FORMULATION

Each film-coated tablet contains:
Montelukast sodium is equivalent to montelukast 5mg
Cetirizine hydrochloride is equivalent to cetirizine 5mg
Montelukast sodium is equivalent to montelukast 10mg
Cetirizine hydrochloride is equivalent to cetirizine 10mg

Each chewable tablet contains:

Montelukast sodium is equivalent to montelukast 5mg
Cetirizine hydrochloride is equivalent to cetirizine 10mg

Each fast melt tablet contains:
Montelukast sodium is equivalent to montelukast 4mg
Cetirizine hydrochloride is equivalent to cetirizine 5mg)

INDICATIONS

MONTELUKAST PLUS CETIRIZINE is indicated for the relief of symptoms associated with seasonal and perennial allergic rhinitis, and chronic urticaria.

CONTRAINDICATIONS

MONTELUKAST PLUS CETIRIZINE is contraindicated in patients with a known hypersensitivity to Montelukast or Cetirizine, patients with severe renal (creatinine clearance less than 10 ml/min) or hepatic impairment, in children 6-11 years of age with renal impairment, and during women who are pregnant or breastfeeding.

DOSAGE AND ADMINISTRATION

Adult and Children > 12 years old

One tablet containing 10mg Montelukast plus 10mg Cetirizine once daily or one tablet containing Montelukast 5mg plus Cetirizine 5mg twice daily.

Elderly

At present there are no data to suggest that the dose need to be reduced in elderly patients.

Patients with Hepatic and Renal Impairment

Dosage should be reduced to half the usual daily dose in patients with hepatic or renal impairment.

Children and Adolescents

Children aged 6 – 12 : one tablet containing 5mg Montelukast plus 5mg Cetirizine once daily or

one chewable tablet containing 5mg Montelukast plus 10mg Cetirizine once daily.

Children aged 2 – 5 : one fast melt tablet containing 4mg Montelukast plus 5mg Cetirizine once daily.

Or as prescribed by the physician.

PHARMACOLOGY

Montelukast

The cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important mediators bind to cysteinyl leukotriene receptors. Cysteinyl leukotrienes 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, cysteinyl leukotrienes 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 cysteinyl leukotrienes has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast is an orally active compound which binds with high affinity and selectivity to the cysteinyl leukotriene type 1 receptor thereby preventing cysteinyl leukotrienes from exerting their affects.

Cetirizine

Cetirizine hydrochloride, a piperazine derivative and metabolite of hydroxyzine, is described as a non-sedating antihistamine which is long-acting and has some mast-cell stabilizing activity. It appears to have a low potential for drowsiness in usual doses and to be virtually free of antimuscarinic activity. It is a selective H1-antagonist with negligible effects on other receptors and so it is virtually free from anticholinergic and antiserotonin effects. Cetirizine inhibits the histamine-mediated “early” phase of the allergic reaction and also reduces the migration of inflammatory cells e.g., eosinophils and the release of mediators associated with the “late” allergic response.

PHARMACOKINETICS

Montelukast

Absorption

Montelukast is rapidly 2 to 4 hours absorbed following oral administration. Mean peak plasma concentration (C_max) is achieved 3 hours (T_max) after administration of a 10mg dose in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and C_max 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. C_max is achieved in 2 hours after administration of the 5mg chewable tablet 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. Steady-state volume of distribution of Montelukast averages 8 -11 liters. Studies in rats with radio labeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radio labeled 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 children. In vitro studies using human liver microsomes indicate that cytochrome P450 3A4, 2A6 and 2C9 are involved in the metabolism of Montelukast. Based on further 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 clearance of Montelukast averages 45 ml/min in healthy adults. Following an oral dose of radio labeled 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.

Elderly

The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of Montelukast are similar in elderly and younger adults. The plasma half-life of Montelukast is slightly longer in the elderly. Due to the Cetirizine component of Montelukast plus Cetirizine however, dosage adjustment may be required in elderly patients (See Dosage and Administration – Elderly).

Patients with Renal Impairment

Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of Montelukast was not evaluated in patients with renal insufficiency. Due to the Cetirizine component of MONTELUKAST PLUS CETIRIZINE however, dosage adjustment is required in patients with renal impairment (See Dosage and Administration – Patients with Renal Impairment).

Patients with Hepatic Impairment

Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Montelukast resulting in 41% (90% CI=7%, 85%) higher mean Montelukast area under the plasma concentration curve (AUC) following a single 10-mg dose. The elimination of Montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of Montelukast in patients with more severe hepatic impairment or with hepatitis has not been evaluated.

