India Product

Fexum M Tablets

Fexum M Tablets

Why you have been prescribed this medicine?

You have been prescribed this medicine if you have any of the following:

     Symptoms associated with seasonal allergic rhinitis.
     Asthma
     Upper Respiratory Tract Infections

When you should consult your doctor?

You should consult your doctor if you experience any of the following:

MONTELUKAST

Montelukast has been evaluated in clinical studies in patients with persistent asthma as follows:

• 10 mg film-coated tablets in approximately 4000 adult asthmatic patients 15 years of age and older.
• 10 mg film-coated tablets in approximately 400 adult asthmatic patients with seasonal allergic rhinitis 15 years of age and older.
• 5 mg chewable tablets in approximately 1750 paediatric asthmatic patients 6 to 14 years of age.

The following drug-related adverse reactions in clinical studies were reported commonly (https://www.medicines.org.uk/emc/images/spc~28170~2~image1.png1/100 to <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo:

Body System Class

Adult Patients 15 years and older
(two 12-week studies; n=795)

Paediatric Patients 6 to 14 years old
(one 8-week study; n=201)
(two 56-week studies; n=615)

Nervous system disorders

headache

headache

Gastrointestinal disorders

abdominal pain

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.

Post marketing experience:

Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Experience Term, in the table below. Frequency Categories were estimated based on relevant clinical trials.

System Organ Class

Adverse Experience Term

Frequency Category*

Infections and infestations

Upper respiratory infection†

Very Common

Blood and lymphatic system disorders

Increased bleeding tendency

Rare

Immune system disorder

Hypersensitivity reactions including anaphylaxis

Uncommon

hepatic eosinophilic infiltration

Very Rare

Psychiatric disorders

dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§)

Uncommon

, disturbance in attention, memory impairment

Rare

hallucinations, disorientation, suicidal thinking and behaviour (suicidality)

Very Rare

Nervous system disorders

Dizziness, drowsiness, paraesthesia/hypoesthesia, seizure

Uncommon

Cardiac disorders

palpitations

Rare

Respiratory. Thoracic and mediastinal disorders

epistaxis

Uncommon

Churg-Strauss Syndrome (CSS) (see section 4.4)

Very Rare

Gastrointestinal disorders

diarrhoea‡, nausea‡, vomiting‡

Common

Dry mouth, dyspepsia

Uncommon

Hepatobiliary disorders

elevated levels of serum transaminases (ALT, AST)

Common

hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).

Very Rare

Skin and subcutaneous tissue disorders

rash‡

Common

bruising, urticaria, pruritus

Uncommon

angioedema

Rare

erythema nodosum, erythema multiforme

Very Rare

Musculoskeletal, connective tissue and bone disorders

arthralgia, myalgia including muscle cramps

Uncommon

General disorders and administration site conditions

pyrexia‡

Common

asthenia/fatigue, malaise, oedema

Uncommon

*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data base: Very Common (https://www.medicines.org.uk/emc/images/spc~28170~2~image2.png 1/10), Common (https://www.medicines.org.uk/emc/images/spc~28170~2~image3.png1/100 to < 1/10), Uncommon (https://www.medicines.org.uk/emc/images/spc~28170~2~image4.png1/1000 to < 1/100), Rare (https://www.medicines.org.uk/emc/images/spc~28170~2~image5.png1/10,000 to < 1/1000), Very Rare (< 1/10,000).
†This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials.
‡This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials.
§ Frequency Category: Rare

 

FEXOFENADINE
The following frequency rating has been used, when applicable:
Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000 and <1/1,000; Very rare <1/10,000 and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In adults, the following undesirable effects have been reported in clinical trials, with an incidence similar to that observed with placebo:

Nervous system disorders
Common: headache, drowsiness, dizziness

Gastrointestinal disorders
Common: nausea

General disorders and administration site conditions

Uncommon: fatigue

In adults, the following undesirable effects have been reported in post-marketing surveillance. The frequency with which they occur is not known (can not be estimated from available data):

Immune system disorders
hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis

Psychiatric disorders
insomnia, nervousness, sleep disorders or nightmares/excessive dreaming (paroniria)

Cardiac disorders
tachycardia, palpitations

Gastrointestinal disorders
Diarrhea

Skin and subcutaneous tissue disorders
rash, urticaria, pruritus

In controlled clinical trials in adults the most commonly reported adverse events related to treatment were headache (7.3%), drowsiness (2.3%), nausea (1.5%) and dizziness (1.5%). The incidence of these events observed with fexofenadine was similar to that observed with placebo.

