Maxstine M Suspension

Bilastine & Montelukast Oral Suspension (10 mg + 4 mg)

Each 5 ml suspension contains :

Bilastine 10 mg

Montelukast Sodium IP

equivalent to Montelukast 4 mg

Flavoured syrupy base q.s.

Colour : Sunset Yellow FCF

Oral Suspension, Bilastine 10 mg & Montelukast 4 mg

4.1 Therapeutic indication

For treatment of allergic rhinitis in children aged 6 to 11 years (both inclusive) with a body weight of at least 20 kg.

4.2 Posology and method of administration Children (6 to 11 years of age)

5 ml once daily or as directed by the Physician.

Method of administration

For oral use only

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

4.3 Contraindications

Known hypersensitivity to Bilastine or Montelukast or any component of the formulation.

History of QT prolongation and/or torsade de pointes, including congenital long QT syndromes.

4.4 Special warnings and precautions for use Cardiovascular

It has been associated with QTc interval prolongation. Drugs that cause QT/QTc prolongation are suspected of increasing the risk of torsade de pointes. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QT/QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. It should not be used in patients with a history of QTc prolongation and/or torsade de pointes, including congenital long QT syndromes. Particular care should be exercised when administering antihistamines, including Bilastine to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. This includes patients who have a history of cardiac arrhythmias; hypokalemia; hypomagnesaemia; significant bradycardia; family history of sudden cardiac death; concomitant use of other QT/QTc-prolonging drugs. When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug.

Hepatic

It has not been studied in subjects with hepatic impairment. Since Bilastine is not metabolized and renal clearance is the major route of elimination, hepatic impairment is not expected to increase systemic exposure above the safety margin.

Renal

In subjects with moderate or severe renal impairment co-administration of Bilastine with P glycoprotein inhibitors, such as ketoconazole, erythromycin, cyclosporine, ritonavir or diltiazem, may increase plasma levels of Bilastine and therefore increase the risk of adverse effects. Co administration of Bilastine and P-glycoprotein inhibitors should be avoided in subjects with moderate or severe renal impairment.

Acute asthma

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. There are no data demonstrating that oral corticosteroids can be reduced when Montelukast is given concomitantly. Patients who have exacerbations of asthma after exercise should have available for rescue a shortacting inhaled beta2-agonist.

Concomitant corticosteroid use

While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.

Aspirin sensitivity

Patients with known aspirin sensitivity should continue avoidance of Aspirin or non-steroidal antiinflammatory agents while taking Montelukast. 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 Aspirinsensitive asthmatic patients.

Eosinophilic conditions

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 which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been 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. A causal association between Montelukast and these underlying conditions has not been established. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.

Neuropsychiatric events

Neuropsychiatric events have been reported in adult, adolescent, and paediatric patients taking Montelukast. Post-marketing reports with Montelukast use include agitation, aggressive behaviour or hostility, anxiousness, depression, disorientation, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behaviour (including suicide), tic, and tremor. The clinical details of some post-marketing reports involving Montelukast appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with Montelukast if such events occur

4.5 Drugs interactions

Interaction with Ketoconazole or Erythromycin

Concomitant intake of Bilastine and Ketoconazole or Erythromycin 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 metabolized. These changes do not appear to affect the safety profile of Bilastine and Ketoconazole or Erythromycin, respectively. Other medicinal products that are substrates or inhibitors of P-gp, such as Cyclosporine, may likewise have the potential to increase plasma concentrations of Bilastine.

Interaction with Diltiazem

Concomitant intake of Bilastine 20 mg and Diltiazem 60 mg increased 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 Lorazepam

Concomitant intake of Bilastine 20 mg and Lorazepam 3 mg for 8 days did not potentiate the depressant CNS effects of Lorazepam

Interaction with Alcohol

The psychomotor performance after concomitant intake of Alcohol and 20 mg Bilastine was similar to that observed after intake of Alcohol and placebo.

