DESLORATADINE: 3,141 Adverse Event Reports & Safety Profile

CLARINEX-D 12 HOUR Extended Release Tablets are oval-shaped blue and white bilayer tablets containing 2.5 mg desloratadine in the blue immediate-release layer and 120 mg of pseudoephedrine sulfate USP in the white extended-release layer which is released slowly, allowing for twice-daily administration. The inactive ingredients contained in CLARINEX-D 12 HOUR Extended Release Tablets are hypromellose USP, microcrystalline cellulose NF, povidone USP, silicon dioxide NF, magnesium stearate NF, corn starch NF, edetate disodium USP, citric acid anhydrous USP, stearic acid NF, and FD&C Blue No. 2 aluminum lake dye. Desloratadine, 1 of the 2 active ingredients of CLARINEX-D 12 HOUR Extended Release Tablets, is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It has an empirical formula: C 19 H 19 ClN 2 and a molecular weight of 310.8. The chemical name is 8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5 H -benzo[5,6] cyclohepta [1,2- b ]pyridine and has the following structure: Pseudoephedrine sulfate, the other active ingredient of CLARINEX-D 12 HOUR Extended Release Tablets, is the synthetic salt of one of the naturally occurring dextrorotatory diastereomers of ephedrine and is classified as an indirect sympathomimetic amine. Pseudoephedrine sulfate is a colorless hygroscopic crystal or white, hygroscopic crystalline powder, practically odorless, with a bitter taste. It is very soluble in water, freely soluble in alcohol, and sparingly soluble in ether. The empirical formula for pseudoephedrine sulfate is (C 10 H 15 NO) 2

• H 2 SO 4 ; the chemical name is benzenemethanol, α-[1-(methylamino) ethyl]-,[ S -( R *, R *)]-, sulfate (2:1)(salt); and the chemical structure is: Chemical Structure Chemical Structure

AND USAGE Desloratadine Oral Solution 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 Desloratadine oral solution 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 Desloratadine oral solution 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 Desloratadine oral solution 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.

1.1 Seasonal Allergic Rhinitis Desloratadine oral solution 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 Desloratadine oral solution 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 Desloratadine oral solution 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.

AND ADMINISTRATION Although the oral solution and the orally disintegrating tablet formulation of desloratadine may be available in the marketplace, CLARINEX ® Oral Solution and CLARINEX ® RediTabs ® Tablets are no longer marketed.

Clarinex

Tablets, Oral Solution, or RediTabs Tablets may be taken without regard to meals. Place CLARINEX (desloratadine) RediTabs Tablets on the tongue and allow to disintegrate before swallowing. Tablet disintegration occurs rapidly. Administer with or without water. Take tablet immediately after opening the blister. 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) . Dosage (by age): Adults and Adolescents 12 Years of Age and Over: CLARINEX Tablets - one 5 mg tablet once daily or CLARINEX RediTabs Tablets - one 5 mg tablet once daily or CLARINEX Oral Solution - 2 teaspoonfuls (5 mg in 10 mL) once daily ( 2 )

Children

6 to 11 Years of Age: CLARINEX Oral Solution - 1 teaspoonful (2.5 mg in 5 mL) once daily or CLARINEX RediTabs Tablets - one 2.5 mg tablet once daily ( 2 )

Children

12 Months to 5 Years of Age: CLARINEX Oral Solution - ½ teaspoonful (1.25 mg in 2.5 mL) once daily ( 2 )

Children

6 to 11 Months of Age: CLARINEX Oral Solution - 2 mL (1 mg) once daily ( 2 )

2.1 Adults and Adolescents 12 Years of Age and Over The recommended dose of CLARINEX Tablets or CLARINEX RediTabs 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.

2.2 Children 6 to 11 Years of Age The recommended dose of CLARINEX Oral Solution is 1 teaspoonful (2.5 mg in 5 mL) once daily. The recommended dose of CLARINEX RediTabs Tablets is one 2.5-mg tablet once daily.

2.3 Children 12 Months to 5 Years of Age The recommended dose of CLARINEX Oral Solution is ½ teaspoonful (1.25 mg in 2.5 mL) once daily.

