Dazit M Actions

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How do you administer this medicine?
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Consists of Desloratadine, Montelukast

Actions of Desloratadine (Dazit M) in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Desloratadine is the orally active, nonsedating, active metabolite of loratadine, with a sustained duration of action that allows once-daily dosing in clinical use.

Mechanism of Action: Desloratadine is a new, selective peripheral histamine H1-receptor antagonist with more potent antiallergenic properties than loratadine itself. It also has anti-inflammatory activity. Desloratadine acts by inhibiting the release of pro-inflammatory mediators from human mast cells/basophils.

Desloratadine was more potent than loratadine with respect to in vivo inhibition of histamine-induced wheal and flare. It does not readily penetrate the central nervous system.

Desloratadine demonstrates H1-receptor specificity including 15- to 50-fold lower affinity for muscarinic receptors compared with H1-receptors.

Clinical studies have demonstrated that desloratadine has a lack of clinically significant cardiovascular toxicity, and unlike most other antihistamines, has decongestant effects.

Pharmacokinetics: After oral administration, desloratadine is rapidly and almost completely absorbed. Peak plasma concentrations are reached within about 3 hrs; the terminal elimination half-life of desloratadine is averaged 24-27 hrs, indicating that desloratadine is suitable for once-daily administration. The pharmacokinetics of desloratadine is linear and exhibits dose proportionality. With daily administration of 5 mg of desloratadine, steady-state serum concentrations are achieved within 7 days.

Desloratadine is rapidly metabolised by hydroxylation to 3-hydroxydesloratadine and excreted mainly in the urine.

Because the bioavailability and absorption of desloratadine are not significantly affected by food, desloratadine may be administered with or without meals.

Pharmacokinetic studies with desloratadine in the elderly and in patients with renal dysfunction are not yet available. The available data for loratadine indicate that the elimination half-life of desloratadine may be increased in patients with chronic renal failure. However, dosage reduction in mild to moderate renal impairment is probably not necessary.

Limited pharmacokinetic data suggest that desloratadine 5 mg daily is likely to be safe in patients with hepatic dysfunction.

How should I take Desloratadine (Dazit M)?

Take Desloratadine (Dazit M) exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Desloratadine (Dazit M) is usually taken once per day. Follow your doctor's instructions.

Do not crush, chew, or break the regular Desloratadine (Dazit M) tablet. Swallow the pill whole.

Measure the liquid form of Desloratadine (Dazit M) with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

To take desloratadine orally disintegrating tablet (Desloratadine (Dazit M) RediTabs):

Call your doctor if your symptoms do not improve.

Store Desloratadine (Dazit M) at room temperature away from moisture and heat.

Desloratadine (Dazit M) administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Desloratadine is usually taken once per day. Follow your doctor's instructions.

Do not crush, chew, or break the regular desloratadine tablet. Swallow the pill whole.

Measure the liquid form of desloratadine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

To take desloratadine orally disintegrating tablet (Desloratadine (Dazit M) RediTabs):

Store at room temperature away from moisture and heat.

Call your doctor if your symptoms do not improve.

Desloratadine (Dazit M) pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

Desloratadine is a long-acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2–3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H1-receptor. Desloratadine inhibited histamine release from human mast cells in vitro. Results of a radiolabeled tissue distribution study in rats and a radioligand H1-receptor binding study in guinea pigs showed that desloratadine did not readily cross the blood brain barrier. The clinical significance of this finding is unknown.

Pharmacodynamics

Wheal and Flare: Human histamine skin wheal studies following single and repeated 5-mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5-mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc: Single daily doses of 45 mg were given to normal male and female volunteers for 10 days. All ECGs obtained in this study were manually read in a blinded fashion by a cardiologist. In Desloratadine (Dazit M)-treated subjects, there was an increase in mean heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both the Bazett and Fridericia methods. Using the QTc (Bazett) there was a mean increase of 8.1 msec in Desloratadine (Dazit M)-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in Desloratadine (Dazit M)-treated subjects relative to placebo. No clinically relevant adverse events were reported.

Pharmacokinetics

Absorption

Following oral administration of a desloratadine 5-mg tablet once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (Tmax) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (Cmax) and AUC of 4 ng/mL and 56.9 ng∙hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (Cmax and AUC) of desloratadine.