Interaction with Grapefruit juice

Concomitant intake of Bilastine 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 food

Food significantly reduces the oral bioavailability of Bilastine by 30%.

Paediatric population

No interaction studies have been performed in children with Bilastine orodispersible suspension. 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.

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 drugs : Theophylline, Prednisone, Prednisolone, Oral contraceptives (Norethindrone 1 mg / Ethinyl Estradiol 35 mcg), Terfenadine, Digoxin, Warfarin, Gemfibrozil, Itraconazole, Thyroid hormones, Sedative hypnotics, Non-steroidal anti-inflammator y agents, Benzodiazepines, Decongestants and Cytochrome P450 (CYP) enzyme inducers.
• In drug interaction studies, the recommended clinical dose of Montelukast did not have clinically important effects on the pharmacokinetics of the following drugs : Oral contraceptives (Norethindrone 1 mg / Ethinyl Estradiol 35 mcg), Terfenadine, Digoxin and Warfarin. Montelukast at doses of ≥ 100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing Norethindrone 1 mg / Ethinyl Estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of Terfenadine (a substrate of CYP3A4) or Fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with Terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of Warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).
• The area under the plasma concentration curve (AUC) for Montelukast was decreased approximately 40% in subjects with co-administration of Phenobarbital. Since Montelukast is metabolised by CYP 3A4, it is reasonable to employ appropriate clinical monitoring in children, when Montelukast is co-administered with inducers of CYP 3A4, such as Phenytoin, Phenobarbital and Rifampicin. • Although additional specific interaction studies were not performed, Montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, Benzodiazepines and Decongestants.
• 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). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
• 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.

4.6 Use in special populations

Pregnancy

There are no or limited amount of data from the use of Maxstine M 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 M during pregnancy. Maxstine M suspension may be used during pregnancy only if it is considered to be clearly essential.

Nursing mothers

The excretion of Maxstine M in milk has not been studied in humans. Available pharmacokinetic data in animals have shown excretion of Maxstine M 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 Maxstine M 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

Patients should be advised not to drive or use machines until they have established their own response to Maxstine M.

4.8 Undesirable effects

The following adverse reactions have been reported during clinical trials and are ranked using the following frequency :

Infections and infestations

Upper respiratory infection, Oral herpes.

Blood and lymphatic system disorders

Increased bleeding tendency, Thrombocytopenia.

Immune system disorder

Hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.

Metabolism and nutrition disorders

Increased appetite.

Psychiatric disorders

Anxiety, Insomnia, Dream abnormalities including nightmares, somnambulism, Agitation including

aggressive behaviour or hostility, Depression, Psychomotor hyperactivity (including irritability, restlessness, tremor), Disturbance in attention, Memory impairment, Hallucinations, disorientation, Suicidal thinking and behaviour (suicidality), Obsessive-compulsive symptoms, Dysphemia.

Nervous system disorders

Somnolence, Headache, Dizziness, Drowsiness paraesthesia/hypoesthesia, Seizure.

Ear and labyrinth disorders

Uncommon - Tinnitus, Vertigo.

Cardiac disorders

Right bundle branch block, Sinus arrhythmia, Electrocardiogram QT prolonged, Palpitations.

Respiratory, thoracic and mediastinal disorders

Dyspnoea, Nasal discomfort, Nasal dryness, Epistaxis, Churg-Strauss Syndrome (CSS), Pulmonary eosinophilia.

Gastrointestinal disorders

Nausea, Stomach discomfort, Abdominal pain, Diarrhoea, Dry mouth, Dyspepsia, Gastritis, Vomiting.

Hepatobiliary disorders

Elevated levels of serum transaminases (ALT, AST), Hepatitis (including cholestatic, hepatocellular and mixed-pattern liver injury).

Skin and subcutaneous tissue disorders

Pruritus, rash, Bruising, Urticaria, Angioedema, Erythema nodosum, Erythema multiforme.

Musculoskeletal and connective tissue disorders

Arthralgia, Myalgia including muscle cramps

General disorders and administration site conditions

Fatigue, Thirst, Pyrexia, Asthenia, Malaise, Oedema.