Events related to treatment that have been reported with an incidence of less than 1% include: fatigue, insomnia, nervousness and sleep disorders or paroniria, such as nightmares and tachycardia, palpitations and diarrhoea. In rare cases, rash, urticaria, pruritus, and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis have also been reported.


WHAT TO DO IF YOU MISS A DOSE?

If it is almost time for your next dose, skip the dose you missed and take    your next dose when you are meant to. Otherwise take it as soon as you remember and then go back to taking it as you would normally.

Things you MUST NOT DO while on this medicine?

Fexum M is contraindicated in patients with known hypersensitivity to montelukast sodium, Fexofenadine or to any other component of this product.

MONTELUKAST

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 doctor's advice as soon as possible if they need more inhalations of short-acting beta-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. 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.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

FEXOFENADINE
As with most new drugs there is only limited data in the elderly and renally or hepatically impaired patients. Fexofenadine hydrochloride should be administered with care in these special groups.

Patients with a history of or ongoing cardiovascular disease should be warned that, antihistamines as a drug class, have been associated with the adverse events, tachycardia and palpitations.

Influence on velocity reactions while driving motor transport and operating other mechanisms:

MONTELUKAST

Montelukast 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.

FEXOFENADINE

On the basis of the pharmacodynamic profile and reported adverse events it is unlikely that fexofenadine hydrochloride tablets will produce an effect on the ability to drive or use machines. In objective tests, Fexofenadine has been shown to have no significant effects on central nervous system function. This means that patients may drive or perform tasks that require concentration. However, in order to identify sensitive people who have an unusual reaction to drugs, it is advisable to check the individual response before driving or performing complicated tasks.

What to do if you accidentally take too much (overdose) of the medicine?

There is no data to prove the overdosage of this combination. However, overdosage has been reported with individual molecules.

MONTELUKAST
No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose 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 dialysable by peritoneal- or haemo-dialysis.

FEXOFENADINE
Symptoms of dizziness, drowsiness, fatigue and dry mouth have been reported with overdose of fexofenadine hydrochloride. Single doses up to 800 mg, and doses up to 690 mg twice daily for 1 month, or 240 mg once daily for 1 year have been administered to healthy subjects without the development of clinically significant adverse events. The maximum tolerated dose of fexofenadine hydrochloride has not been established.
Standard measures should be considered to remove any unabsorbed fexofenadine. Symptomatic and supportive treatment is recommended. Haemodialysis does not effectively remove fexofenadine hydrochloride from blood.

Is it safe in pregnancy and breast-feeding?

Pregnancy

There are no adequate and well-controlled studies of either montelukast or fexofenadine in pregnant women. Limited animal studies do not indicate the direct or indirect harmful outcomes with respect to the effects on pregnancy, embryonal/foetal development, parturition, or postnatal development. Because animal reproduction studies are not always predictive of human response, Fexum M Tablets should 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. There are no data on the content of human milk after administering fexofenadine hydrochloride. However, when terfenadine was administered to nursing mothers, fexofenadine was found to cross into human breast milk. Therefore, Fexum M Tablets are not recommended for nursing mothers.

Storage Conditions:

Do not store above 30°C. Store in the original package.

Drug Description

Active substances: Each film-coated tablet contains:

120mg of fexofenadine hydrochloride, which is equivalent to 112mg of fexofenadine.
Montelukast sodium, which is equivalent to 10 mg montelukast.

Excipients:

Indications and dosage.

Indications:
Fexum M Tablets are indicated for:

  • Relief of symptoms associated with seasonal allergic rhinitis.
  • Asthma
  • Upper Respiratory Tract Infections

             Dosage:

Side effects and drug interactions.

Side effects:
MONTELUKAST

Montelukast has been evaluated in clinical studies in patients with persistent asthma as follows:

• 10 mg film-coated tablets in approximately 4000 adult asthmatic patients 15 years of age and older.
• 10 mg film-coated tablets in approximately 400 adult asthmatic patients with seasonal allergic rhinitis 15 years of age and older.
• 5 mg chewable tablets in approximately 1750 paediatric asthmatic patients 6 to 14 years of age.

