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Overdose

In the event of overdose, consider standard measures to remove any unabsorbed drug. Symptomatic and supportive treatment is recommended. Desloratadine and 3-hydroxydesloratadine are not eliminated by hemodialysis.

Information regarding acute overdosage is limited to experience from post-marketing adverse event reports and from clinical trials conducted during the development of the CLARINEX product. In a dose-ranging trial, at doses of 10 mg and 20 mg/day somnolence was reported.

In another study, no clinically relevant adverse events were reported in normal male and female volunteers who were given single daily doses of CLARINEX 45 mg for 10 days.

Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 120 times the AUC in humans at the recommended daily oral dose). The oral median lethal dose in mice was 353 mg/kg (estimated desloratadine exposures were approximately 290 times the human daily oral dose on a mg/m² basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated desloratadine exposures were approximately 810 times the human daily oral dose on a mg/m² basis).

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Contraindications

CLARINEX Tablets and Oral Solution are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients or to loratadine.

Undesirable effects

The following adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity reactions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Allergic Rhinitis: In multiple-dose placebo-controlled trials, 2834 patients ages 12 years or older received CLARINEX Tablets at doses of 2.5 mg to 20 mg daily, of whom 1655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between CLARINEX and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the CLARINEX group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving desloratadine. All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of CLARINEX Tablets (5 mg once daily), and that were more common with CLARINEX Tablets than placebo, are listed in Table 1.

Table 1: Incidence of Adverse Events Reported by ≥ 2% of Adult and Adolescent Allergic Rhinitis Patients Receiving CLARINEX Tablets

The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in CLARINEX and placebotreated patients.

There were no differences in adverse events for subgroups of patients as defined by gender, age, or race.

Chronic Idiopathic Urticaria: In multiple-dose, placebo-controlled trials of chronic idiopathic urticaria, 211 patients ages 12 years or older received CLARINEX Tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received CLARINEX Tablets and that were more common with CLARINEX than placebo were (rates for CLARINEX and placebo, respectively): headache (14%, 13%), nausea (5%, 2%), fatigue (5%, 1%), dizziness (4%, 3%), pharyngitis (3%, 2%), dyspepsia (3%, 1%), and myalgia (3%, 1%).

Two hundred and forty-six pediatric subjects 6 months to 11 years of age received CLARINEX Oral Solution for 15 days in three placebo-controlled clinical trials. Pediatric subjects aged 6 to 11 years received 2.5 mg once a day, subjects aged 1 to 5 years received 1.25 mg once a day, and subjects 6 to 11 months of age received 1.0 mg once a day.

In subjects 6 to 11 years of age, no individual adverse event was reported by 2 percent or more of the subjects.

In subjects 2 to 5 years of age, adverse events reported for CLARINEX and placebo in at least 2 percent of subjects receiving CLARINEX Oral Solution and at a frequency greater than placebo were fever (5.5%, 5.4%), urinary tract infection (3.6%, 0%) and varicella (3.6%, 0%).

In subjects 12 months to 23 months of age, adverse events reported for the CLARINEX product and placebo in at least 2 percent of subjects receiving CLARINEX Oral Solution and at a frequency greater than placebo were fever (16.9%, 12.9%), diarrhea (15.4%, 11.3%), upper respiratory tract infections (10.8%, 9.7%), coughing (10.8%, 6.5%), appetite increased (3.1%, 1.6%), emotional lability (3.1%, 0%), epistaxis (3.1%, 0%), parasitic infection (3.1%, 0%), pharyngitis (3.1%, 0%), rash maculopapular (3.1%, 0%).

In subjects 6 months to 11 months of age, adverse events reported for CLARINEX and placebo in at least 2 percent of subjects receiving CLARINEX Oral Solution and at a frequency greater than placebo were upper respiratory tract infections (21.2%, 12.9%), diarrhea (19.7%, 8.1%), fever (12.1%, 1.6%), irritability (12.1%, 11.3%), coughing (10.6%, 9.7%), somnolence (9.1%, 8.1%), bronchitis (6.1%, 0%), otitis media (6.1%, 1.6%), vomiting (6.1%, 3.2%), anorexia (4.5%, 1.6%), pharyngitis (4.5%, 1.6%), insomnia (4.5%, 0%), rhinorrhea (4.5%, 3.2%), erythema (3.0%, 1.6%), and nausea (3.0%, 0%).

There were no clinically meaningful changes in any electrocardiographic parameter, including the QTc interval. Only one of the 246 pediatric subjects receiving CLARINEX Oral Solution in the clinical trials discontinued treatment because of an adverse event.

Because adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following spontaneous adverse events have been reported during the marketing of desloratadine: tachycardia, palpitations, rare cases of hypersensitivity reactions (such as rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis), psychomotor hyperactivity, movement disorders (including dystonia, tics, and extrapyramidal symptoms), seizures, and elevated liver enzymes including bilirubin, and very rarely, hepatitis.

Therapeutic indications

CLARINEX® is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 2 years of age and older.

CLARINEX is indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 6 months of age and older.

CLARINEX is indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 6 months of age and older.

Pharmacodynamic properties

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.

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 CLARINEX-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 CLARINEX-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

Pharmacokinetic properties

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 CLARINEX Oral Solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of CLARINEX Oral Solution containing 5 mg of desloratadine was bioequivalent to a single dose of 5-mg CLARINEX Tablet. Food had no effect on the bioavailability (AUC and Cmax) of CLARINEX Oral Solution.

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.

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 CLARINEX 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.

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.

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Fertility, pregnancy and lactation

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, desloratadine should be used during pregnancy only if clearly needed.

