00 hours after dosing (within ± 40 minutes of the scheduled time). A urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, marijuana, cocaine and morphine) and a breath test for alcohol consumption were done during check-in of each period. Subjects were questioned for well-being at the time of clinical examination and recording of vital signs. 

Clinical examination, measurement of vital signs and questioning for well-being was performed prior to check-out only for the subjects who were dosed.

A safety sample was collected for post-study safety assessment (hematology and biochemistry) from all dosed subjects at the end of the study.

Results:

  1. Pharmacokinetic and Statistical Evaluation:

Table A: Descriptive Statistics of Formulation Means for Bilastine obtained by a Non- Compartmental Model (N = 23)

Pharmacokinetic Parameters (Units)

Mean ± SD (Un-transformed data)

Test Product (T)

Reference Product (R)

Cmax (ng/mL)

163.2667 ± 44.37082

174.2467 ± 50.28948

AUC0-t (ng.hr/mL)

1111.2269 ± 392.83343

1099.5059 ± 420.34004

AUC0- (ng.hr/mL)

1186.2117 ± 489.33779

1153.0334 ± 469.40621

Kel (hr-1)

0.1564 ± 0.07263

0.1550 ± 0.07379

t 1/2 (hr)

6.5823 ± 8.08276

5.7742 ± 3.22950

Tmax (hr)

2.257 ± 1.2953

1.790 ± 0.6764

Extrapolated AUC (%)

4.380 ± 7.8037

3.783 ± 3.0883

 

Median (Min-Max)

Tmax (hr)

1.750 (0.750 - 6.000)

1.750 (0.750 - 3.000)

 

Table B: Geometric Least Squares Means, Ratios and 90% Confidence Intervals for Pharmacokinetic Parameters (Cmax, AUC0-t and AUC0-∞) of Bilastine (N = 23)

 

Pharmacokinetic Parameters (Units)

Ln- transformed

90% Confidence Interval (Parametric)

 

ISCV (%)

Geometric Least Squares Mean

Test Product (T)

Reference Product (R)

T/R (%)

Lower

Upper

Cmax (ng/mL)

156.721

166.520

94.12

83.23

106.42

24.55

AUC0-t (ng.hr/mL)

1036.160

1020.610

101.52

91.08

113.17

21.62

AUC0-∞(ng.hr/mL)

1087.148

1061.180

102.45

91.24

115.04

23.12

 

Table C: Descriptive Statistics for Montelukast obtained by a Non- Compartmental Model (N = 23)

 

Pharmacokinetic Parameters (Units)

Mean ± SD (Un-transformed data)

Test Product (T)

Reference Product (R)

Cmax (ng/mL)

198.2364 ± 36.53193

218.5937 ± 50.77232

AUC 0-t (ng.hr/mL)

1338.7697 ± 341.27446

1433.4477 ± 340.59936

AUC 0-∞ (ng.hr/mL)

1394.4819 ± 344.08591

1496.2176 ± 361.96475

Kel (hr-1)

0.1323 ± 0.04133

0.1313 ± 0.04601

t 1/2 (hr)

5.9225 ± 2.38880

6.2476 ± 3.47742

Tmax (hr)

2.673 ± 0.8188

2.523 ± 1.2380

Extrapolated AUC (%)

4.185 ± 2.9474

4.050 ± 2.8406

 

Median (Min-Max)

Tmax (hr)

2.670 (1.500 - 5.000)

2.670 (1.500 - 6.000)

 

Table D: Geometric Least Squares Means, Ratios and 90% Confidence Intervals for Pharmacokinetic Parameters (Cmax, AUC0-t and AUC0-∞) of Montelukast (N = 23)

 

 

Pharmacokinetic Parameters (Units)

Ln- transformed

90% Confidence Interval (Parametric)

 

ISCV (%)

Geometric Least Squares Mean

Test Product (T)

Reference Product (R)

T/R (%)

Lower

Upper

Cmax (ng/mL)

195.002

212.161

91.91

80.79

104.56

25.81

AUC0-t (ng.hr/mL)

1286.539

1385.408

92.86

81.52

105.79

26.08

AUC0-¥ (ng.hr/mL)

1343.928

1444.409

93.04

81.83

105.80

25.71

Safety Evaluation

No serious or life-threatening adverse events were reported during the course of the study.  The incidence of adverse events (AEs), both overall and IMP-related, was low for both parts of the study.

