Hiskast LV Actions

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Actions of Hiskast LV 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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Pharmacotherapeutic Group: Antihistamine for systemic use, piperazine derivative.

Pharmacology: Pharmacodynamics: Mechanism of Action/Pharmacodynamic Effects: Hiskast LV, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that Hiskast LV has high affinity for human H1-receptors (Ki=3.2 nmol/L). Hiskast LV has an affinity 2-fold higher than that of cetirizine (Ki=6.3 nmol/L). Hiskast LV dissociates from H1-receptors with a t½ of 115±38 min.

After single administration, Hiskast LV shows a receptor occupancy of 90% at 4 hrs and 57% at 24 hrs. Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose, Hiskast LV has comparable activity to cetirizine, both in the skin and in the nose.

The pharmacodynamic activity of Hiskast LV has been studied in randomized, controlled trials: In a study comparing the effects of Hiskast LV 5 mg, desloratadine 5 mg and placebo on histamine-induced wheal and flare, Hiskast LV treatment resulted in significantly decreased wheal and flare formation which was highest in the first 12 hrs and lasted for 24 hrs (p<0.001), compared with placebo and desloratadine.

The onset of action of Hiskast LV 5 mg in controlling pollen-induced symptoms has been observed at 1-hr post-drug intake in placebo-controlled trials in the model of the allergen challenge chamber.

In vitro studies (Boyden chambers and cell layers techniques) show that Hiskast LV inhibits eotaxin-induced eosinophil transendothelial migration through both dermal and lung cells. A pharmacodynamic experimental study in vivo (skin chamber technique) showed 3 main inhibitory effects of Hiskast LV 5 mg in the first 6 hrs of pollen-induced reaction, compared with placebo in 14 adult patients: Inhibition of vascular cell adhesion molecule 1 (VCAM-1) release, modulation of vascular permeability and a decrease in eosinophil recruitment.

The efficacy and safety of Hiskast LV has been demonstrated in several double-blind, placebo-controlled, clinical trials performed in adult patients suffering from seasonal, perennial or persistent allergic rhinitis. Hiskast LV has been shown to significantly improve symptoms of allergic rhinitis including nasal obstruction in some studies.

A 6-month clinical study in 551 patients (including 278 Hiskast LV-treated patients) suffering from persistent allergic rhinitis (symptoms present 4 days a week for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen demonstrated that Hiskast LV 5 mg was clinically and statistically significantly more potent than placebo on the relief from the total symptom score of allergic rhinitis throughout the whole duration of the study, without any tachyphylaxis. During the whole duration of the study, Hiskast LV significantly improved the quality of life of the patients.

The pediatric safety and efficacy of Hiskast LV tablets has been studied in 2 placebo-controlled clinical trials, including patients 6-12 years and suffering from seasonal and perennial allergic rhinitis, respectively. In both trials, Hiskast LV significantly improved symptoms and increased health-related quality of life.

In a placebo-controlled clinical trial including 166 patients suffering from chronic idiopathic urticaria, 85 patients were treated with placebo and 81 patients with Hiskast LV 5 mg once daily >6 weeks. Treatment with Hiskast LV resulted in significant decrease in pruritus severity over the 1st week and over the total treatment period as compared to placebo. Hiskast LV also resulted in a larger improvement of health-related quality of life as assessed by the Dermatology Life Quality Index as compared to placebo. Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since histamine release is a causal factor in urticarial diseases, Hiskast LV is expected to be effective in providing symptomatic relief for other urticarial conditions in addition to chronic idiopathic urticaria.

Pharmacokinetic/Pharmacodynamic Relationship: The action on histamine-induced skin reactions is out of phase with the plasma concentrations. Electrocardiograms (ECGs) did not show relevant effects of Hiskast LV on QT interval.

Pediatric Data for

Oral Drops and

Oral Solution:

In children <6 years, clinical safety has been established from several short- or long-term therapeutic studies: One (1) clinical trial in which 29 children 2-6 years with allergic rhinitis were treated with Hiskast LV 1.25 mg twice daily for 4 weeks.

One (1) clinical trial in which 114 children 1-5 years with allergic rhinitis or chronic idiopathic urticaria were treated with Hiskast LV 1.25 mg twice daily for 2 weeks.

One (1) clinical trial in which 45 children 6-11 months with allergic rhinitis or chronic idiopathic urticaria were treated with Hiskast LV 1.25 mg once daily for 2 weeks.

One (1) long-term (18 months) clinical trial in 255 Hiskast LV-treated atopic subjects aged 12-24 months at inclusion.

The safety profile was similar to that seen in the short-term studies conducted in children 1-5 years.

Clinical Studies: There are no relevant data available.

Pharmacokinetics: The pharmacokinetics of Hiskast LV are linear with dose- and time-dependent with intersubject variability. The pharmacokinetic profile is the same when given as the single enantiomer or when given as cetirizine. No chiral inversion occurs during the process of absorption and elimination.

Absorption: Hiskast LV is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations (Cmax) are achieved 0.9 hr after dosing. Steady state is achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. The extent of absorption is dose-independent and is not altered by food, but the peak concentration is reduced and delayed.

