Montair Lc Tablets

8/13/2019 Montair Lc Tablets

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Montelukast sodium & Levocetirizine dihydrochloride tablets

Montair LC Tablets

COMPOSITION

Each uncoated tablet contains:Montelukast sodium equivalent toMontelukast................................10 mgLevocetirizine dihydrochloride.....5 mgExcipients........................................q.s.

DOSAGE FORMOral Tablets

DESCRIPTIONMONTAIR LC Tablets is a combination ofMontelukast Sodium & Levocetirizine

Dihydrochloride.

Montelukast sodium is a selective and orally active leukotriene receptorantagonist that inhibits the cysteinyl leukotriene CysLT1receptor.

Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonistof peripheral H1-receptors.

It has been demonstrated by recent studies that the treatment of AR withconcomitant administration of an antileukotriene (montelukast) and anantihistamine (levocetirizine), shows significantly better symptom relief comparedwith the modest improvement of rhinitis symptomatology with each of thetreatments alone.

PHARMACOLOGYAs MONTAIR LC is a combination of Montelukast and Levocetirizine, thepharmacological properties of both the molecules are given separately:

PharmacodynamicsMontelukast:

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatoryeicosanoids 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 otherpro-inflammatory cells (including eosinophils and certain myeloid stem cells).CysLTs have been correlated with the pathophysiology of asthma and allergicrhinitis.


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In allergic rhinitis, CysLTs are released from the nasal mucosa after allergenexposure during both early- and late-phase reactions and are associated withsymptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shownto 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 ofLTD4at the CysLT1receptor without any agonist activity.

Levocetirizine:

Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selectiveantagonist of peripheral H1-receptors. Binding studies revealed that levocetirizinehas high affinity for human H1-receptors (Ki = 3.2 nmol/l). Levocetirizine has anaffinity 2-fold higher than that of cetirizine (Ki = 6.3 nmol/l). Levocetirizinedissociates from H1 -receptors with a half-life of 115 38 min. After singleadministration, levocetirizine shows receptor occupancy of 90% at 4 hours and57% at 24 hours.

The onset of action of levocetirizine 5 mg in controlling pollen-induced symptomshas been observed at 1 hour post drug intake in placebo controlled trials in themodel of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show thatlevocetirizine inhibits eotaxin-induced eosinophil transendothelial migrationthrough both dermal and lung cells. A pharmacodynamic experimental study invivo (skin chamber technique) showed three main inhibitory effects oflevocetirizine 5 mg in the first 6 hours of pollen-induced reaction, compared withplacebo in 14 adult patients: Inhibition of VCAM-1 release, modulation ofvascular permeability, and a decrease in eosinophil recruitment.

Pharmacodynamic studies in healthy volunteers demonstrate that, at half thedose, levocetirizine has comparable activity to cetirizine, both in the skin and inthe nose.

Pharmacokinetic/pharmacodynamic relationship: 5 mg levocetirizine provide asimilar pattern of inhibition of histamine-induced wheal and flare than 10 mgcetirizine. As for cetirizine, the action on histamine-induced skin reactions wasout of phase with the plasma concentrations. ECGs did not show relevant effectsof levocetirizine on QT interval.

PharmacokineticsMontelukast:

Absorption:After administration of the 10-mg film-coated tablet to fasted adults, the meanpeak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax).The mean oral bioavailability is 64%. The oral bioavailability and Cmax are notinfluenced by a standard meal in the morning.


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Distribution:Montelukast is more than 99% bound to plasma proteins. The steady-statevolume 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 steadystate 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 wasrecovered in 5-day fecal collections and


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conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 whilearomatic 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 concentrationsachieved following a 5 mg oral dose.

Due to its low metabolism and absence of metabolic inhibition potential, theinteraction 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 bodyclearance is 0.63 ml/min kg. The major route of excretion of levocetirizine andmetabolites is via urine, accounting for a mean of 85.4% of the dose. Excretionvia faeces accounts for only 12.9% of the dose. Levocetirizine is excreted bothby glomerular filtration and active tubular secretion.

INDICATIONSMONTAIR LC Tablets are indicated for relief of symptoms of allergic rhinitis(seasonal and perennial).

