Montelukast Sodium & Levocetirizine Hydrochloride Dispersible Tablets [4 mg + 2.5 mg]

Each uncoated dispersible tablet contains:

Montelukast Sodium IP

equivalent to Montelukast 4 mg

Levocetirizine Hydrochloride IP 2.5 mg

Excipients q.s.

Colour: Lake of Quinoline Yellow

Dispersible tablet [4 mg + 2.5 mg]

4.1 Therapeutic indications

For relief of symptoms of allergic rhinitis (seasonal and perennial).

4.2 Posology and method of administration

Children (2-5 years): 1 tablet once daily Nukast ® 4DT Tablet can be taken with or without food.

Hepatic Impairment No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency.

Directions for use:

Disperse the tablet in one teaspoonful of previously boiled & cooled water before administration.

4.3 Contraindications

• Known hypersensitivity to montelukast, levocetirizine or cetirizine, or to any of the excipients.
• End stage renal disease at less than 10 ml/min creatinine clearance.
• Patients undergoing haemodialysis.
• Children with impaired renal function.

4.4 Special warnings and precautions for use

Montelukast

Acute Asthma: Montelukast is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β2-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 anti-inflammatory agents while taking montelukast.

Eosinophilic Conditions: Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

Neuropsychiatric Events: Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast if such events occur.

Phenylketonuria: Phenylketonuric patients should be informed about the presence of phenylalanine (a component of aspartame) in this product.

Levocetirizine

Somnolence: Concurrent use of levocetirizine with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

Urinary Retention: Levocetirizine should be used with caution in patients with predisposing factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention. Discontinue, if urinary retention occurs.

4.5 Drug Interactions

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 and warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal antiinflammatory agents, benzodiazepines, decongestants, and CYP 450 enzyme inducers. 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, caution should be exercised, particularly 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.

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.

Levocetirizine

In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to metabolic interactions. Levocetirizine at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4. No in vivo drug-drug interaction studies have been performed with levocetirizine. Drug interaction studies have been performed with racemic cetirizine.

Antipyrine, Azithromycin, Cimetidine, Erythromycin, Ketoconazole, Theophylline, and Pseudoephedrine

Pharmacokinetic interaction studies performed with racemic cetirizine demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, glipizide and diazepam, azithromycin, ketoconazole and cimetidine. There was a small decrease (~16%) in the clearance of cetirizine caused by a 400 mg dose of theophylline. It is possible that higher theophylline doses could have a greater effect.

The extent of absorption of levocetirizine is not reduced with food although the rate of absorption is decreased.

Ritonavir

Ritonavir increased the plasma AUC of cetirizine by about 42% accompanied by an increase in half-life (53%) and a decrease in clearance (29%) of cetirizine. The disposition of ritonavir was not altered by concomitant cetirizine administration.

4.6 Use in special populations

Paediatric

The safety and efficacy of levocetrizine in paediatric patients under 2 years of age have not been established.

Pregnancy

No clinical studies available in human pregnancy. Therefore, Nukast ® 4DT Tablet should not be used in pregnancy.

Lactation

It is not known if montelukast is excreted in human milk. Cetirizine has been reported to be excreted in human breast milk. Because levocetirizine is also expected to be excreted in human milk this combination is not recommended during lactation.

Hepatic insufficiency

As levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely that the clearance of levocetirizine is significantly decreased in patients with solely hepatic impairment. But montelukast is mainly excreted through bile; caution is to be exercised while prescribing this combination in patients with impaired hepatic function. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis has not been evaluated.

Renal impairment

Levocetirizine is known to be substantially excreted by the kidneys and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Dosage adjustment may be required in patients with impaired renal function. Hence this combination is not recommended in patients with impaired renal function. Driving and using machines

4.7 Effects on ability to drive and use machines

Nukat has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.

4.8 Undesirable effects

Montelukast

The most common adverse reactions (incidence ≥ 5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.

Pediatric Patients 2 to 5 Years of Age (≥ 2%)

Asthma: Fever, cough, abdominal pain, diarrhea, headache, rhinorrhea, sinusitis, otitis, influenza, rash, ear pain, gastroenteritis, eczema, urticaria, varicella, pneumonia, dermatitis, and conjunctivitis, thirst.

Pediatric Patients 2 to 14 Years of Age (≥ 2%)

Seasonal Allergic Rhinitis: Headache, otitis media, pharyngitis, and upper respiratory infection.

Pediatric Patients 6 to 23 Months of Age with Asthma (≥ 2%)

upper respiratory infection, wheezing; otitis media; pharyngitis, tonsillitis, cough; and rhinitis.

Levocetirizine

Use of levocetirizine has been associated with somnolence, fatigue, asthenia, and urinary retention.

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: www.medico@zuventus.com
• Website: https://www.zuventus.com/drug-safety-reporting

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

4.9 Overdose

No specific information is available on the treatment of overdosage with Nukast ® 4DT Tablet. Symptoms of overdose may include drowsiness, abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. Gastric lavage should be considered following short-term ingestion of Nukast ® 4DT Tablet.

5.1 Pharmacodynamic properties

Montelukast

The cysteinyl leukotrienes (LTC 4 , LTD 4 , LTE 4 ) are products of arachidonic acid metabolism and are released from various cells including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT 1 ) 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 airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. 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. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT 1 receptor. Montelukast inhibits physiologic actions of LTD 4 at the CysLT 1 receptor without any agonist activity.