Six (06) adverse events were reported in subject nos.09, 17, 18, 20, 22 and 24 during post-study clinical laboratory safety evaluation (clinically significant changes in laboratory parameters).

Clinically significant laboratory abnormalities (documented as adverse events) detected during the post-study clinical laboratory safety evaluation were Increased SGOT and SGPT (01 subject, 2.12%), Increased Total Bilirubin (03 subject, 6.38%), Decreased Haemoglobin and PCV (01 subject 2.12%) and Decreased Platelet count (01 subject 2.12%)  These adverse events were detected during the end of study safety analysis and could not be attributed to either the test (T) or the reference (R) product. Hence, adverse events associated with post-study laboratory results were imputed to both formulations.  

These adverse events were detected during the end of study safety analysis and could not be attributed to either the test (T) or the reference (R) product. Hence, adverse events associated with post-study laboratory results were imputed to both formulations.

All Adverse events was graded as ‘mild’ in intensity.

Two adverse events possibly to be related to the study drug administered and four adverse event unlikely to be related to the study drug administered.

The test (T) and reference (R) products were comparable in their safety and tolerability.

The test product (T) was found to be safe and well tolerated upon administration of single dose of Bilastine 10mg + Montelukast 4mg oral suspension in healthy adult human subjects under fasting conditions.

Conclusion:

Bilastine:

The 90% confidence intervals of the differences of least squares means for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Bilastine is within the bioequivalence acceptance limits of 80.00 - 125.00%.

Montelukast:

The 90% confidence intervals of the differences of least squares means for the Ln-transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ of Montelukast is within the bioequivalence acceptance limits of 80.00 - 125.00%.

Hence, it is concluded that the test product (T) Bilastine 10mg + Montelukast 4mg oral suspension and 4mL of Bilastine 2.5mg/ml Solution and 4 mL of Montelukast suspension 5mg/5ml are bioequivalent with respect to rate and extent of absorption.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Bilastine

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, the 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 1,000 mg/kg/day did not induce any effect on female and male reproductive organs. Mating, fertility and pregnancy indices were not affected.

As per a distribution study in rats with determination of drug concentrations by autoradiography, bilastine does not accumulate in the CNS.

Montelukast

In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed, which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastrointestinal symptoms, loose stools and ion imbalance. These occurred at dosages that provided >17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose).

In animal studies, montelukast did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69-fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure >24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Montelukast has been shown to cross the placental barrier and is excreted in the breast milk of animals.

No deaths occurred following a single oral administration of montelukast sodium at doses up to 5,000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).

Montelukast was determined not to be phototoxic in mice for ultra-violet (UVA, UVB) or visible light spectra at doses up to 500 mg/kg/day (approximately >200-fold, based on systemic exposure).

Montelukast was neither mutagenic in in vitro and in vivo tests nor tumourigenic in rodent species.

Description

Bilastine is a second-generation H1-antihistamine indicated for the treatment of allergic rhinitis. Bilastine is known chemically as 2- piperidin-1-yl} ethyl) phenyl]-2-methylpropanoic acid; 2- piperidin-1-yl] ethyl] phenyl]-2-methylpropanoic acid. Its empirical formula is C28H37N3O3 and the molecular weight is 463.61168 g/mol.

Montelukast is a leukotriene receptor antagonist that inhibits the physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity. Montelukast is chemically known as -1- phenyl]-3- propyl] thio] methyl] cyclopropane acetic acid. Its empirical formula is C35H35ClNO3S and the molecular weight is 608.18.

Pharmaceutical Particulars

Incompatibilities

No incompatibility study has been found.

Shelf-Life

18 months.

Packaging Information

BILAFAV M Suspension:

Available in a 30 mL amber-coloured PET bottle. (Physician sample pack)

Available in a 60 mL amber-coloured PET bottle. (Sales pack)

Storage and Handling Instructions

Store at a temperature not exceeding 30ºC, protected from light and moisture.

Keep out of reach of children.

SHAKE WELL BEFORE USE

Patient Counselling Information

What is BILAFAV M Suspension?