The pharmacokinetic profile of Desloratadine (Dazit M)

Oral Solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of Desloratadine (Dazit M)

Oral Solution containing 5 mg of desloratadine was bioequivalent to a single dose of 5-mg Desloratadine (Dazit M) Tablet. Food had no effect on the bioavailability (AUC and Cmax) of Desloratadine (Dazit M)

Oral Solution.

The pharmacokinetic profile of Desloratadine (Dazit M) RediTabs Tablets was evaluated in a three-way crossover study in 24 adult volunteers. A single Desloratadine (Dazit M) RediTabs Tablet containing 5 mg of desloratadine was bioequivalent to a single 5-mg Desloratadine (Dazit M) RediTabs Tablet (original formulation) for both desloratadine and 3-hydroxydesloratadine. Food and water had no effect on the bioavailability (AUC and Cmax) of Desloratadine (Dazit M) RediTabs Tablets.

Distribution

Desloratadine and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89% bound to plasma proteins, respectively. Protein binding of desloratadine and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism

Desloratadine (a major metabolite of loratadine) is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxydesloratadine have not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of desloratadine. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of desloratadine (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1,462) and Hispanics (2%, n=1,063). The median exposure (AUC) to desloratadine in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of desloratadine cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with Desloratadine (Dazit M)

Oral Solution for 15–35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.

Elimination

The mean plasma elimination half-life of desloratadine was approximately 27 hours. Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to desloratadine.

Special Populations

Geriatric Subjects: In older subjects (≥65 years old; n=17) following multiple-dose administration of Desloratadine (Dazit M) Tablets, the mean Cmax and AUC values for desloratadine were 20% greater than in younger subjects (<65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the two age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects ≥65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects: In subjects 6 to 11 years old, a single dose of 5 mL of Desloratadine (Dazit M)

Oral Solution containing 2.5 mg of desloratadine, resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5-mg Desloratadine (Dazit M) Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of Desloratadine (Dazit M)

Oral Solution containing 1.25 mg of desloratadine, resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single 5-mg Desloratadine (Dazit M) Tablet. However, the Cmax and AUC of the metabolite (3-hydroxydesloratadine) were 1.27 and 1.61 times higher for the 5-mg dose of

Oral Solution administered in adults compared to the Cmax and AUC obtained in children 2 to 11 years of age receiving 1.25–2.5 mg of Desloratadine (Dazit M)

Oral Solution.

A single dose of either 2.5 mL or 1.25 mL of Desloratadine (Dazit M)

Oral Solution containing 1.25 mg or 0.625 mg, respectively, of desloratadine was administered to subjects 6 to 11 months of age and 12 to 23 months of age. The results of a population pharmacokinetic analysis indicated that a dose of 1 mg for subjects aged 6 to 11 months and 1.25 mg for subjects 12 to 23 months of age is required to obtain desloratadine plasma concentrations similar to those achieved in adults administered a single 5-mg dose of Desloratadine (Dazit M)

Oral Solution.

The Desloratadine (Dazit M) RediTabs 2.5-mg tablet has not been evaluated in pediatric patients. Bioequivalence of the Desloratadine (Dazit M) RediTabs Tablet and the original Desloratadine (Dazit M) RediTabs Tablets was established in adults. In conjunction with the dose-finding studies in pediatrics described, the pharmacokinetic data for Desloratadine (Dazit M) RediTabs Tablets supports the use of the 2.5-mg dose strength in pediatric patients 6 to 11 years of age.

Renally Impaired: Desloratadine pharmacokinetics following a single dose of 7.5 mg were characterized in patients with mild (n=7; creatinine clearance 51–69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34–43 mL/min/1.73 m2), and severe (n=6; creatinine clearance 5–29 mL/min/1.73 m2) renal impairment or hemodialysis dependent (n=6) patients. In patients with mild and moderate renal impairment, median Cmax and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who were hemodialysis dependent, Cmax and AUC values increased by approximately 1.7- and 2.5-fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended.

Hepatically Impaired: Desloratadine pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in patients with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of desloratadine in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Dosage adjustment for patients with hepatic impairment is recommended.

Gender: Female subjects treated for 14 days with Desloratadine (Dazit M) Tablets had 10% and 3% higher desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine Cmax and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race: Following 14 days of treatment with Desloratadine (Dazit M) Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

Drug Interactions: In two controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) volunteers, desloratadine 7.5 mg (1.5 times the daily dose) once daily was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In three separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of 5 mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady-state conditions to normal healthy male and female volunteers. Although increased plasma concentrations (Cmax and AUC0-24 hrs) of desloratadine and 3-hydroxydesloratadine were observed, there were no clinically relevant changes in the safety profile of desloratadine, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs, and adverse events.