DOSAGE AND ADMINISTRATIONAdults (>15 years):1 tablet once daily

CONTRAINDICATIONSMONTAIR LC Tablets are contraindicated in patients with knownhypersensitivity to Montelukast, levocetirizine, to other piperazine derivatives, orto any of the excipients. Patients with rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency or glucose-galactose malabsorptionshould not take this medicine. Aso contradicted in patients with severe renalimpairment at less than 10 ml/min creatinine clearance.

WARNINGS AND PRECAUTIONSMontelukast:

Eosinophilic Conditions:In rare cases, patients on therapy with montelukast may present with systemiceosinophilia, sometimes presenting with clinical features of vasculitis consistentwith Churg-Strauss syndrome, a condition, which is often treated with systemiccorticosteroid therapy. These events usually, but not always, have beenassociated with the reduction of oral corticosteroid therapy. Physicians should bealert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiaccomplications, and/or neuropathy presenting in their patients. A causalassociation between Montelukast and these underlying conditions has not beenestablished.


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Patients with known aspirin sensitivity should continue avoidance of aspirin ornon-steroidal antiinflammatory agents while taking Montelukast.

Levocetirizine:

Avoid engaging in hazardous occupations requiring complete mental alertness

such as driving or operating machinery when taking levocetirizine. Avoidconcurrent use of alcohol or other central nervous system depressants withlevocetirizine.

Drug InteractionsMontelukast:

In drug-interaction studies, the recommended clinical dose of montelukast did nothave clinically important effects on the pharmacokinetics of the following drugs:theophylline, prednisone, prednisolone, oral contraceptives (norethindrone1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin.

Although additional specific interaction studies were not performed, montelukastwas used concomitantly with a wide range of commonly prescribed drugs inclinical studies without evidence of clinical adverse interactions. Thesemedications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Phenobarbital, which induces hepatic metabolism, decreased the AUC ofmontelukast approximately 40% following a single 10-mg dose of montelukast.No dosage adjustment for montelukast is recommended. It is reasonable toemploy appropriate clinical monitoring when potent cytochrome P450 enzymeinducers, such as phenobarbital or rifampin, are co-administered withmontelukast.

Levocetirizine:

In vitro data indicate that levocetirizine is unlikely to produce pharmacokineticinteractions 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 cetirizinedemonstrated that cetirizine did not interact with antipyrine, pseudoephedrine,erythromycin, azithromycin, ketoconazole and cimetidine. There was a smalldecrease (~16%) in the clearance of cetirizine caused by a 400 mg dose oftheophylline. It is possible that higher theophylline doses could have a greatereffect.

The extent of absorption of levocetirizine is not reduced with food, although therate of absorption is decreased.


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

In sensitive patients the simultaneous administration of cetirizine or levocetirizineand alcohol or other CNS depressants may have effects on the central nervoussystem, although it has been shown that the racemate cetirizine does notpotentiate the effect of alcohol.

Renal ImpairmentLevocetirizine is known to be substantially excreted by the kidneys and the risk ofadverse reactions to this drug may be greater in patients with impaired renalfunction. Dosage adjustment may be required in patients with impaired renalfunction. Hence this combination should be used with caution in such patients.

Hepatic ImpairmentAs levocetirizine is mainly excreted unchanged by the kidneys, it is unlikely thatthe clearance of levocetirizine is significantly decreased in patients with solelyhepatic impairment. But montelukast is mainly excreted through bile; caution isto be exercised while prescribing this combination in patients with impairedhepatic function.

PregnancyThere are no adequate and well controlled studies of either montelukast orlevocetirizine in pregnant women. Because animal reproduction studies are notalways predictive of human response, this combination should not be usedduring pregnancy only if it is considered to be clearly essential.

LactationIt is not known if montelukast is excreted in human milk. Cetirizine has beenreported to be excreted in human breast milk. Because levocetirizine is alsoexpected to be excreted in human milk this combination is not recommendedduring lactation.

Effects on ability to drive and use machinesComparative clinical trials have revealed no evidence that levocetirizine at therecommended dose impairs mental alertness, reactivity or the ability to drive.Nevertheless, some patients could experience somnolence, fatigue and astheniaunder therapy with Levocetirizine. Therefore, patients intending to drive, engagein potentially hazardous activities or operate machinery should take theirresponse to the medicinal product into account.

