Zykids Forte

Each chewable tablet contains: Montelukast (as sodium), USP 5 mg, Levocetirizine hydrochloride, USP 5 mg.

Pharmacology: Pharmacodynamics: 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 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 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.
Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.
Levocetirizine: Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H₁-receptors. Binding studies revealed that Levocetirizine has high affinity for human H₁-receptors (Ki = 3.2 nmol/L). Levocetirizine has an affinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/L). Levocetirizine dissociates from H₁-receptors with a half-life of 115 ± 38 minutes.
After a single administration, levocetirizine shows receptor occupancy of 90% at 4 hours and 57% at 24 hours.
The onset of action of Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1 hour post drug intake in placebo controlled trials in the model of the allergen challenge chamber.
In vitro studies (Boyden chambers and cell layers techniques) show that Levocetirizine exhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo skin chamber technique) showed three main inhibitory effects of Levocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared with placebo in 14 adult patients: Inhibition of VCAM-1 release modulation of vascular permeability, and a decrease in eosinophil recruitment.
Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
Pharmacokinetic/pharmacodynamic relationship: 5 mg Levocetirizine provide a similar pattern of inhibition of histamine-induced wheal and flare than 10 mg Cetirizine. As for cetirizine, the action on histamine-induced skin reactions was out of phase with the plasma concentrations. ECGs did not show relevant effects of Levocetirizine on QT interval.
Pharmacokinetics: Montelukast: Absorption: Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved three 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 were 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 in two hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
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 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. Following an oral dose of radiolabeled 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 extensively via the bile. In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Montelukast is nearly linear for oral doses up to 50mg. During once-daily dosing with 10mg Montelukast, there is little accumulation of the parent drug in plasma (14%).
Levocetirizine: The pharmacokinetics of levocetirizine is linear with dose and time independent with low intersubject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.
Absorption: Levocetirizine is rapidly and extensively absorbed following oral administration. Peak plasma concentrations are achieved 0.9 g h after dosing. Steady state is achieved after two days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg dose once daily, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: Tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier.
The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 L/kg.
Biotransformation: 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. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5 mg oral dose.
Due to its low metabolism and absence of metabolic inhibition potential, the interaction of levocetirizine with other substances, or vice-versa, is unlikely.
Elimination: The plasma half-life in adults is 7.9 ± 1.9 hours. The mean apparent total body clearance in adult is 0.63 mL/min kg. 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.

Montelukast plus Levocetirizine is indicated for the relief of symptoms associated with seasonal and perennial allergic rhinitis.

Patients with hepatic disease: No dosage adjustment is needed in patients solely with mild to moderate hepatic impairment. Usage is not recommended in patients with severe hepatic impairment.
Children and Adolescents: Children aged 6-14: one chewable tablet containing 5 mg Montelukast and 2.5 mg Levocetirizine or 5 mg Montelukast and 5 mg Levocetirizine once daily. Or as prescribed by the physician.

There is no data reported on the overdosage of this combination. However, overdosage has been reported with individual molecules.
Montelukast: There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of Montelukast and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
Levocetirizine: Symptoms of overdose may include drowsiness in adults. There is no known specific antidote to Levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Levocetirizine is not effectively removed by dialysis and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested.

It is contraindicated in patients with known hypersensitivity to montelukast, levocetirizine, to other piperazine derivatives or to any of the excipients. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Also, contraindicated in patients with severe renal impairment at less than 10 mL/min creatinine clearance.

Montelukast: Eosinophilic conditions: In rare cases, patients on therapy with anti-asthma agents including montelukast may present with systematic 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, vasculitis 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 with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking Montelukast.
Neuropsychiatric events have been reported in adults, adolescents, and children.
Levocetirizine: Caution should be taken in patients with predisposing factors of urinary retention (e.g., spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of urinary retention.
Caution should be taken in patients with epilepsy and patients at risk of convulsion as levocetirizine may cause seizure aggravation. Response to allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.
Pruritus may occur when levocetirizine is stopped even if those symptoms were not present before treatment initiation. The symptoms may resolve spontaneously. In some cases, the symptoms may be intense and may require treatment to be restarted. The symptoms should resolve when the treatment is restarted. Avoid concurrent use of alcohol with Levocetirizine.
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 should be used with caution in such patients.
Hepatic Impairment: 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 must be exercised while prescribing this combination in patients with impaired hepatic function.