Renal and urinary disorders

Enuresis in children.

Investigations

Increased gammaglutamyltransferase, Increased ALT and AST, Increased blood creatinine, Increased Blood TG, Increased weight.

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

4.9 Overdose

Information regarding acute overdose of Bilastine is retrieved from the experience of clinical trials conducted during the development and the post-marketing surveillance. In clinical trials, after administration of Bilastine at doses 10 to 11 times the therapeutic dose (220 mg as single dose or 200 mg/day for 7 days) to 26 adult healthy volunteer’s 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. 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 one week without clinically important adverse experiences. There have been reports of acute overdose in post-marketing experience and clinical studies with Montelukast. These include reports in adults and children with a dose as high as 1000 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. In the event of overdose symptomatic and supportive treatment is recommended.

5.1 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

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs 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.

5.2 Pharmacodynamic properties

Bilastine

Highly selective for H1 receptors, but has little or no affinity for other receptors. In vitro binding affinity of Maxstine M to H1 receptors was 3-fold higher than that of cetirizine and 5-fold higher than that of Fexofenadine.

Potent and lasting antihistamine action at least similar to cetirizine and superior to Fexofenadine (4 to 11 times).

Rapid onset of action and possesses antihistaminic as well as anti-allergic properties Maxstine M is a “Non- brain-penetrating antihistamine” which has brain H1 receptor occupancy (H1RO) is nearly 0%.

Montelukast

Montelukast is an orally active compound which 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 β 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

5.3 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

In vitro and in vivo studies have shown that Bilastine is a substrate Interaction with Ketoconazole or Erythromycin and Interaction with Diltiazem and OATP Interaction with grapefruit juice. At therapeutic doses Bilastine is 84 - 90% bound to plasma proteins.

Biotransformation

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

Elimination

In a mass balance study performed in healthy adult volunteers, after administration of a single dose 14 of 20 mg C-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.

Montelukast

Absorption

Montelukast is rapidly and nearly completely absorbed following oral administration. Peak plasma concentrations of Montelukast occur 2 to 4 hours after oral doses. The mean oral bioavailability is 64% to 73%. The oral bioavailability and Cmax are not influenced by a standard meal. For the 4 mg chewable suspension, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.

Distribution

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

Metabolism

Montelukast is extensively metabolized in the liver by cytochrome P450 isoenzymes, mainly by CYP2C8 and to a lesser extent by CYP3A4 and CYP2C9. Therapeutic plasma concentrations of Montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and pediatric patients.

Elimination

The plasma clearance of Montelukast averages 45 ml/min in healthy adults. Montelukast and its metabolites are excreted principally in the faeces via the bile. Elimination Half-life : 2.7 to 5.5 hours. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day fecal 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.

6.1 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 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 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.

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, gastro-intestinal symptoms, loose stools and ion imbalance. These occurred at dosages which 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 breast milk of animals. No deaths occurred following a single oral administration of Montelukast sodium at doses up to 5000 mg/kg 2 2 in mice and rats (15,000 mg/m and 30,000 mg/m 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 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 tumorigenic in rodent species.

Bilastine is a novel, benzimidazole-piperidine derivative that is a highly selective second-generation H1 antihistamine. Montelukast sodium, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

A bottle of 60 ml.

8.4 Storage and handing instructions Store at a temperature not exceeding 30°C, protected from light and moisture.

Keep out of reach of children.

Keep bottle well closed after every use.

• Do not take this medicine, if you are allergic to Bilastine or Montelukast.
• Signs of an allergic reaction include a rash, itching or shortness of breath.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
• Be alert for changes in behaviour or new neuropsychiatric symptoms when taking Montelukast sodium. If changes in behaviour are observed, or if new NP symptoms or suicidal thoughts and/or behaviour occur, advise patients to discontinue Montelukast sodium and contact a healthcare provider immediately.
• If you have any further questions, ask your doctor or pharmacist.

20 October 2022