Desloratadine was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the area under the concentration-time curve (AUC) in humans at the recommended daily oral dose. An increase in pre-implantation loss and a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose. Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Desloratadine had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose. The AUCs in comparison referred to the desloratadine exposure in rabbits and the sum of desloratadine and its metabolites exposures in rats, respectively.

Qualitative and quantitative composition

CLARINEX Tablets are light blue, film-coated tablets embossed with “C5” containing 5 mg desloratadine.

CLARINEX Oral Solution is a clear orange-colored liquid containing 0.5 mg desloratadine/1 mL.

CLARINEX Tablets: Embossed “C5”, light blue, film-coated tablets that are packaged in high-density polyethylene plastic bottles of 100 (NDC 0085-1264-01) and 500 (NDC 0085-1264-02).

CLARINEX Oral Solution: Clear orange-colored liquid containing 0.5 mg/1 mL desloratadine in a 16-ounce Amber glass bottle (NDC 0085-1334-01) and a 4-ounce Amber glass bottle (NDC 0085-1334-02).

• CLARINEX Tablets: Protect Unit-of-Use packaging and Unit-Dose Hospital Pack from excessive moisture. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Heat Sensitive. Avoid exposure at or above 30°C (86°F).
• CLARINEX Oral Solution: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from light.

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA. Manufactured by: Schering-Plough Canada, Inc., Pointe Claire, Quebec, Canada. Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of Merck &  Co., Inc., Whitehouse Station, NJ 08889, USA. Revised: Nov 2013

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of desloratadine. If such a reaction occurs, therapy with CLARINEX should be stopped and alternative treatment should be considered.

See FDA-Approved Patient Labeling (PATIENT INFORMATION).

• Patients should be instructed to use CLARINEX as directed.
• As there are no food effects on bioavailability, patients can be instructed that CLARINEX Tablets or Oral Solution may be taken without regard to meals.
• Patients should be advised not to increase the dose or dosing frequency as studies have not demonstrated increased effectiveness at higher doses and somnolence may occur.

The carcinogenic potential of desloratadine was assessed using a loratadine study in rats and a desloratadine study in mice. In a 2-year study in rats, loratadine was administered in the diet at doses up to 25 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 30 times the AUC in humans at the recommended daily oral dose). A significantly higher incidence of hepatocellular tumors (combined adenomas and carcinomas) was observed in males given 10 mg/kg/day of loratadine and in males and females given 25 mg/kg/day of loratadine. The estimated desloratadine and desloratadine metabolite exposures in rats given 10 mg/kg of loratadine were approximately 7 times the AUC in humans at the recommended daily oral dose. The clinical significance of these findings during long-term use of desloratadine is not known.

In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day desloratadine, respectively, did not show significant increases in the incidence of any tumors. The estimated desloratadine and desloratadine metabolite exposures in mice at these doses were 12 and 27 times, respectively, the AUC in humans at the recommended daily oral dose.

In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

There was no effect on female fertility in rats at desloratadine doses up to 24 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 130 times the AUC in humans at the recommended daily oral dose). A male specific decrease in fertility, demonstrated by reduced female conception rates, decreased sperm numbers and motility, and histopathologic testicular changes, occurred at an oral desloratadine dose of 12 mg/kg in rats (estimated desloratadine and desloratadine metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 8 times the AUC in humans at the recommended daily oral dose).

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, desloratadine should be used during pregnancy only if clearly needed.

Desloratadine was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the area under the concentration-time curve (AUC) in humans at the recommended daily oral dose. An increase in pre-implantation loss and a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose. Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Desloratadine had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose. The AUCs in comparison referred to the desloratadine exposure in rabbits and the sum of desloratadine and its metabolites exposures in rats, respectively.

Desloratadine passes into breast milk; therefore, a decision should be made whether to discontinue nursing or to discontinue desloratadine, taking into account the benefit of the drug to the nursing mother and the possible risk to the child.

The recommended dose of CLARINEX Oral Solution in the pediatric population is based on cross-study comparison of the plasma concentration of CLARINEX in adults and pediatric subjects. The safety of CLARINEX Oral Solution has been established in 246 pediatric subjects aged 6 months to 11 years in three placebo-controlled clinical studies. Since the course of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria and the effects of CLARINEX are sufficiently similar in the pediatric and adult populations, it allows extrapolation from the adult efficacy data to pediatric patients. The effectiveness of CLARINEX Oral Solution in these age groups is supported by evidence from adequate and well-controlled studies of CLARINEX Tablets in adults. The safety and effectiveness of CLARINEX Tablets or CLARINEX Oral Solution have not been demonstrated in pediatric patients less than 6 months of age.

Clinical studies of desloratadine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Dosage adjustment for patients with renal impairment is recommended.

Dosage adjustment for patients with hepatic impairment is recommended.

Dosage (Posology) and method of administration

CLARINEX Tablets or Oral Solution may be taken without regard to meals.

The age-appropriate dose of CLARINEX Oral Solution should be administered with a commercially available measuring dropper or syringe that is calibrated to deliver 2 mL and 2.5 mL (½ teaspoon).

The recommended dose of CLARINEX Tablets is one 5-mg tablet once daily. The recommended dose of CLARINEX Oral Solution is 2 teaspoonfuls (5 mg in 10 mL) once daily.

The recommended dose of CLARINEX Oral Solution is 1 teaspoonful (2.5 mg in 5 mL) once daily.

The recommended dose of CLARINEX Oral Solution is ½ teaspoonful (1.25 mg in 2.5 mL) once daily.

The recommended dose of CLARINEX Oral Solution is 2 mL (1 mg) once daily.

In adult patients with liver or renal impairment, a starting dose of one 5-mg tablet every other day is recommended based on pharmacokinetic data. Dosing recommendation for children with liver or renal impairment cannot be made due to lack of data.

Interaction with other medicinal products and other forms of interaction

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 (see Table 2), 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