Actions of Ltcet in details
Pharmacology: Ltcet 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: Ltcet is a new, selective peripheral histamine H1-receptor antagonist with more potent antiallergenic properties than loratadine itself. It also has anti-inflammatory activity. Ltcet acts by inhibiting the release of pro-inflammatory mediators from human mast cells/basophils.
Ltcet 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.
Ltcet demonstrates H1-receptor specificity including 15- to 50-fold lower affinity for muscarinic receptors compared with H1-receptors.
Clinical studies have demonstrated that Ltcet has a lack of clinically significant cardiovascular toxicity, and unlike most other antihistamines, has decongestant effects.
Pharmacokinetics: After oral administration, Ltcet is rapidly and almost completely absorbed. Peak plasma concentrations are reached within about 3 hrs; the terminal elimination half-life of Ltcet is averaged 24-27 hrs, indicating that Ltcet is suitable for once-daily administration. The pharmacokinetics of Ltcet is linear and exhibits dose proportionality. With daily administration of 5 mg of Ltcet, steady-state serum concentrations are achieved within 7 days.
Ltcet is rapidly metabolised by hydroxylation to 3-hydroxydesloratadine and excreted mainly in the urine.
Because the bioavailability and absorption of Ltcet are not significantly affected by food, Ltcet may be administered with or without meals.
Pharmacokinetic studies with Ltcet 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 Ltcet 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 Ltcet 5 mg daily is likely to be safe in patients with hepatic dysfunction.
How should I take Ltcet?
Take Ltcet 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.
Ltcet is usually taken once per day. Follow your doctor's instructions.
Do not crush, chew, or break the regular Ltcet tablet. Swallow the pill whole.
Measure the liquid form of Ltcet 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 Ltcet orally disintegrating tablet (Ltcet RediTabs):
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Keep the tablet in its blister pack until you are ready to take the medicine. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.
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Using dry hands, remove the tablet and place it on your tongue. It will begin to dissolve right away.
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Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
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Swallow several times as the tablet dissolves. If desired, you may drink water to help swallow the dissolved tablet.
Call your doctor if your symptoms do not improve.
Store Ltcet at room temperature away from moisture and heat.
Ltcet administration
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.
Ltcet is usually taken once per day. Follow your doctor's instructions.
Do not crush, chew, or break the regular Ltcet tablet. Swallow the pill whole.
Measure the liquid form of Ltcet 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 Ltcet orally disintegrating tablet (Ltcet RediTabs):
- Keep the tablet in its blister pack until you are ready to take the medicine. Open the package and peel back the foil from the tablet blister. Do not push a tablet through the foil or you may damage the tablet.
- Using dry hands, remove the tablet and place it on your tongue. It will begin to dissolve right away.
- Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.
- Swallow several times as the tablet dissolves. If desired, you may drink water to help swallow the dissolved tablet.
Store at room temperature away from moisture and heat.
Call your doctor if your symptoms do not improve.
Ltcet pharmacology
Mechanism of Action
Ltcet 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), Ltcet shows significant interaction with the human histamine H1-receptor. Ltcet 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 Ltcet 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 Ltcet 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 Ltcet 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 Ltcet-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 Ltcet-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in Ltcet-treated subjects relative to placebo. No clinically relevant adverse events were reported.
Pharmacokinetics
Absorption
Following oral administration of a Ltcet 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 Ltcet.
The pharmacokinetic profile of Ltcet
Oral Solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of Ltcet
Oral Solution containing 5 mg of Ltcet was bioequivalent to a single dose of 5-mg Ltcet Tablet. Food had no effect on the bioavailability (AUC and Cmax) of Ltcet
Oral Solution.
The pharmacokinetic profile of Ltcet RediTabs Tablets was evaluated in a three-way crossover study in 24 adult volunteers. A single Ltcet RediTabs Tablet containing 5 mg of Ltcet was bioequivalent to a single 5-mg Ltcet RediTabs Tablet (original formulation) for both Ltcet and 3-hydroxydesloratadine. Food and water had no effect on the bioavailability (AUC and Cmax) of Ltcet RediTabs Tablets.
Distribution
Ltcet and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89% bound to plasma proteins, respectively. Protein binding of Ltcet and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.
Metabolism
Ltcet (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 Ltcet. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of Ltcet (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to Ltcet less than 0.1, or a subject with a Ltcet 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 Ltcet in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of Ltcet cannot be prospectively identified and will be exposed to higher levels of Ltcet following dosing with the recommended dose of Ltcet. 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 Ltcet
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 Ltcet 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-Ltcet 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 Ltcet.
Special Populations
Geriatric Subjects: In older subjects (≥65 years old; n=17) following multiple-dose administration of Ltcet Tablets, the mean Cmax and AUC values for Ltcet 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 Ltcet 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 Ltcet
Oral Solution containing 2.5 mg of Ltcet, resulted in Ltcet plasma concentrations similar to those achieved in adults administered a single 5-mg Ltcet Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of Ltcet
Oral Solution containing 1.25 mg of Ltcet, resulted in Ltcet plasma concentrations similar to those achieved in adults administered a single 5-mg Ltcet 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 Ltcet
Oral Solution.
A single dose of either 2.5 mL or 1.25 mL of Ltcet
Oral Solution containing 1.25 mg or 0.625 mg, respectively, of Ltcet 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 Ltcet plasma concentrations similar to those achieved in adults administered a single 5-mg dose of Ltcet
Oral Solution.
The Ltcet RediTabs 2.5-mg tablet has not been evaluated in pediatric patients. Bioequivalence of the Ltcet RediTabs Tablet and the original Ltcet RediTabs Tablets was established in adults. In conjunction with the dose-finding studies in pediatrics described, the pharmacokinetic data for Ltcet RediTabs Tablets supports the use of the 2.5-mg dose strength in pediatric patients 6 to 11 years of age.
Renally Impaired: Ltcet 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. Ltcet and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of Ltcet and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended.
Hepatically Impaired: Ltcet 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 Ltcet 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 Ltcet 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 Ltcet Tablets had 10% and 3% higher Ltcet 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 Ltcet Tablets, the Cmax and AUC values for Ltcet 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, Ltcet 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, Ltcet 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 Ltcet and 3-hydroxydesloratadine were observed, there were no clinically relevant changes in the safety profile of Ltcet, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs, and adverse events.
| Ltcet | 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% |
References
- 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).
- 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).
- EPA DSStox. "Desloratadine: 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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Information checked by Dr. Sachin Kumar, MD Pharmacology