The following drug-related adverse reactions in clinical studies were reported commonly (https://www.medicines.org.uk/emc/images/spc~28170~2~image1.png1/100 to <1/10) in asthmatic patients treated with montelukast and at a greater incidence than in patients treated with placebo:

Body System Class

Adult Patients 15 years and older
(two 12-week studies; n=795)

Paediatric Patients 6 to 14 years old
(one 8-week study; n=201)
(two 56-week studies; n=615)

Nervous system disorders

headache

headache

Gastrointestinal disorders

abdominal pain

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.

Post marketing experience:

Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Experience Term, in the table below. Frequency Categories were estimated based on relevant clinical trials.

System Organ Class

Adverse Experience Term

Frequency Category*

Infections and infestations

Upper respiratory infection†

Very Common

Blood and lymphatic system disorders

Increased bleeding tendency

Rare

Immune system disorder

Hypersensitivity reactions including anaphylaxis

Uncommon

hepatic eosinophilic infiltration

Very Rare

Psychiatric disorders

dream abnormalities including nightmares, insomnia, somnambulism, anxiety, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§)

Uncommon

, disturbance in attention, memory impairment

Rare

hallucinations, disorientation, suicidal thinking and behaviour (suicidality)

Very Rare

Nervous system disorders

Dizziness, drowsiness, paraesthesia/hypoesthesia, seizure

Uncommon

Cardiac disorders

palpitations

Rare

Respiratory. Thoracic and mediastinal disorders

epistaxis

Uncommon

Churg-Strauss Syndrome (CSS) (see section 4.4)

Very Rare

Gastrointestinal disorders

diarrhoea‡, nausea‡, vomiting‡

Common

Dry mouth, dyspepsia

Uncommon

Hepatobiliary disorders

elevated levels of serum transaminases (ALT, AST)

Common

hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury).

Very Rare

Skin and subcutaneous tissue disorders

rash‡

Common

bruising, urticaria, pruritus

Uncommon

angioedema

Rare

erythema nodosum, erythema multiforme

Very Rare

Musculoskeletal, connective tissue and bone disorders

arthralgia, myalgia including muscle cramps

Uncommon

General disorders and administration site conditions

pyrexia‡

Common

asthenia/fatigue, malaise, oedema

Uncommon

*Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data base: Very Common (https://www.medicines.org.uk/emc/images/spc~28170~2~image2.png 1/10), Common (https://www.medicines.org.uk/emc/images/spc~28170~2~image3.png1/100 to < 1/10), Uncommon (https://www.medicines.org.uk/emc/images/spc~28170~2~image4.png1/1000 to < 1/100), Rare (https://www.medicines.org.uk/emc/images/spc~28170~2~image5.png1/10,000 to < 1/1000), Very Rare (< 1/10,000).
†This adverse experience, reported as Very Common in the patients who received montelukast, was also reported as Very Common in the patients who received placebo in clinical trials.
‡This adverse experience, reported as Common in the patients who received montelukast, was also reported as Common in the patients who received placebo in clinical trials.
§ Frequency Category: Rare

FEXOFENADINE
The following frequency rating has been used, when applicable:
Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000 and <1/1,000; Very rare <1/10,000 and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In adults, the following undesirable effects have been reported in clinical trials, with an incidence similar to that observed with placebo:

Nervous system disorders
Common: headache, drowsiness, dizziness

Gastrointestinal disorders
Common: nausea

General disorders and administration site conditions

Uncommon: fatigue

In adults, the following undesirable effects have been reported in post-marketing surveillance. The frequency with which they occur is not known (can not be estimated from available data):

Immune system disorders
hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis

Psychiatric disorders
insomnia, nervousness, sleep disorders or nightmares/excessive dreaming (paroniria)

Cardiac disorders
tachycardia, palpitations

Gastrointestinal disorders
Diarrhea

Skin and subcutaneous tissue disorders
rash, urticaria, pruritus

In controlled clinical trials in adults the most commonly reported adverse events related to treatment were headache (7.3%), drowsiness (2.3%), nausea (1.5%) and dizziness (1.5%). The incidence of these events observed with fexofenadine was similar to that observed with placebo.