Geriatric UseMontelukast:


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No overall differences in safety or effectiveness were observed between thesesubjects and younger subjects, and other reported clinical experience has notidentified differences in responses between the elderly and younger patients, butgreater sensitivity of some older individuals cannot be ruled out.

Levocetirizine:

Clinical studies of levocetirizine for each approved indication did not includesufficient numbers of patients aged 65 years and older to determine whether theyrespond differently than younger patients. Other reported clinical experience hasnot identified differences in responses between the elderly and younger patients.In general, dose selection for an elderly patient should be cautious, usuallystarting at the low end of the dosing range reflecting the greater frequency ofdecreased hepatic, renal, or cardiac function and of concomitant disease or otherdrug therapy.

UNDESIRABLE EFFECTS

There is no data available on undesirable effects of this combination. However,side effects have been reported with individual molecules.

MontelukastCommon side effects include dyspepsia, abdominal pain, rash, dizziness,headache, fatigue, fever, trauma, cough, nasal congestion.

The following adverse reactions have been reported in post-marketing use:

Blood and lymphatic system disorders: increased bleeding tendency.Immune system disorders: hypersensitivity reactions including anaphylaxis,hepatic eosinophilic infiltration.

Psychiatric disorders: dream abnormalities including nightmares, hallucinations,insomnia, irritability, anxiety, restlessness, agitation including aggressivebehaviour, tremor, depression, suicidal thinking and behaviour (suicidality) invery rare cases.

Nervous system disorders: dizziness drowsiness, paraesthesia/hypoesthesia,seizure.

Cardiac disorders: palpitations.

Gastro-intestinal disorders: diarrhoea, dry mouth, dyspepsia, nausea, vomiting.

Hepatobiliary disorders: elevated levels of serum transaminases (ALT, AST),cholestatic hepatitis

Skin and subcutaneous tissue disorders: angiooedema, bruising, urticaria,pruritus, rash, erythema nodosum.


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Musculoskeletal and connective tissue disorders: arthralgia, myalgia includingmuscle cramps

General disorders and administration site conditions: asthenia/fatigue, malaise,oedema.

Very rare cases of Churg-Strauss Syndrome (CSS) have been reported duringmontelukast treatment in asthmatic patients. In rare cases, patients with asthmaon therapy with Montelukast may present with systemic eosinophilia, sometimespresenting with clinical features of vasculitis consistent with Churg-Strausssyndrome. A causal association between Montelukast and these underlyingconditions has not been established.

LevocetirizineUse 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 orabdominal pain were observed.

In addition to the adverse reactions reported during clinical studies and listedabove, very rare cases of the following adverse drug reactions have beenreported in post-marketing experience.

Immune system disorders: hypersensitivity including anaphylaxis

Psychiatric disorders: aggression, agitation

Nervous system disorders: convulsion

Eyes disorders: visual disturbances

Cardiac disorders: palpitations

Respiratory, thoracic, and mediastinal disorders: dyspnoea

Gastrointestinal disorders: nausea

Hepatobiliary disorders: hepatitis

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drugeruption, pruritus, rash, urticaria

Musculoskeletal, connective tissues, and bone disorders: myalgia

Investigations: weight increased, abnormal liver function tests


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OVERDOSAGEThere 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 andclinical studies with montelukast. These include reports in adults and childrenwith a dose as high as 1000 mg. The clinical and laboratory findings observedwere consistent with the safety profile in adults and pediatric patients. Therewere no adverse experiences in the majority of overdosage reports. The mostfrequently occurring adverse experiences were consistent with the safety profileof montelukast and included abdominal pain, somnolence, thirst, headache,vomiting and psychomotor hyperactivity.

It is not known whether montelukast is removed by peritoneal dialysis orhemodialysis.

LevocetirizineSymptoms of overdose may include drowsiness in adults. There is no knownspecific antidote to levocetirizine. Should overdose occur, symptomatic orsupportive treatment is recommended. Levocetirizine is not effectively removedby dialysis and dialysis will be ineffective unless a dialyzable agent has beenconcomitantly ingested.

PACKAGING INFORMATIONMONTAIR LC tablets Blister pack of 10 tablets

Last Updated: May 2009

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Montair Lc Tablets