Levocetirizine

Levocetirizine is the R-enantiomer and the active form of cetirizine. It is an orally active, potent, selective and long acting H 1 -histamine receptor antagonist with no anticholinergic activity. It blocks the binding of histamine to H 1 receptors thus preventing its systemic effects, such as vasodilation, edema, mucous secretion, and smooth muscle contraction. This results in providing relief from the symptoms of allergic rhinitis and asthma including sneezing, itching, rhinorrhea, dyspnea, bronchial hypersensitivity and mucus accumulation.

It has been demonstrated by recent studies that the treatment of Allergic rhinitis and asthma with concomitant administration of an anti-leukotriene (montelukast) and an antihistamine (levocetirizine), shows significantly better symptom relief and additional improvement in quality of life when compared with each agent given alone.

5.2 Pharmacokinetic Properties

Absorption: For the 4 mg chewable tablet, the mean C max is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state. The safety of montelukast in patients with asthma was also demonstrated in clinical trials in which the 4 mg chewable tablets were administered in the evening without regard to the time of food ingestion.

Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 g hour after dosing. Steady state is achieved after two days. Peak concentrations are typically 270ng/ml and 308ng/ml following a single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food, but T max was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, levocetirizine can be administered with or without food.

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 postdose were minimal in all other tissues.

The mean plasma protein binding of levocetirizine in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.

Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.

The extent of metabolism of levocetirizine in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation.

Elimination: The plasma clearance of montelukast averages 45 mL/min in healthy adults. 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.

The plasma half-life in healthy adult subjects was about 8 to 9 hours after administration of oral tablets and oral solution. The mean apparent total body clearance is 0.63 ml/ kg/ min. The major route of excretion of levocetirizine and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via faeces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance.

6.1 Animal Toxicology or Pharmacology

Montelukast sodium was found not to be genotoxic. Montelukast sodium was negative in microbial and mammalian cell mutagenesis assays, with and without metabolic activation. There was no evidence of clastogenic activity in the in vitro chromosomal aberration assay in Chinese Hamster Ovary cells, with or without a microsomal enzyme activation system, or of DNA damage in the in vitro alkaline elution assay in rat hepatocytes. Similarly, there was no induction of chromosomal aberrations in bone marrow cells of male or female mice.

Montelukast sodium was not carcinogenic when administered at oral doses of up to 200 mg/kg/day in 104-week study in rats, nor at oral doses up to 100 mg/kg/day in a 91-week study in mice. Systemic exposure in these studies, in terms of the plasma AUC for parent drug, was at least 30 times higher than that in humans at recommended dose levels.

Levocetrizine

Levocetirizine is the R-enantiomer of the marketed cetirizine. The long term oral toxicity, fertility and early developmental and prenatal postnatal developmental toxicity studies with cetirizine represent the toxicity profile of levocetirizine with supplemental bridging toxicity, developmental and genotoxicity studies conducted with levocetirizine. In genotoxicity studies, cetirizine was negative in the Ames, Human Peripheral

Lymphocytes

Chromosomal Aberration, Mouse Lymphoma and Mouse Micronucleus assays. Levocetirizine, In the carcinogenicity studies in rodents, the dietary doses were 1, 4 and 16 mg/kg for the mouse and 3, 8 and 20 mg/kg for the rat. The rats showed liver toxicity (hypertrophy, vacuolation and fat deposit). No tumors were seen in rats that were clinically significant, while male mice showed benign liver tumors which were due to enzyme induction.

Levocetirizine hydrochloride, is an orally active H1-receptor antagonist. The chemical name is 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid;hydrochloride.

Levocetirizine dihydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine dihydrochloride is C₂₁H₂₆Cl₂N₂O₃ . The molecular weight is 425.3 g/mol and the chemical structure is shown below:

Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT 1 receptor. Montelukast sodium USP is described

chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl]thio]methyl]   cyclopropaneacetic acid, monosodium salt. The empirical formula is C 35 H 35 CINNaO 3 S, and its molecular weight is 608.17. The structural formula is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

30 Months

Packaging information

100 ml bottle

8.4 Storage and handling instructions

Store in a dry place below 30°C, away from light and moisture.

Keep out of reach of children.

Nature and contents of container

Blister ALU-ALU 1x10T

• Somnolence Caution patients against engaging in activities requiring complete mental alertness, and motor coordination after ingestion of levocetirizine dihydrochloride oral solution.
• Concomitant Use of Alcohol and other Central Nervous System Depressants Instruct patients to avoid concurrent use of levocetirizine dihydrochloride oral solution with alcohol or other central nervous system depressants because additional reduction in mental alertness may occur.
• Advise patients to not ingest more than the recommended dose of levocetirizine dihydrochloride oral solution because of the increased risk of somnolence at higher doses.
• Advise patients about the potential risk for serious neuropsychiatric symptoms and behavioral changes with montelukast sodium use.
• Discuss the benefits and risks of montelukast sodium with patients when prescribing or continuing treatment with montelukast sodium.
• Advise patients to monitor for changes in behavior or neuropsychiatric symptoms in patients taking montelukast sodium.
• Instruct patients to discontinue montelukast sodium and contact a healthcare provider immediately if changes in behavior or thinking that are not typical for the patient occur, or if the patient develops suicidal ideation or suicidal behavior.
• Advise patients to take montelukast sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
• Advise Patients that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes.
• Advise patients to seek medical attention if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
• Instruct patients to continue other anti-asthma medications as prescribed unless instructed by a physician.
• Instruct patients with known aspirin sensitivity to continue avoidance of aspirin or non- steroidal anti-inflammatory agents while taking montelukast sodium.