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