BILAFAV M Oral Suspension contains bilastine 10 mg and montelukast 4 mg. Bilastine is a second-generation antihistamine medication that binds with high affinity and selectivity to the histamine H1 receptor. Montelukast is a leukotriene receptor antagonist that binds with high affinity and selectivity to the CysLT1 (cysteinyl leukotriene) receptor. BILAFAV M Suspension is indicated for the treatment of allergic rhinitis in children 6 to 11years of age with a body weight of at least 20 kg.

  • Do not give BILAFAV M Suspension:
  • If your child has an allergy to bilastine or montelukast or any of the other ingredients of this medicine.
  • If your child is below 6 years of age.
  • Before you give BILAFAV M Suspension to your child, tell your healthcare provider about all his/her medical conditions, including if your child
  • has moderate or severe renal impairment;
  • is allergic to aspirin; and/or,
  • has or has had mental health problems.

Tell your doctor or your healthcare provider if your child is taking or has recently taken or might take any other medicines, including medicines obtained without a prescription. This includes medicines, herbal remedies, health products or supplements that you have obtained without a prescription

Please discuss with your doctor if your child is taking any of the following medicines before starting BILAFAV M Suspension:

  • Ketoconazole (an antifungal medicine)
  • Erythromycin (an antibiotic)
  • Diltiazem (to treat angina)
  • Cyclosporine (to reduce the activity of the 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)
  • Phenobarbital (used for the treatment of epilepsy)
  • Phenytoin (used for the treatment of epilepsy)
  • Rifampicin (used to treat tuberculosis and some other infections)
  • Gemfibrozil (used for the treatment of high lipid levels in plasma).

How should BILAFAV M Suspension be taken?

  • Always take/administer this medicine exactly as prescribed by the doctor. Check with your doctor or pharmacist if you are not sure.
  • You should give your child only 5 mL of this suspension once a day or as prescribed by your doctor.
  • This suspension is to be taken by mouth.
  • This suspension should not be given with food or with grapefruit juice or other fruit juices, as this will decrease the effect of bilastine.
  • This suspension must be given 1 hour before or 2 hours after intake of food or fruit juice.

What are the possible side effects of BILAFAV M Suspension?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If your child experiences symptoms of an allergic reaction, the signs of which may include difficulty in breathing, dizziness, collapsing or losing consciousness, swelling of the face, lips, tongue or throat, and/or swelling and redness of the skin, stop giving the medicine and seek urgent medical advice straight away.

Other side effects that may be experienced in children are as follows:

Common (may affect up to 1 in 10 people)

  • rhinitis (nasal irritation)
  • allergic conjunctivitis (eye irritation)
  • headache
  • stomach pain (abdominal/upper abdominal pain)
  • diarrhoea
  • hyperactivity
  • asthma
  • scaly and itchy skin
  • rash
  • thirst

Uncommon (may affect up to 1 in 100 people)

  • eye irritation
  • dizziness
  • loss of consciousness
  • diarrhoea
  • nausea (the feeling of being sick)
  • lip swelling
  • eczema
  • urticaria (hives)
  • fatigue
  • allergic reactions, including swelling of the face, lips, tongue and/or throat, which may cause difficulty in breathing or swallowing
  • behaviour- and mood-related changes: agitation, including aggressive behaviour or hostility, depression
  • seizure

Side effects that may be experienced in adults and adolescents are as follows:

Common (may affect up to 1 in 10 people)

  • headache
  • drowsiness

Uncommon (may affect up to 1 in 100 people)

  • abnormal ECG heart tracing
  • blood tests, which show changes in the way the liver is working
  • dizziness
  • stomach pain
  • tiredness
  • increased appetite
  • irregular heartbeat
  • increased weight
  • nausea (the feeling of being sick)
  • anxiety
  • dry or uncomfortable nose
  • belly pain
  • diarrhoea
  • gastritis (inflammation of the stomach wall)
  • vertigo (a feeling of dizziness or spinning)
  • feeling of weakness
  • thirst
  • dyspnoea (difficulty in breathing)
  • dry mouth
  • indigestion
  • itching
  • cold sores (oral herpes)
  • fever
  • tinnitus (ringing in the ears)
  • difficulty in sleeping
  • blood tests, which show changes in the way the kidneys are working
  • blood fats increased