Cetirizine

Cetirizine is rapidly absorbed from the gastrointestinal tract after oral administration, peak plasma concentrations being attained within about one hour. Food delays the time to peak plasma concentrations but does not decrease the amount of drug absorbed. It is highly bound to plasma proteins and has an elimination half-life of about 10 hours in adults, 6 hours in children 6-12 years and 5 hours in children 2-6 years. These data are consistent with the urinary excretion half-life of the drug. This cumulative urinary excretion represents about 2/3 of the dose given in both adults and children. Consequently, the apparent plasma clearance in children is higher than that measured in adults. Plasma linearly related to the dose given.

Cetirizine has been detected in breast milk. Cetirizine is excreted primarily in the urine mainly as unchanged drug. Cetirizine does not appear to cross the blood-brain barrier to a significant extent.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Cetirizine

Reduced dosage is recommended for patients with hepatic or renal impairment.

Effects on the Ability to Drive or Operate Machinery

Studies in healthy volunteers at 20 and 25mg/day have not revealed effects on alertness or reaction time; however, patients are advised not to exceed the recommended dose if driving or operating machinery.

DRUG INTERACTIONS

Montelukast

In drug-interactions 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 (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 metabolised by CYP 3A4, caution should be exercised, particularly in children, when Montelukast is coadministered with inducers of CYP 3A4, 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 drugs 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 drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide).

Cetirizine

Some interactions are less likely with Cetirizine than with non-sedating antihistamines such as astemizole and terfenadine, since Cetirizine appears to have low hepatic metabolism and little arrhythmogenic potential.

Concomitant use of Cetirizine and pilsicainide may increase the serum concentration of both drugs which may lead to drug toxicities.

Anticoagulants

There has been a report of a raised INR and severe epistaxis in a patient after the addition of Cetirizine to long-term acenocoumarol.

ADVERSE EFFECTS

Montelukast

Montelukast has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with montelukast (M) occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo (P), regardless of causality assessment; Body As A Whole; Asthenia / fatigue M (1.8%), P (1.2%). Fever: M (0.6%), P (3.0%). Abdominal Pain: M (2.9%), P (2.5%) Trauma: M (1.0%), P (0.8%). Digestive System Disorders: Dyspepsia M (2.1%), P (1.1%). Infectious gastroenteritis: M (2.1%), P (1.1%). Dental Pain: M (1.7%), P (1.0%). Nervous System / Psychiatric: Dizziness M (1.9%), P (1.4%). Headache: M (18.4%), P (18.1%). Respiratory System Disorders: Congestion, nasal M (1.6%), P (1.3%). Cough M (2.7%), P (2.4%). Influenza: M (4.2%), P (3.9%). Skin/Skin Appendages Disorder; Rash M (1.6%), P (1.2%). Laboratory Adverse Experiences;* ALT increased M (2.1%), P (2.0%). AST increased M (1.6%), P (1.2%). Pyuria: M (1.0%), P (0.9%).

Cetirizine

There have been occasional reports of mild and transient subjective side effects e.g., headache, dizziness, drowsiness, agitation, dry mouth and gastrointestinal discomfort.

Arrhythmias

The ECG effects of Cetirizine when administered a dose of up to six times the usual recommended dose did not prolong the QT interval.

Hypersensitivity

Hypersensitivity reactions manifest as urticaria and fixed drug eruptions have been reported with Cetirizine.

Sedation

CNS depression is the most common adverse effect of Cetirizine. The sedative effect can range from slight drowsiness to deep sleep.

USE IN PREGNANCY AND LACTATION

No well controlled trials have been performed with either Montelukast or Cetirizine in women who are pregnant. Therefore use of MONTELUKAST PLUS CETIRIZINE is not recommended in women who are pregnant. It is not known whether Montelukast or Cetirizine are excreted in breast milk. Therefore use of MONTELUKAST PLUS CETIRIZINE is not recommended in women who are breast feeding.

CAUTION

Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

STORE AT TEMPERATURES NOT EXCEEDING 30^OC. PROTECT FROM LIGHT.

AVAILABILITY

Montelukast sodium + Cetirizine hydrochloride (Alduet) 5mg/5mg Film-Coated Tablet X Alu-alu blister pack of 10’s, box of 30 film-coated tablets
Montelukast sodium + Cetirizine hydrochloride (Alduet) 10mg/10mg Film-Coated Tablet X Alu-alu blister pack of 10’s, box of 30 film-coated tablets
Montelukast sodium + Cetirizine hydrochloride (Alduet) 5mg/10mg Chewable Tablet X Alu-alu blister pack of 10’s, box of 30 tablets
Montelukast sodium + Cetirizine hydrochloride (Alduet) 4mg/5mg Fast Melt Tablet X Alu-alu blister pack of 10’s, box of 30 tablets