Events related to treatment that have been reported with an incidence of less than 1% include: fatigue, insomnia, nervousness and sleep disorders or paroniria, such as nightmares and tachycardia, palpitations and diarrhoea. In rare cases, rash, urticaria, pruritus, and hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis have also been reported.

Drug interactions
                          
MONTELUKAST
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 metabolised 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 metabolised 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.
Based on in vitro data, clinically important drug interactions with less potent inhibitors of CYP 2C8 (e.g., trimethoprim) are not anticipated. Co-administration of montelukast with itraconazole, a strong inhibitor of CYP 3A4, resulted in no significant increase in the systemic exposure of montelukast.

 FEXOFENADINE
Fexofenadine does not undergo hepatic biofransforrnation and therefore will not interact with other drugs through hepatic mechanisms. Coadministration of fexofenadine hydrochloride with erythromycin or ketoconazole has been found to result in a 2-3 times increase in the level of fexofenadine in plasma. The changes were not accompanied by any effects on the QT interval and were not associated with any increase in adverse events compared to the drugs given singly.
Animal studies have shown that the increase in plasma levels of fexofenadine observed after coadministration of erythromycin or ketoconazole, appears to be due to an increase in gastrointestinal absorption and either a decrease in biliary excretion or gastrointestinal secretion, respectively.
No interaction between fexofenadine and omeprazole has been observed. However, the administration of an antacid containing aluminium and magnesium hydroxide gels 15 minutes prior to fexofenadine hydrochloride caused a reduction in bioavailability, most likely due to binding in the gastrointestinal tract. It is advisable to leave 2 hours between administration of fexofenadine hydrochloride and aluminium and magnesium hydroxide containing antacids.

Warnings and precautions

IMONTELUKAST

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 doctor's advice as soon as possible if they need more inhalations of short-acting beta-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. 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.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

FEXOFENADINE

As with most new drugs there is only limited data in the elderly and renally or hepatically impaired patients. Fexofenadine hydrochloride should be administered with care in these special groups.

Patients with a history of or ongoing cardiovascular disease should be warned that, antihistamines as a drug class, have been associated with the adverse events, tachycardia and palpitations.


Overdosage and Contraindications

Overdosage:
There is no data to prove the overdosage of this combination. However, overdosage has been reported with individual molecules.

MONTELUKAST

No specific information is available on the treatment of overdose with montelukast. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with montelukast. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients. There were no adverse experiences in the majority of overdose 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 dialysable by peritoneal- or haemo-dialysis.

FEXOFENADINE

Symptoms of dizziness, drowsiness, fatigue and dry mouth have been reported with overdose of fexofenadine hydrochloride. Single doses up to 800 mg, and doses up to 690 mg twice daily for 1 month, or 240 mg once daily for 1 year have been administered to healthy subjects without the development of clinically significant adverse events. The maximum tolerated dose of fexofenadine hydrochloride has not been established.

Standard measures should be considered to remove any unabsorbed fexofenadine. Symptomatic and supportive treatment is recommended. Haemodialysis does not effectively remove fexofenadine hydrochloride from blood.

Contraindications
Fexum M is contraindicated in patients with known hypersensitivity to montelukast sodium, Fexofenadine or to any other component of this product.

Clinical pharmacology.

PHARMACOLOGICAL PROPERTIES:

As Fexum M is a combination of Montelukast and Fexofenadine; the pharmacological properties of both the molecules are given separately:

Pharmacodynamic properties
MONTELUKAST

Pharmacotherapeutic group: Other systemic drugs for obstructive airway diseases, Leukotriene receptor antagonists  ATC-code: R03D C03

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.

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 beta-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.

In studies in adults, montelukast, 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total beta-agonist use (-26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma symptoms scores was significantly better than placebo.

Studies in adults demonstrated the ability of montelukast to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclometasone plus montelukast vs beclometasone, respectively for FEV1: 5.43% vs 1.04%; beta-agonist use: -8.70% vs 2.64%). Compared with inhaled beclometasone (200 μg twice daily with a spacer device), montelukast demonstrated a more rapid initial response, although over the 12-week study, beclometasone provided a greater average treatment effect (% change from baseline for montelukast vs beclometasone, respectively for FEV1: 7.49% vs 13.3%; beta-agonist use: -28.28% vs -43.89%). However, compared with beclometasone, a high percentage of patients treated with montelukast achieved similar clinical responses (e.g., 50% of patients treated with beclometasone achieved an improvement in FEV1 of approximately 11% or more over baseline while approximately 42% of patients treated with montelukast achieved the same response).

