Philcet Plus

Montelukast sodium, levocetirizine hydrochloride.

Each film-coated tablet contains: Montelukast (as sodium) 10 mg, Levocetirizine Hydrochloride 5 mg.
Montelukast Sodium: Montelukast sodium, the active ingredient in montelukast sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
Montelukast sodium 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 C₃₅H₃₅ClNNaO₃S, and its molecular weight is 608.18.
Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
Levocetirizine hydrochloride: Levocetirizine hydrochloride, the active component of levocetirizine hydrochloride tablets, is an orally active H1-receptor antagonist. The chemical name is (R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-1-piperazinyl] ethoxy] acetic acid hydrochloride. Levocetirizine hydrochloride is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties. The empirical formula of levocetirizine hydrochloride is C₂₁H₂₅ClN₂O₃•2HCl. The molecular weight is 461.82.
Levocetirizine hydrochloride is a white, crystalline powder and is water soluble.

Pharmacology: Pharmacodynamics: Montelukast Sodium: Montelukast is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, montelukast inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a β agonist was additive to that caused by montelukast. Treatment with montelukast inhibited both early- and late phase bronchoconstriction due to antigen challenge. Montelukast, compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with montelukast significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control. Circulating levels do not overcome the effect of telmisartan on blood pressure.
Levocetirizine hydrochloride: Studies in adult healthy subjects showed that levocetirizine at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine 2 2 1 21 25 2 3 1 1 exhibited no clear change in the inhibition of the wheal and flare reaction. Levocetirizine at a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown. A QT/QTc study using a single dose of 30 mg of levocetirizine did not demonstrate an effect on the QTc interval. While a single dose of levocetirizine had no effect, the effects of levocetirizine may not be at steady state following single dose. The effect of levocetirizine on the QTc interval following multiple dose administration is unknown. Levocetirizine is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long post-marketing history of cetirizine without reports of QT prolongation.
Mechanism of Action: Montelukast Sodium: 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 asthma, leukotriene-mediated effects include bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. 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.
Levocetirizine hydrochloride: 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 a receptor occupancy of 90% at 4 hours and 57% at 24 hours. 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 Sodium: Absorption: Montelukast is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 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 where 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 2 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 8-11 litres. Studies in rats with radiolabelled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.
Biotransformation: Montelukast is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and children. Cytochrome P450 2C8 is the major enzyme in the metabolism of montelukast. Additionally, CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of montelukast in healthy subjects that received 10 mg montelukast daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of montelukast is minimal.
Elimination: The plasma half-life in adults is 7.9 ± 1.9 hours. The half-life is shorter in small children. 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 feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.
Levocetirizine hydrochloride: 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 0.9 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 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. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the CNS compartment. In human, 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 half-life is shorter in small children. 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 feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion.

Montelukast and Levocetirizine combined therapy is prescribed for the systemic treatment of allergic reactions such as chronic urticaria, obstructive airway diseases and rhinitis.

Chronic asthma: Adult: 10 mg once daily in the evening.
Child: 2-5 yr: 4 mg daily; 6-14 yr: 5 mg daily; >15 yr: 10 mg once daily. All doses to be taken in the evening.
Allergic rhinitis: Adult: 10 mg once daily in the evening.
Prophylaxis of exercise-induced asthma: Adult: 10 mg at least 2 hr prior to exercise; do not admin additional doses within 24 hr.
Child: >15 yr: 10 mg at least 2 hr prior to exercise; do not admin additional doses within 24 hr.

Symptoms: Symptoms of overdose may include drowsiness in adults. In children, agitation and restlessness may initially occur, followed by drowsiness in children. 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.
Management of overdoses: There is no known specific antidote to levocetirizine. Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered shortly after ingestion of the drug. Levocetirizine is not effectively removed by hemodialysis.
No specific information is available on the treatment of overdose with montelukast. It is not known whether montelukast is dialysable by peritoneal- or haemo-dialysis were consistent with the safety profile in adults and paediatric patients.

It is contraindicated in: Patients who are hypersensitive to any component of this product or to Montelukast sodium, Levocetirizine or cetirizine.
Patients with completely impaired renal function (anuria).

Precaution is recommended with concurrent intake of alcohol (see Interactions).
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.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
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 β-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting β-agonists than usual.
Montelukast should not be substituted abruptly for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when montelukast is given concomitantly.
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.
This medicinal product contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Neuropsychiatric events have been reported in adults, adolescents, and children taking montelukast.
Use in Children: The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of levocetirizine.