Table 2: Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
Desloratadine 3-Hydroxydesloratadine
Cmax AUC0-24 hrs Cmax AUC0-24 hrs
Erythromycin

(500 mg Q8h)

+ 24% + 14% + 43% + 40%

Ketoconazole

(200 mg Q12h)

+ 45%

+ 39%

+ 43%

+ 72%

Azithromycin

(500 mg day 1,

250 mg QD x 4 days)

+ 15%

+ 5%

+ 15%

+ 4%

Fluoxetine

(20 mg QD)

+ 15%

+ 0%

+ 17%

+ 13%

Cimetidine

(600 mg Q12h)

+ 12%

+ 19%

- 11%

- 3%

Actions of Montelukast (Dazit M) in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Pharmacodynamics: Montelukast is a selective and active leukotriene receptor antagonist. Montelukast inhibits bronchoconstriction due to antigen challenge. Montelukast is a selective leukotriene receptor antagonist of the cysteinyl leukotriene CysLT1 receptor. The cysteinyl leukotrienes (LTC 4, LTD 4, LTE 4) are products of arachidonic acid metabolism that are released from various cells, including mast cells and eosinophils. They bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Binding of cysteinyl leukotrienes to leukotriene receptors has been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction and altered cellular activity associated with the inflammatory process, factors that contribute to the signs and symptoms of asthma.

It binds to CysLT type-1 receptors found in human airway (smooth muscle cells and macrophages), which prevents airway edema, smooth muscle contraction and other respiratory inflammation. The leukotrienes are also released from the nasal mucosa after allergen exposure where montelukast sodium may inhibit symptoms of allergic rhinitis.

Montelukast binding to the CysLT1 receptor is high-affinity and selective, preferring the CysLT1 receptor to other pharmacologically important airway receptors eg, the prostanoid, cholinergic or β-adrenergic receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptors, without any agonist activity.

Montelukast causes bronchodilation within 2 hrs of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.

Pharmacokinetics: Absorption: Montelukast is rapidly and nearly completely absorbed following oral administration. Peak plasma concentrations of montelukast occur 3-4 hrs after oral doses. The mean oral bioavailability is 64%. The oral bioavailability and peak plasma concentration (Cmax) are not influenced by a standard meal.

Distribution: Montelukast is >99% bound to plasma proteins. The steady-state volume of distribution of montelukast averages 8-11 L. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier.

Metabolism: Montelukast is extensively metabolized in the liver by cytochrome P-450 isoenzymes CYP3A4 and CYP2C9. Therapeutic plasma concentrations of montelukast do not inhibit cytochromes P-450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.

Elimination: The plasma clearance of montelukast averages 45 mL/min in healthy adults. Montelukast and its metabolites are excreted principally in the faeces via the bile.

Elimination Half-Life: 2.7-5 hrs.

How should I take Montelukast (Dazit M)?

Take Montelukast (Dazit M) exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Montelukast (Dazit M) is usually taken once daily in the evening for prevention of asthma or allergy symptoms. For exercise-induced bronchoconstriction, take a single dose at least 2 hours before you exercise, and do not take another dose for at least 24 hours. Follow your doctor's instructions.

Montelukast (Dazit M) is not a rescue medicine. It will not work fast enough to treat an asthma attack. Use only a fast acting inhalation medicine for an asthma attack. Tell your doctor if it seems like your asthma medications don't work as well.

Swallow the regular tablet whole, with a glass of water.

The Montelukast (Dazit M) chewable tablet must be chewed completely before you swallow it.

The oral granules can be placed directly into the mouth and swallowed, or mixed with a spoonful of applesauce, mashed carrots, rice, or ice cream.

Oral granules can also be mixed with 1 teaspoon of baby formula or breast milk. Do not use any other type of liquid for mixing the granules. Other liquids can be taken before or after taking the medicine.

After opening or mixing the oral granules, you must use them within 15 minutes. Do not save an open packet or mixed medicine for later use.

It may take up to several weeks before your symptoms improve. Keep using Montelukast (Dazit M) as directed and tell your doctor if your symptoms do not improve after several weeks of treatment.

If you also take a steroid asthma medicine, do not stop using it suddenly without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Asthma is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice, even if you have no asthma symptoms.

