Desloratadine

CLARINEX is a histamine-1 (H1) receptor antagonist indicated for: Seasonal Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 2 years of age and older. ( 1.1 ) Perennial Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 6 months of age and older. ( 1.2 ) Chronic Idiopathic Urticaria: symptomatic relief of pruritus, reduction in the number of hives, and size of hives in patients 6 months of age and older. ( 1.3 )

1.1 Seasonal Allergic Rhinitis 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.

1.2 Perennial Allergic Rhinitis 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.

1.3 Chronic Idiopathic Urticaria 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.

CLARINEX Tablets are supplied as: Light blue, film-coated tablets embossed with “C5” containing 5 mg desloratadine. Light blue, film-coated tablets embossed with an elongated letters “S” and “P” on one side and plain on the other, containing 5 mg desloratadine. CLARINEX Tablets – 5 mg ( 3 )

CLARINEX Tablets, RediTabs, and Oral Solution are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients or to loratadine [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ]. Hypersensitivity ( 4 , 6.2 )

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported. In such cases, stop CLARINEX at once and consider alternative treatments. ( 5.1 )

5.1 Hypersensitivity Reactions 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 Adverse Reactions (6.2) .]

The following adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity reactions. [See Warnings and Precautions (5.1) .] The most common adverse reactions (reported in ≥2% of adult and adolescent patients with allergic rhinitis and greater than placebo) were pharyngitis, dry mouth, myalgia, fatigue, somnolence, dysmenorrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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. Adults and Adolescents 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 Adverse Event CLARINEX Tablets 5 mg (n=1655) Placebo (n=1652) Infections and Infestations Pharyngitis 4.1% 2.0% Nervous System Disorders Somnolence 2.1% 1.8% Gastrointestinal Disorders Dry Mouth 3.0% 1.9% Musculoskeletal and Connective Tissue Disorders Myalgia 2.1% 1.8% Reproductive System and Breast Disorders Dysmenorrhea 2.1% 1.6% General Disorders and Administration Site Conditions Fatigue 2.1% 1.2% The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in CLARINEX and placebo-treated 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%). Pediatrics 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.

6.2 Post-Marketing Experience 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: Cardiac disorders: tachycardia, palpitations Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: rash, pruritus Nervous system disorders: psychomotor hyperactivity, movement disorders (including dystonia, tics, and extrapyramidal symptoms), seizures (reported in patients with and without a known seizure disorder) Immune system disorders: hypersensitivity reactions (such as urticaria, edema and anaphylaxis) Investigations: elevated liver enzymes including bilirubin Hepatobiliary disorders: hepatitis Metabolism and nutrition disorders: increased appetite

7.1 Inhibitors of Cytochrome P450 3A4 In controlled clinical studies co-administration of desloratadine with ketoconazole, erythromycin, or azithromycin resulted in increased plasma concentrations of desloratadine and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of desloratadine. [See Clinical Pharmacology (12.3) .]

7.2 Fluoxetine In controlled clinical studies co-administration of desloratadine with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), resulted in increased plasma concentrations of desloratadine and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of desloratadine. [See Clinical Pharmacology (12.3) .]

7.3 Cimetidine In controlled clinical studies co-administration of desloratadine with cimetidine, a histamine H2-receptor antagonist, resulted in increased plasma concentrations of desloratadine and 3 hydroxydesloratadine, but there were no clinically relevant changes in the safety profile of desloratadine. [See Clinical Pharmacology (12.3) .]

Renal impairment: dosage adjustment is recommended ( 2.5 , 8.6 , 12.3 ) Hepatic impairment: dosage adjustment is recommended ( 2.5 , 8.7 , 12.3 )

8.1 Pregnancy Risk Summary The limited available data with CLARINEX in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are no adequate and well-controlled studies in pregnant women. Desloratadine given during organogenesis to pregnant rats was not teratogenic at the summed area under the concentration-time curve (AUC)-based exposures of desloratadine and its metabolite approximately 320 times that at the recommended human daily oral dose (RHD) of 5 mg/day. Desloratadine given during organogenesis to pregnant rabbits was not teratogenic at the AUC-based exposures of desloratadine approximately 230 times that at the RHD. Desloratadine given to pregnant rats during organogenesis through lactation resulted in reduced body weight and slow righting reflex of F 1 pups at the summed AUC-based exposures of desloratadine and its metabolite approximately 70 times or greater than that at the RHD [see Data ] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Desloratadine was given orally during organogenesis to pregnant rats at doses of 6, 24 and 48 mg/kg/day (approximately 50, 200 and 320 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). No fetal malformations were present. Reduced fetal weights and skeletal variations noted at doses of 24 and 48 mg/kg/day were likely secondary to the maternal toxicities of reduced body weight gain and food consumption observed at the same doses. Desloratadine was also given orally during organogenesis to pregnant rabbits at doses of 15, 30 and 60 mg/kg/day (approximately 30, 70 and 230 times the AUC-based exposure of desloratadine at the RHD). No adverse effects to the fetus were noted. Reduced maternal body weight gain was noted in rabbits at 60 mg/kg/day. In a peri- and post-natal development study, desloratadine was given to rats orally during the peri-natal (Gestation Day 6) through lactation periods (Postpartum Day 21) at doses of 3, 9 and 18 mg/kg/day. Reduced body weight and slow righting reflex were reported in F 1 pups at doses of 9 mg/kg/day or greater (approximately 70 times or greater than the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Desloratadine had no effect on F 1 pup development at 3 mg/kg/day (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Maternal toxicities including reduced body weight gain and food consumption were noted at 18 mg/kg/day for F 0 dams. F 1 offspring were subsequently mated and there was no developmental toxicity for F 2 pups observed.

8.2 Lactation Risk Summary Desloratadine passes into breast milk. There are not sufficient data on the effects of desloratadine on the breastfed infant or the effects of desloratadine on milk production. The decision should be made whether to discontinue nursing or to discontinue desloratadine, taking into account the developmental and health benefits of breastfeeding, the nursing mother's clinical need, and any potential adverse effects on the breastfed infant from desloratadine or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Infertility There are no data available on human infertility associated with desloratadine. There were no clinically relevant effects of desloratadine on female fertility in rats. A male specific decrease in fertility occurred at an oral desloratadine dose of 12 mg/kg or greater in rats (approximately 65 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Male fertility was unaffected at a desloratadine dose of 3 mg/kg (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). [See Nonclinical Toxicology (13.1) .]

8.4 Pediatric Use 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. [See Clinical Pharmacology (12.3) .] The CLARINEX RediTabs 2.5-mg tablet has not been evaluated in pediatric patients. Bioequivalence of the CLARINEX RediTabs Tablet and the previously marketed RediTabs Tablet was established in adults. In conjunction with the dose-finding studies in pediatrics described, the pharmacokinetic data for CLARINEX RediTabs supports the use of the 2.5-mg dose strength in pediatric patients 6 to 11 years of age.

8.5 Geriatric Use 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. [See Clinical Pharmacology (12.3) .]

8.6 Renal Impairment Dosage adjustment for patients with renal impairment is recommended [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment Dosage adjustment for patients with hepatic impairment is recommended [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ].

Desloratadine is a long-acting tricyclic histamine antagonist with selective H 1 -receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2–3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H 1 -receptor. Desloratadine inhibited histamine release from human mast cells in vitro . Results of a radiolabeled tissue distribution study in rats and a radioligand H 1 -receptor binding study in guinea pigs showed that desloratadine did not readily cross the blood brain barrier. The clinical significance of this finding is unknown.