Distribution: No tissue distribution data are available in humans, neither concerning the passage of Hiskast LV through the blood-brain barrier. In rats and dogs, the highest tissue levels are found in liver and kidneys, the lowest in the central nervous system (CNS) compartment. In humans, Hiskast LV is 90% bound to plasma proteins. The distribution of Hiskast LV is restrictive, as the volume of distribution is 0.4 L/kg.

Metabolism: The extent of metabolism of Hiskast LV in humans is <14% of the dose and therefore, differences resulting from genetic polymorphism or concomitant intake of enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation and taurine conjugation. Dealkylation pathways are primarily mediated by CYP3A4 while aromatic oxidation involved multiple and/or unidentified CYP isoforms. Hiskast LV had no effect on the activities of CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak concentrations achieved following a 5-mg oral dose.

Due to its low metabolism and absence of metabolic inhibition potential, the interaction of Hiskast LV with other substances or vice versa, is unlikely.

Elimination: The plasma t½ in adults is 7.9±1.9 hrs. The mean apparent total body clearance in adults is 0.63 mL/min/kg. The major route of excretion of Hiskast LV and metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Hiskast LV is excreted both by glomerular filtration and active tubular secretion.

Children: Data from a pediatric pharmacokinetic study with oral administration of a single dose of Hiskast LV 5 mg in 14 children 6-11 years with body weight ranging between 20 and 40 kg show that Cmax and area under the concentration-time curve (AUC) values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hrs, weight-normalized, total body clearance was 30% greater and the elimination t½ 24% shorter in this pediatric population than in adults. Dedicated pharmacokinetic studies have not been conducted in pediatric patients <6 years. A retrospective population pharmacokinetic analysis was conducted in 324 subjects (181 children 1-5 years, 18 children 6-11 years, and 124 adults 18-55 years) who received single or multiple doses of Hiskast LV ranging from 1.25-30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years is expected to result in plasma concentrations similar to those of adults receiving 5 mg once daily.

Elderly: Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of Hiskast LV 30 mg for 6 days in 9 elderly subjects (65-74 years), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for Hiskast LV, as Hiskast LV and cetirizine are both predominantly excreted in urine. Therefore, the Hiskast LV dose should be adjusted in accordance with renal function in elderly patients.

Renal Impairment: The apparent body clearance of Hiskast LV is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of Hiskast LV based on creatinine clearance (CrCl) in patients with moderate and severe renal impairment. In anuric end-stage renal disease subjects, the total body clearance is decreased by approximately 80% when compared to normal subjects. The amount of Hiskast LV removed during a standard 4-hr hemodialysis procedure was <10%.

Hepatic Impairment: The pharmacokinetics of Hiskast LV in hepatically impaired subjects have not been tested. Patients with chronic liver diseases (hepatocellular, cholestatic and biliary cirrhosis) given 10 mg or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in t½ along with a 40% decrease in clearance compared to healthy subjects.

Other Patient Characteristics: Gender: Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The t½ was slightly shorter in women (7.08±1.72 hrs) than in men (8.62±1.84 hrs); however, the body weight-adjusted oral clearance in women (0.67±0.16 mL/min/kg) appears to be comparable to that in men (0.59±0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

Race: The effect of race on Hiskast LV has not been studied. As Hiskast LV is primarily renally excreted, and there are no important racial differences in CrCl, pharmacokinetic characteristics of Hiskast LV are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Toxicology: Nonclinical Information: Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

How should I take Hiskast LV?

Take Hiskast LV exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

You may take Hiskast LV with or without food.

Measure the oral solution with a marked measuring spoon, oral syringe, or medicine cup.

Dosing

The dose of Hiskast LV will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Hiskast LV. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Missed Dose

If you miss a dose of Hiskast LV, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Hiskast LV 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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Follow the directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

It is very important not to give a child more than the prescribed dose of this medication. A child's body absorbs twice as much of the same dose size of Hiskast LV as an adult's body.

Taking more of this medication will not make it more effective, and may cause severe drowsiness.

You may take this medication with or without food.

Measure liquid medicine 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.

Call your doctor if your symptoms do not improve, if they get worse, or if you also have a fever.

Store at room temperature away from moisture and heat.

Hiskast LV 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

Hiskast LV, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of Hiskast LV has been documented in a variety of animal and human models. In vitro binding studies revealed that Hiskast LV has an affinity for the human H1-receptor 2-fold higher than that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively). The clinical relevance of this finding is unknown.

Pharmacodynamics

Studies in adult healthy subjects showed that Hiskast LV at doses of 2.5 mg and 5 mg inhibited the skin wheal and flare caused by the intradermal injection of histamine. In contrast, dextrocetirizine exhibited no clear change in the inhibition of the wheal and flare reaction. Hiskast LV at a dose of 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (aged 6 to 11 years) and the activity persisted for at least 24 hours. The clinical relevance of histamine wheal skin testing is unknown.

