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Smicet-m
Composition
Each uncoated tablet contains:
Montelukast sodium equivalent to
Montelukast................................10 mg
Levocetirizine dihydrochloride.....5 mg
DESCRIPTION
Montelukast sodium is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
Levocetirizine, the R-enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors.
It has been demonstrated by recent studies that the treatment of AR with concomitant administration of an montelukast and an levocetirizine,
shows significantly better symptom relief compared with the modest improvement of rhinitis symptomatology with each of the treatments alone.
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 (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 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 min. After 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 inhibits 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,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.
Pharmacokinetics
Montelukast:
Absorption: After administration of the 10-mg film-coated tablet to fasted adults, the 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 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 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. 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 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 is 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 0.9 g h 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 the peak concentration is reduced and delayed.

Distribution:
No tissue distribution data are available in humans, neither concerning the passage of levocetirizine through the blood-brain-barrier. Levocetirizine is 90% bound to plasma proteins. 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 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.
Indications
Mon/levo are indicated for relief of symptoms of allergic rhinitis (seasonal and perennial).
Dosage and Administration
Adults ( >15 years ) : 1 tablet once daily
Contraindication
Mon/levo are 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. Aso contradicted in patients with severe renal impairment at less than 10 ml/min creatinine clearance.
Warning and Precautions
Montelukast:
Eosinophilic Conditions:
In rare cases, patients 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 with known aspirin sensitivity should continue avoidance of aspirin or non-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. Avoid concurrent use of alcohol or other central nervous system depressants with levocetirizine.
Drug Interactions
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 antiinflammatory 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. 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.

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 is to be exercised while prescribing this combination in patients with impaired hepatic function.

Pregnancy

There are no adequate and well controlled studies of either montelukast or levocetirizine in pregnant women. Because animal reproduction studies are not always predictive of human response, this combination should not be used during pregnancy only if it is considered to be clearly essential.

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.

Effects on ability to drive and use machines
Comparative clinical trials have revealed no evidence that levocetirizine at the recommended dose impairs mental alertness, reactivity or the ability to drive. Nevertheless, some patients could experience somnolence, fatigue and asthenia under therapy with Levocetirizine. Therefore, patients intending to drive, engage in potentially hazardous activities or operate machinery should take their response to the medicinal product into account.
Geriatric Use
Montelukast:
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Levocetirizine:
Clinical studies of levocetirizine for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

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

Montelukast
Common 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 aggressive behaviour, tremor, depression, suicidal thinking and behaviour (suicidality) in very 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.
Musculoskeletal and connective tissue disorders: arthralgia, myalgia including muscle cramps
General disorders and administration site conditions: asthenia/fatigue, malaise, oedema.
Very rare cases of Churg-Strauss Syndrome (CSS) have been reported during montelukast treatment in asthmatic patients. In rare cases, 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 causal association between Montelukast and these underlying conditions has not been established.

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.
In addition to the adverse reactions reported during clinical studies and listed above, very rare cases of the following adverse drug reactions have been reported 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 drug eruption, pruritus, rash, urticaria

* Musculoskeletal, connective tissues, and bone disorders: myalgia

* Investigations: weight increased, abnormal liver function tests
Overdosage
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.
 

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