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

  • palpitations (rapid, irregular heartbeat)
  • tachycardia (abnormally fast heartbeat)
  • vomiting

Rare (may affect up to 1 in 1,000 people)

  • increased bleeding tendency
  • tremor
  • palpitations

Very rare (may affect up to 1 in 10,000 people)

  • combination of symptoms such as flu-like illness, ‘pins and needles’ sensation or numbness of the arms and legs, worsening of pulmonary symptoms and/or rash (Churg-Strauss syndrome)
  • low blood platelet count
  • behaviour- and mood-related changes: hallucinations, disorientation, suicidal thoughts and actions
  • swelling (inflammation) of the lungs
  • severe skin reactions (erythema multiforme) that may occur without warning
  • inflammation of the liver (hepatitis)

How should BILAFAV M Suspension be stored?

  • Keep this medicine out of the sight and reach of children.
  • Store protected from light and moisture at a temperature not exceeding 30ºC.
  • Do not use this medicine after the expiry date, which is stated on the carton after EXP. The expiry date refers to the last day of that month.

General information about the safe and effective use of this drug

BILAFAV M Suspension contains bilastine 10 mg and montelukast 4 mg. Bilastine is a second-generation antihistamine medication that has high affinity and selectivity for the histamine H1 receptor, and montelukast is a leukotriene receptor antagonist that binds with high affinity and selectivity to the CysLT1 receptor. BILAFAV M Suspension is indicated for the treatment of allergic rhinitis in children 6 to 11 years of age.

  • Do not give this medicine, if your child has allergy to bilastine or montelukast or any of the other ingredients of this medicine.
  • Do not give this medicine to children under 6 years of age.
  • Do not exceed the recommended dose. If symptoms persist, consult your doctor.
  • There are no or limited amount of data from the use of bilastine and montelukast in pregnant women and during breastfeeding and on the effects on fertility. If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or your healthcare provider for advice before taking this medicine or before taking any medicine.
  • It has been demonstrated that bilastine 10 mg does not affect the driving performance in adults. However, the response from each patient to the medicine may be different. Therefore, the patient should check how this medicine affects him/her before driving or operating machinery.
  • If your child’s asthma or breathing gets worse, tell your doctor immediately.
  • BILAFAV M Suspension is not meant to treat acute asthma attacks. If an attack occurs, follow the instructions your doctor has given you for your child. Always have your child’s inhaled rescue medicine for asthma attacks with you.
  • It is important that your child takes all the asthma medications prescribed by your doctor. BILAFAV M Suspension should not be used instead of other asthma medications your doctor has prescribed for your child.
  • If your child is on anti-asthma medicines, be aware that if he/she develops a combination of symptoms such as flu-like illness, ‘pins and needles’ sensation or numbness of the arms or legs, worsening of pulmonary symptoms, and/or rash, you should consult your doctor.
  • Your child should not take acetyl-salicylic acid (aspirin) or anti-inflammatory medicines (also known as non-steroidal anti-inflammatory drugs or NSAIDs) if they make his/her asthma worse.
  • Please be aware that various neuropsychiatric events (for example, behaviour- and mood-related changes) have been reported in adults, adolescents and children taking medicine containing montelukast as a key ingredient. Thus, you should monitor for changes in behaviour or neuropsychiatric symptoms in your child.
  • If your child develops such symptoms while taking BILAFAV M Suspension,
    • discontinue BILAFAV M Suspension and contact a healthcare provider immediately if changes in behaviour or thinking that are not typical for your child occur, or if he/she develops suicidal ideation or suicidal behaviour.

What are the ingredients in BILAFAV M Suspension?

BILAFAV M Suspension contains bilastine 10 mg and montelukast 4 mg.

Details of The Manufacturer

Mfd. by: Synokem Pharmaceuticals Ltd.,

Plot No. 35-36, Sector-6A, Integrated Industrial Estate (SIDCUL), Ranipur,

(BHEL), Haridwar–249403 (Uttarakhand)

Marketed by: Cipla Ltd

Regd. Office: Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India

Details of Permission or Licence Number with Date

17/UA/2005

Date of Revision

21/03/2022