Store Montelukast (Dazit M) at room temperature away from moisture and heat. Do not open a packet of oral granules until you are ready to use the medicine.

Montelukast (Dazit M) administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Montelukast is usually taken once daily in the evening for prevention of asthma or allergy symptoms. For exercise-induced bronchoconstriction, take a single dose at least 2 hours before you exercise, and do not take another dose for at least 24 hours. Follow your doctor's instructions.

If you already take this medication to prevent asthma or allergy symptoms, do not use it for exercise-induced bronchoconstriction.

Swallow the regular tablet whole, with a glass of water.

The chewable tablet must be chewed completely before you swallow it.

The oral granules can be placed directly into the mouth and swallowed, or mixed with a spoonful of applesauce, mashed carrots, rice, or ice cream.

Oral granules can also be mixed with 1 teaspoon of baby formula or breast milk. Do not use any other type of liquid for mixing the granules. Other liquids can be taken before or after taking the medicine.

After opening or mixing the oral granules, you must use them within 15 minutes. Do not save an open packet or mixed medicine for later use.

Montelukast will not work fast enough to treat an asthma attack that has already begun. Use only a fast-acting inhalation medicine to treat an asthma attack. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing attacks.

It may take up to several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after several weeks of treatment.

Asthma is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice, even if you have no asthma symptoms.

If you also take a steroid asthma medicine, do not stop using it suddenly without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

Store at room temperature away from moisture and heat. Do not open a packet of oral granules until you are ready to use the medicine.

Montelukast (Dazit M) pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.

Mechanism of Action

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids 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 airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. 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.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

Pharmacodynamics

Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Montelukast (Dazit M) inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Montelukast (Dazit M) on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Montelukast (Dazit M), a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received Montelukast (Dazit M), a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of Montelukast (Dazit M). The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known.

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed following oral administration. 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.

For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.

For the 4-mg chewable tablet, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.

The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The co-administration of the oral granule formulation with applesauce did not have a clinically significant effect on the pharmacokinetics of montelukast. A high fat meal in the morning did not affect the AUC of montelukast oral granules; however, the meal decreased Cmax by 35% and prolonged Tmax from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours.

The safety and efficacy of Montelukast (Dazit M) in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of Montelukast (Dazit M) in patients with asthma was also demonstrated in clinical trials in which the 4-mg chewable tablet and 4-mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of Montelukast (Dazit M) in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose 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 pediatric patients.

In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.

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 are 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%).

Special Populations

Hepatic Insufficiency: 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 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 (Dazit M) in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Renal Insufficiency: Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Gender: The pharmacokinetics of montelukast are similar in males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Adolescents and Pediatric Patients: Pharmacokinetic studies evaluated the systemic exposure of the 4-mg oral granule formulation in pediatric patients 6 to 23 months of age, the 4-mg chewable tablets in pediatric patients 2 to 5 years of age, the 5-mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10-mg film-coated tablets in young adults and adolescents ≥15 years of age.

The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥15 years of age.

The mean systemic exposure of the 4-mg chewable tablet in pediatric patients 2 to 5 years of age and the 5-mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4-mg chewable tablet should be used in pediatric patients 2 to 5 years of age.

In children 6 to 11 months of age, the systemic exposure to montelukast and the variability of plasma montelukast concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4296 ng•hr/mL [range 1200 to 7153]) was 60% higher and the mean Cmax (667 ng/mL [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng•hr/mL [range 1521 to 4595]) and mean Cmax (353 ng/mL [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng•hr/mL [range 2229 to 5408]) was 33% higher and the mean Cmax (562 ng/mL [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of montelukast in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above. The 4-mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.

Drug-Drug Interactions

Theophylline, Prednisone, and Prednisolone: Montelukast (Dazit M) has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. 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, and prednisolone.

Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.

Oral Contraceptives, Terfenadine, Digoxin, and Warfarin: In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants: Although additional specific interaction studies were not performed, Montelukast (Dazit M) 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 anti-inflammatory agents, benzodiazepines, and decongestants.

Cytochrome P450 (CYP) Enzyme Inducers: Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for Montelukast (Dazit M) is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with Montelukast (Dazit M).

Effect of Montelukast on Cytochrome P450 (CYP) Enzymes: Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Cytochrome P450 (CYP) Enzyme Inhibitors: In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil.



References

  1. DailyMed. "DESLORATADINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. NCIt. "Desloratadine: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
  3. EPA DSStox. "Montelukast: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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