Montelukast sodium, levocetirizine hydrochloride.
Orange colour round shape, biconvex film-coated tablets.
Each film-coated tablet contains: Montelukast Sodium BP equivalent to Montelukast 10 mg, Levocetirizine Hydrochloride (as Dihydrochloride) 5 mg.
Pharmacology: Pharmacodynamics: Pharmacodynamic properties: As Montelukast + Levocetirizine HCl (Leukast Plus) is a combination of Montelukast and Levocetirizine; the pharmacological properties of both the molecules are given separately.
Montelukast: Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics.
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 min. 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.
Pharmacokinetics: Montelukast: Absorption: Mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.
Distribution: Montelukast is more than 99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8 to 11 liters.
Metabolism: Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in pediatric patients.
Elimination: Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urines. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (~14%).
Levocetirizine: The pharmacokinetics of levocetirizine are linear with dose and time-independent with low inter-subject 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 0.9h after dosing. Steady state is achieved after two days. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.
Distribution: No tissue distribution data are available in humans. Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is restrictive, as the volume of distribution is 0.4 L/kg.
Biotransformations: 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.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Levocetirizine: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.
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 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 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 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.
Levocetirizine: Indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis; the relief of symptoms of chronic idiopathic urticaria.
Montelukast: Montelukast is indicated in the treatment of asthma as add-on therapy in those 6 months to 5 year old patients with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom "as-needed" short acting beta-agonists provide inadequate clinical control of asthma.
Montelukast may also be an alternative treatment option to low-dose inhaled corticosteroids for 2 to 5 year old patients with mild persistent asthma who do not have a recent history of serious asthma attacks that required oral corticosteroid use, and who have demonstrated that they are not capable of using inhaled corticosteroids.
Montelukast is also indicated in the prophylaxis of asthma from 2 years of age and older in which the predominant component is exercise-induced bronchoconstriction.
For treatment of allergic rhinitis and chronic asthma.
(Adults): Consider administration of 10 mg once a day in the evening.
For Prophylaxis of exercise-induced asthma.
(Adults): Consider administration of 10 mg of Montelukast + Levocetirizine HCl (Leukast Plus), at least two hours before exercise.
Or as prescribed by the physician.
There is no data to prove 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 and initially agitation and restlessness followed by drowsiness, in children. 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.
Montelukast + Levocetirizine HCl (Leukast Plus) is contraindicated in patients with known hypersensitivity to montelukast sodium, levocetirizine or cetirizine or to any other component of this product. Montelukast + Levocetirizine HCl (Leukast Plus) is also contraindicated in patients with severe renal impairment at less than 10 mL/min creatinine clearance. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.
Use in Pregnancy & Lactation: See Use in Pregnancy & Lactation for further information.
Levocetirizine: Do not exceed the stated dose.
The use of levocetirizine hydrochloride is not recommended in children aged less than 6 years.
At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.
Caution in epileptic patients and patients at risk of convulsions is recommended.
Montelukast: The diagnosis of persistent asthma in very young children (6 months-2 years) should be established by a paediatrician or pulmonologist.
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.
Montelukast should not be abruptly substituted for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.
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 which is often treated with systemic corticosteroid therapy. These cases usually, but not always, have been associated with the reduction or withdrawal of oral corticosteroid therapy. The possibility that leukotriene receptor antagonists may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established. Physicians should be alert to eosinophilia, vasculitic 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.
Treatment with montelukast does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.
Renal Impairment: As levocetirizine is mainly excreted through urine, 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 montelukast is mainly excreted through bile, caution is to be exercised while prescribing this combination in patients with impaired hepatic function.
Effects on ability to drive and use machines: Montelukast + Levocetirizine HCl (Leukast Plus) is not expected to affect a patient's ability to drive a car or operate machinery.
However, in very rare cases, individuals have reported drowsiness or dizziness.
Pregnancy USFDA pregnancy category B. Montelukast + Levocetirizine HCl (Leukast Plus) may not cause harm to an unborn foetus. Before Montelukast treatment, the patient should discuss with the physician, if they are planning for a pregnancy.
Nursing Mother: It is unclear whether the drug could pass through the breast milk to a breast feeding baby. Consult a physician before taking Montelukast + Levocetirizine HCl (Leukast Plus), if the patient is a nursing mother.
Pregnancy: Levocetirizine: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no malformative or feto/neonatal toxicity. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development.
The use of levocetirizine may be considered during pregnancy, if necessary.
Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human.
Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions associated with levocetirizine may be observed in breastfed infants. Therefore, caution should be exercised when prescribing levocetirizine to lactating women.
Montelukast: Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development.
Limited data from available pregnancy databases do not suggest a causal relationship between montelukast and malformations (i.e. limb defects) that have been rarely reported in worldwide post marketing experience.
Montelukast may be used during pregnancy only if it is considered to be clearly essential.
Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk.
Montelukast may be used in breastfeeding mothers only if it is considered to be clearly essential.
Montelukast: Common side effects include dyspepsia, abdominal pain, rash, dizziness, headache, fatigue, fever, trauma, cough, nasal congestion.
Levocetirizine: Use of levocetirizine has been associated with somnolence, fatigue, nasopharyngitis, dry mouth, and pharyngitis in subjects 12 years of age and older. Further uncommon incidences of adverse reactions like asthenia or abdominal pain were observed.
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, prednisone, 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 a single 10-mg 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 is 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 performed with racemic cetirizine 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 a greater effect.
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.
Store at temperatures not exceeding 30°C.
R03DC53 - montelukast, combinations ; Belongs to the class of leukotriene receptor antagonists. Used in the systemic treatment of obstructive airway diseases.
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