Pregnancy: Animal studies do not indicate harmful effects with respect to effects on pregnancy or embryonal/foetal development. However must not use during pregnancy only if it is considered to be clearly essential.
Breast-Feeding: 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. It is unknown whether montelukast is excreted in human milk. Studies in rats have shown that montelukast is excreted in milk. Montelukast may be used in breast-feeding only if it is considered to be clearly essential.

Montelukast & Levocetirizine are generally well tolerated. Common side effects, which might be seen with the combination, are dyspepsia, abdominal pain, rash, dizziness, headache, fatigue, and somnolence. Sometimes, hypersensitivity, irritability, restlessness, insomnia, vomiting and diarrhoea may occur. In rare cases, patients may present with systemic eosinophilia, sometimes presenting with clinical features of consistent with Churg-Strauss Syndrome.
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 medicinal product at the recommended dose of 5 mg daily. From this pooling, following incidence of adverse drug reactions were reported at rates of 1 % or greater (common: ≥1/100 to <1/10) under levocetirizine 5 mg or placebo: See Table 1.

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Further uncommon incidences of adverse reactions (uncommon ≥1/1000, <1/100) like asthenia or abdominal pain were observed.
The incidence of sedating adverse drug reactions such as somnolence, fatigue, and asthenia was altogether more common (8.1 %) under levocetirizine 5 mg than under placebo (3.1%).
Paediatric 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. (See Table 2.)

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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. (See Table 3.)

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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.
Metabolism and nutrition disorders: Not known: increased appetite.
Psychiatric disorders: Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation, nightmare.
Nervous system disorders: Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia.
Ear and labyrinth disorders: Not known: vertigo.
Eyes disorders: Not known: visual disturbances, blurred vision, oculogyration.
Cardiac disorders: Not known: palpitations, tachycardia.
Gastrointestinal disorders: Not known: nausea, vomiting, diarrhea.
Hepatobiliary disorders: Not known: hepatitis.
Renal and urinary disorders: Not known: dysuria, urinary retention.
Skin and subcutaneous tissue disorders: Not known: angioneurotic edema, fixed drug eruption, pruritus, rash, urticaria.
Musculoskeletal, connective tissues, and bone disorders: Not known: myalgia, arthralgia.
General disorders and administration site conditions: Not known: edema.
Montelukast has been evaluated in clinical studies as follows: The following drug-related adverse reactions 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: See Table 4.

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With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric patients 6 to 14 years of age, the safety profile did not change.
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 5.)

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No interaction studies have been performed with levocetirizine (including no studies with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated that there were no clinically relevant adverse interactions (with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). A small decrease in the clearance of cetirizine (16%) was observed in a multiple dose study with theophylline (400 mg once a day); while the disposition of theophylline was not altered by concomitant cetirizine administration. In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
The extent of absorption of levocetirizine is not reduced with food, although the rate of absorption is decreased. In sensitive patients the concurrent administration of cetirizine or levocetirizine and alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.
Montelukast may be administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma. In drug-interactions studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following medicinal products: theophylline, prednisone, prednisolone, oral contraceptives (ethinyl estradiol/norethindrone 35/1), terfenadine, digoxin and warfarin.
The area under the plasma concentration curve (AUC) for montelukast was decreased approximately 40% in subjects with co-administration of phenobarbital. Since montelukast is metabolized by CYP 3A4, 2C8, and 2C9, caution should be exercised, particularly in children, when montelukast is co-administered with inducers of CYP 3A4, 2C8, and 2C9, such as phenytoin, phenobarbital and rifampicin.
In vitro studies have shown that montelukast is a potent inhibitor of CYP 2C8. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of medicinal products primarily metabolized by CYP 2C8) demonstrated that montelukast does not inhibit CYP 2C8 in vivo. Therefore, montelukast is not anticipated to markedly alter the metabolism of medicinal products metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).
In vitro studies have shown that montelukast is a substrate of CYP 2C8, and to a less significant extent, of 2C9, and 3A4. In a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) gemfibrozil increased the systemic exposure of montelukast by 4.4-fold. No routine dosage adjustment of montelukast is required upon co-administration with gemfibrozil or other potent inhibitors of CYP 2C8, but the physician should be aware of the potential for an increase in adverse reactions.

Store at temperatures not exceeding 30°C.

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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