Montelukast: Montelukast has been evaluated for clinical studies in approximately 4,000 adult and adolescent patients 15 years of age and older for 10 mg and approximately 1,750 paediatric patients and adolescents 6 to 14 years of age for 5 mg.
The following drug related adverse reaction in clinical studies were reported commonly (≥1/100 to <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo: Adult and Adolescent Patients 15 years and older (two 12-week studies; n=795 (A), Paediatric Patients 6 to 14 years old (one 8-week study; n=201) (two 56-week studies; n=615) (P), Nervous system disorders: (A) headache, (P) headache, Gastrointestinal disorders: (A) abdominal pain.
Tabulated list of Adverse Reactions: Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Experience Term, in the table as follows. Frequency Categories were estimated based on relevant clinical trials. (See Table.)

Click on icon to see table/diagram/image

Levocetirizine: Adults and adolescents above 12 years of age: In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in the Levocetirizine 5 mg group had at least one adverse drug reaction compared to 11.3% in the placebo group. 91.6% of these adverse drug reactions were mild to moderate. In therapeutic trials, the dropout rate due to adverse events was 1.0% (9/935) with Levocetirizine 5 mg and 1.8% (14/771) with placebo. Clinical therapeutic trials with Levocetirizine included 935 subjects exposed to the drug at the recommended dose of 5 mg daily. From this data, the following adverse drug reactions were reported at rates of 1% or greater during treatment with Levocetirizine 5 mg (L) or placebo (P): Headache: L (2.6%), P (3.2%). Somnolence: L (5.2%), P (1.4%). Dry Mouth: L (2.6%), P (1.6%). Fatigue: L (2.5%), P (1.2%).
Pediatric population: In two placebo-controlled studies in pediatric patients aged 6-11 months and aged 1 year to less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for 2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo (L) or placebo (P); Diarrhea: L (1.9%), Vomiting: L (0.6%), P (1.2%). Constipation: L (1.3%), Somnolence: L (1.9%), P (2.4%), Sleep disorder: L (1.3%).
In children aged 6-12 years double blind placebo controlled studies were performed where 243 children were exposed to 5 mg levocetirizine daily for variable periods ranging from less than 1 week to 13 weeks. The following incidence of adverse drug reactions was reported at rates of 1% or greater under levocetirizine or placebo (L) or placebo (P); Headache: L (0.8%), P (2.1%), Somnolence: L (2.9%), P (0.4%).
List of Adverse Reactions: Adverse reaction from post-marketing experience are per System Organ Class and per frequency. The frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).
Immune system disorders: Not known: hypersensitivity including Anaphylaxis.
Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare.
Ear and labyrinth disorders: Not known: vertigo.
Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration.
Cardiac disorders: Not known: palpitations, tachycardia.
Respiratory, thoracic and mediastinal disorders: Not known: dyspnoea.
Gastrointestinal disorders: Not known: nausea, vomiting, diarrhoea.
Hepatobiliary disorders: Not known: hepatitis.
Renal and urinary disorders: Not known: dysuria, urinary retention.
Skin and subcutaneous tissue disorders: Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria not known (cannot be estimated from the available data).
Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia.
General disorders and administration site conditions: Not known: oedema.
Investigations: weight increased, abnormal liver function tests. After levocetirizine discontinuation, pruritus has been reported.

Montelukast: In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin and warfarin.
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.
Phenobarbital which induces hepatic metabolism decreased the AUC of Montelukast approximately 40% following single 10mg dose of Montelukast. No dosage adjustment for Montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers such as phenobarbital or rifampin are co-administered with Montelukast.
Levocetirizine: In vitro data indicate that Levocetirizine unlikely to produce pharmacokinetic interactions through inhibition or induction of liver drug-metabolizing enzymes. No in-vivo drug-drug interaction studies have been performed with Levocetirizine. Drug interaction studies have been performed with racemic cetirizine Pharmacokinetic interaction studies have been perfomed with racemic demonstrated that cetirizine did not interact with antipyrine, pseudoephedrine, erythromycin, 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 greater effect. The extent of absorption of Levocetirizine is not reduced with food, although the rate of absorption is decreased.
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. In sensitive patients, the simultaneous administration of cetirizine or Levocetirizine and alcohol or other CNS depressants may have effects on the central nervous system although it has been shown that the racemate cetirizine does not potentiate the effect of alcohol.

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

Antihistamines & Antiallergics

R03DC53 - montelukast, combinations ; Belongs to the class of leukotriene receptor antagonists. Used in the systemic treatment of obstructive airway diseases.

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