A clinical study was conducted to evaluate montelukast for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis. In this study, montelukast 10 mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score, compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhea, sneezing, nasal itching) and the Nighttime Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not a primary objective in this study.

In an 8-week study in paediatric patients 6 to 14 years of age, montelukast 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased "as-needed" beta-agonist use (-11.7% vs +8.2% change from baseline). Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for montelukast vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.

In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with montelukast, compared with placebo, resulted in significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline and decrease in total beta-agonist use -27.78% vs 2.09% change from baseline).

FEXOFENADINE

Pharmacotherapeutic Group: Antihistamines for systemic use, ATC code: RO6A X26.

Mechanism of action - Fexofenadine hydrochloride is a non-sedating H1antihistamine. Fexofenadine is a pharmacologically active metabolite of terfenadine.

Clinical efficacy and Safety - Human histamine wheal and flare studies following single and twice daily doses of fexofenadine hydrochloride demonstrate that the drug exhibits an antihistaminic effect beginning within one hour, achieving maximum at 6 hours and lasting 24 hours. There is no evidence of tolerance to these effects after 28 days of dosing. A positive dose-response relationship between doses of 10mg to 130mg taken orally was found to exist. In this model of antihistaminic activity, it was found that doses of at least 130mg were required to achieve a consistent effect that was maintained over a 24 hour period. Maximum inhibition in skin wheal and flare areas was greater than 80%. Clinical studies conducted in seasonal allergic rhinitis have shown that a dose of 120mg is sufficient for 24 hour efficacy.

No significant differences in QTc, intervals were observed in adult and adolescent patients with seasonal allergic rhinitis, when given fexofenadine hydrochloride up to 240 mg twice daily for 2 weeks when compared to placebo. Also, no significant change in QTc intervals was observed in healthy adult subjects given fexofenadine hydrochloride up to 60 mg twice daily for 6 months. 400 mg twice daily for 6.5 days and 240 mg once daily for 1 year, when compared to placebo.

Fexofenadine at concentrations 32 times greater than the therapeutic concentration in man had no effect on the delayed rectifier K+ channel cloned from human heart. Fexofenadine hydrochloride (5-10mg/kg per orally) inhibited antigen induced bronchospasm in sensitised guinea pigs and inhibited histamine release at supratherapeutic concentrations (10- 100µM) from peritoneal mast cells.

Pharmacokinetic properties

MONTELUKAST
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 clearance of montelukast averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled montelukast, 86% of the radioactivity was recovered in 5-day faecal 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.
Characteristics in patients
No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because montelukast and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of montelukast in patients with severe hepatic insufficiency (Child-Pugh score>9).
With high doses of montelukast (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.

FEXOFENADINE
Absorption - Fexofenadine hydrochloride is rapidly absorbed into the body following oral administration, with Tmax occurring at approximately 1-3 hours post dose. The mean Cmax value was approximately 427ng/rnl following the administration of a 120mg dose once daily.
Distribution - Fexofenadine is 60-70% plasma protein bound.
Biotransformation and elimination - Fexofenadine undergoes negligible metabolism (hepatic or non-hepatic), as it was the only major compound identified in urine and faeces of animals and man. The plasma concentration profiles of fexofenadine follow a bi-exponential decline with a terminal elimination half-life ranging from 11 to 15 hours after multiple dosing. The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120mg BID.
A dose of 240mg BID produced slightly greater than proportional increase (8.8%) in steady state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at these doses between 40-mg and 240mg taken daily. The major route of elimination is believed to be via biliary excretion while up to 10% of ingested dose is excreted unchanged through the urine.

Pharmaceutical characteristics:

General physic-chemical properties:  Tablets.
Beige coloured, rounded square shaped, film-coated tablets debossed with 'X' on one side and '54' on other side. The tablets are 8.1 mm in diameter.

Shelf-life:
3 years.

Storage:
Do not store above 30°C. Store in the original package.

Package:
The blister pack (PVC/aluminium) contains 60 tablets.

Conditions of supply.
Without prescription.

CERTIFICATES

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INDIA
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