Hatric 3 Actions
Pharmacotherapeutic Group: Antihistamine for systemic use, piperazine derivative.
Pharmacology: Pharmacodynamics: Mechanism of Action/Pharmacodynamic Effects: Hatric 3, the (R) enantiomer of cetirizine, is a potent and selective antagonist of peripheral H1-receptors. Binding studies revealed that Hatric 3 has high affinity for human H1-receptors (Ki=3.2 nmol/L). Hatric 3 has an affinity 2-fold higher than that of cetirizine (Ki=6.3 nmol/L). Hatric 3 dissociates from H1-receptors with a t½ of 115±38 min.
After single administration, Hatric 3 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, Hatric 3 has comparable activity to cetirizine, both in the skin and in the nose.
The pharmacodynamic activity of Hatric 3 has been studied in randomized, controlled trials: In a study comparing the effects of Hatric 3 5 mg, desloratadine 5 mg and placebo on histamine-induced wheal and flare, Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 has been demonstrated in several double-blind, placebo-controlled, clinical trials performed in adult patients suffering from seasonal, perennial or persistent allergic rhinitis. Hatric 3 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 Hatric 3-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 Hatric 3 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, Hatric 3 significantly improved the quality of life of the patients.
The pediatric safety and efficacy of Hatric 3 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, Hatric 3 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 Hatric 3 5 mg once daily >6 weeks. Treatment with Hatric 3 resulted in significant decrease in pruritus severity over the 1st week and over the total treatment period as compared to placebo. Hatric 3 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, Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 1.25 mg once daily for 2 weeks.
One (1) long-term (18 months) clinical trial in 255 Hatric 3-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 Hatric 3 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: Hatric 3 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 Hatric 3 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, Hatric 3 is 90% bound to plasma proteins. The distribution of Hatric 3 is restrictive, as the volume of distribution is 0.4 L/kg.
Metabolism: The extent of metabolism of Hatric 3 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. Hatric 3 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 Hatric 3 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 Hatric 3 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. Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3, as Hatric 3 and cetirizine are both predominantly excreted in urine. Therefore, the Hatric 3 dose should be adjusted in accordance with renal function in elderly patients.
Renal Impairment: The apparent body clearance of Hatric 3 is correlated to the creatinine clearance. It is therefore recommended to adjust the dosing intervals of Hatric 3 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 Hatric 3 removed during a standard 4-hr hemodialysis procedure was <10%.
Hepatic Impairment: The pharmacokinetics of Hatric 3 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 Hatric 3 has not been studied. As Hatric 3 is primarily renally excreted, and there are no important racial differences in CrCl, pharmacokinetic characteristics of Hatric 3 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.
Take Hatric 3 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 Hatric 3 with or without food.
Measure the oral solution with a marked measuring spoon, oral syringe, or medicine cup.
The dose of Hatric 3 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 Hatric 3. 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.
If you miss a dose of Hatric 3, 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.
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.
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 Hatric 3 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.
Hatric 3, the active enantiomer of cetirizine, is an anti-histamine; its principal effects are mediated via selective inhibition of H1 receptors. The antihistaminic activity of Hatric 3 has been documented in a variety of animal and human models. In vitro binding studies revealed that Hatric 3 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.
Studies in adult healthy subjects showed that Hatric 3 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. Hatric 3 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 Hatric 3 did not demonstrate an effect on the QTc interval. While a single dose of Hatric 3 had no effect, the effects of Hatric 3 may not be at steady state following single dose. The effect of Hatric 3 on the QTc interval following multiple dose administration is unknown. Hatric 3 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.
Hatric 3 exhibited linear pharmacokinetics over the therapeutic dose range in adult healthy subjects.
Hatric 3 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 Hatric 3 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, Hatric 3 can be administered with or without food.
A dose of 5 mg (10 mL) of Hatric 3 oral solution is bioequivalent to a 5 mg dose of Hatric 3 tablets. Following oral administration of a 5 mg dose of Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3 was approximately 0.63 mL/kg/min. The major route of excretion of Hatric 3 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. Hatric 3 is excreted both by glomerular filtration and active tubular secretion. Renal clearance of Hatric 3 correlates with that of creatinine clearance. In patients with renal impairment the clearance of Hatric 3 is reduced.
In vitro data on metabolite interaction indicate that Hatric 3 is unlikely to produce, or be subject to metabolic interactions. Hatric 3 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 Hatric 3. Studies have been performed with the racemic cetirizine.
Data from a pediatric pharmacokinetic study with oral administration of a single dose of 5 mg Hatric 3 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 Hatric 3 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 Hatric 3 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 Hatric 3, as Hatric 3 and cetirizine are both predominantly excreted in urine. Therefore, the Hatric 3 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 Hatric 3 has not been studied. As Hatric 3 is primarily renally excreted, and there are no important racial differences in creatinine clearance, pharmacokinetic characteristics of Hatric 3 are not expected to be different across races. No race-related differences in the kinetics of racemic cetirizine have been observed.
Hatric 3 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 Hatric 3 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 Hatric 3 based on creatinine clearance in patients with mild, moderate, or severe renal impairment. In end-stage renal disease patients (CLCR < 10 mL/min) Hatric 3 is contraindicated. The amount of Hatric 3 removed during a standard 4-hour hemodialysis procedure was <10%.
The dosage of Hatric 3 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.
Hatric 3 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 Hatric 3 is mainly excreted unchanged by the kidney, it is unlikely that the clearance of Hatric 3 is significantly decreased in patients with solely hepatic impairment.
|With a meal||1||33.3%|
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Information checked by Dr. Sachin Kumar, MD Pharmacology