A QT/QTc study using a single dose of 30 mg of Hiskast LV did not demonstrate an effect on the QTc interval. While a single dose of Hiskast LV had no effect, the effects of Hiskast LV may not be at steady state following single dose. The effect of Hiskast LV on the QTc interval following multiple dose administration is unknown. Hiskast LV is not expected to have QT/QTc effects because of the results of QTc studies with cetirizine and the long post-marketing history of cetirizine without reports of QT prolongation.

Pharmacokinetics

Hiskast LV exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.

Hiskast LV is rapidly and extensively absorbed following oral administration. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet. The accumulation ratio following daily oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/mL and 308 ng/mL following a single and a repeated 5 mg once daily dose, respectively. Food had no effect on the extent of exposure (AUC) of the Hiskast LV tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal; therefore, Hiskast LV can be administered with or without food.

A dose of 5 mg (10 mL) of Hiskast LV oral solution is bioequivalent to a 5 mg dose of Hiskast LV tablets. Following oral administration of a 5 mg dose of Hiskast LV oral solution to healthy adult subjects, the mean peak plasma concentrations were achieved approximately 0.5 hour post-dose.

The mean plasma protein binding of Hiskast LV in vitro ranged from 91 to 92%, independent of concentration in the range of 90-5000 ng/mL, which includes the therapeutic plasma levels observed. Following oral dosing, the average apparent volume of distribution is approximately 0.4 L/kg, representative of distribution in total body water.

The extent of metabolism of Hiskast LV in humans is less than 14% of the dose and therefore differences resulting from genetic polymorphism or concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.

The plasma half-life in adult healthy subjects was about 8 to 9 hours after administration of oral tablets and oral solution, and the mean oral total body clearance for Hiskast LV was approximately 0.63 mL/kg/min. The major route of excretion of Hiskast LV and its metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via feces accounts for only 12.9% of the dose. Hiskast LV is excreted both by glomerular filtration and active tubular secretion. Renal clearance of Hiskast LV correlates with that of creatinine clearance. In patients with renal impairment the clearance of Hiskast LV is reduced.

In vitro data on metabolite interaction indicate that Hiskast LV is unlikely to produce, or be subject to metabolic interactions. Hiskast LV at concentrations well above Cmax level achieved within the therapeutic dose ranges is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, and 3A4, and is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9 and 3A4.

No formal in vivo drug interaction studies have been performed with Hiskast LV. Studies have been performed with the racemic cetirizine.

Data from a pediatric pharmacokinetic study with oral administration of a single dose of 5 mg Hiskast LV in 14 children age 6 to 11 years with body weight ranging between 20 and 40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy adult subjects in a cross-study comparison. The mean Cmax was 450 ng/mL, occurring at a mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the elimination half-life 24% shorter in this pediatric population than in adults.

Dedicated pharmacokinetic studies have not been conducted in pediatric patients younger than 6 years of age. A retrospective population pharmacokinetic analysis was conducted in 323 subjects (181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55 years of age) who received single or multiple doses of Hiskast LV ranging from 1.25 mg to 30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily to children 6 months to 5 years of age results in plasma concentrations similar to those of adults receiving 5 mg once daily.

Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat oral administration of 30 mg Hiskast LV for 6 days in 9 elderly subjects (65–74 years of age), the total body clearance was approximately 33% lower compared to that in younger adults. The disposition of racemic cetirizine has been shown to be dependent on renal function rather than on age. This finding would also be applicable for Hiskast LV, as Hiskast LV and cetirizine are both predominantly excreted in urine. Therefore, the Hiskast LV dose should be adjusted in accordance with renal function in elderly patients.

Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hr) than in men (8.62 ± 1.84 hr); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16 mL/min/kg) appears to be comparable to that in men (0.59 ± 0.12 mL/min/kg). The same daily doses and dosing intervals are applicable for men and women with normal renal function.

The effect of race on Hiskast LV has not been studied. As Hiskast LV is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of Hiskast LV are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.

Hiskast LV exposure (AUC) exhibited 1.8-, 3.2-, 4.3-, and 5.7-fold increase in mild, moderate, severe, renal impaired, and end-stage renal disease patients, respectively, compared to healthy subjects. The corresponding increases of half-life estimates were 1.4-, 2.0-, 2.9-, and 4-fold, respectively.

The total body clearance of Hiskast LV after oral dosing was correlated to the creatinine clearance and was progressively reduced based on severity of renal impairment. Therefore, it is recommended to adjust the dose and dosing intervals of Hiskast LV based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CLCR < 10 mL/min) Hiskast LV is contraindicated. The amount of Hiskast LV removed during a standard 4-hour hemodialysis procedure was <10%.

The dosage of Hiskast LV should be reduced in patients with mild renal impairment. Both the dosage and frequency of administration should be reduced in patients with moderate or severe renal impairment.

Hiskast LV has not been studied in patients with hepatic impairment. The non-renal clearance (indicative of hepatic contribution) was found to constitute about 28% of the total body clearance in healthy adult subjects after oral administration.

As Hiskast LV is mainly excreted unchanged by the kidney, it is unlikely that the clearance of Hiskast LV is significantly decreased in patients with solely hepatic impairment.


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References

  1. NCIt. "Levocetirizine: 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).
  2. EPA DSStox. "Levocetirizine: 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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