2.4 Children 6 to 11 Months of Age The recommended dose of CLARINEX Oral Solution is 2 mL (1 mg) once daily.

2.5 Adults with Hepatic or Renal Impairment 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

CLARINEX-D 12 HOUR Extended Release Tablets are contraindicated in: Patients with hypersensitivity to any of its ingredients, or to loratadine [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Patients with narrow-angle glaucoma Patients with urinary retention Patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment [see Drug Interactions (7.1) ] Patients with severe hypertension or severe coronary artery disease Hypersensitivity ( 4 ) Narrow-Angle Glaucoma ( 4 )

Urinary

Retention ( 4 )

Patients

Receiving MAO Inhibitors or within 14 days of stopping such treatment ( 4 ) Severe hypertension or severe coronary artery disease. ( 4 )

REACTIONS 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 Sun Pharmaceutical Industries, Inc., at 1-866-923-4914 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, 2,834 patients ages 12 years or older received desloratadine tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between desloratadine and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the desloratadine 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 desloratadine tablets (5 mg once daily), and that were more common with desloratadine 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 Desloratadine Tablets Adverse Event Desloratadine Tablets 5 mg (n = 1,655) Placebo (n = 1,652) Infections and Infestations Pharyngitis 4.1% 2% Nervous System Disorders Somnolence 2.1% 1.8% Gastrointestinal Disorders Dry Mouth 3% 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 desloratadine 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 desloratadine tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received desloratadine tablets and that were more common with desloratadine than placebo were (rates for desloratadine 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 desloratadine 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 desloratadine and placebo in at least 2 percent of subjects receiving desloratadine 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 desloratadine product and placebo in at least 2 percent of subjects receiving desloratadine 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 desloratadine and placebo in at least 2 percent of subjects receiving desloratadine 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%, 1.6%), and nausea (3%, 0%). There were no clinically meaningful changes in any electrocardiographic parameter, including the QTc interval. Only one of the 246 pediatric subjects receiving desloratadine 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

AND PRECAUTIONS Cardiovascular and central nervous system effects: Use with caution in patients with cardiovascular disorders. ( 5.1 ) Coexisting conditions: Use with caution in patients with increased intraocular pressure, prostatic hypertrophy, diabetes mellitus, or hyperthyroidism. ( 5.2 )

5.1 Cardiovascular and Central Nervous System Effects The pseudoephedrine sulfate contained in CLARINEX-D 12 HOUR Extended Release Tablets, like other sympathomimetic amines, can produce cardiovascular and central nervous system (CNS) effects in some patients such as insomnia, dizziness, weakness, tremor, or arrhythmias. In addition, central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has been reported. Therefore, CLARINEX-D 12 HOUR Extended Release Tablets should be used with caution in patients with cardiovascular disorders, and should not be used in patients with severe hypertension or severe coronary artery disease.

5.2 Coexisting Conditions CLARINEX-D 12 HOUR Extended Release Tablets contain pseudoephedrine sulfate, a sympathomimetic amine, and therefore should be used with caution in patients with diabetes and hyperthyroidism. Also use with caution in patients with prostatic hypertrophy or increased intraocular pressure, as urinary retention and narrow-angle glaucoma may occur <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

5.3 Co-Administration with Monoamine Oxidase (MAO) Inhibitors CLARINEX-D 12 HOUR Extended Release Tablets should not be used in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment as an increase in blood pressure or hypertensive crisis, may occur <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions (7.1) ]</span>.

5.4 Hypersensitivity Reactions Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of desloratadine a component of CLARINEX-D 12 HOUR Extended Release Tablets. If such a reaction occurs, therapy with CLARINEX-D 12 HOUR Extended Release Tablets should be stopped and alternative treatment should be considered <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>.

5.5 Renal Impairment CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with renal impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

5.6 Hepatic Impairment CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

INTERACTIONS No specific interaction studies have been conducted with CLARINEX-D 12 HOUR Extended Release Tablets.

Monoamine

Oxidase (MAO) Inhibitors: Do not use. May potentiate the effect of pseudoephedrine on vascular system. ( 7.1 )

7.1 Monoamine Oxidase Inhibitors CLARINEX-D 12 HOUR Extended Release Tablets should not be used in patients receiving monoamine oxidase (MAO) inhibitor therapy or within fourteen (14) days of stopping such treatment because the action of pseudoephedrine a component of CLARINEX-D 12 HOUR Extended Release tablets on the vascular system may be potentiated by these agents <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.3) ]</span>.

7.2 Beta-Adrenergic Blocking Agents The antihypertensive effects of beta-adrenergic blocking agents, methyldopa, and reserpine, may be reduced by sympathomimetics such as pseudoephedrine. Exercise caution when using CLARINEX-D 12 HOUR Extended Release Tablets with these agents.

7.3 Digitalis Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Exercise caution when using CLARINEX-D 12 HOUR Extended Release Tablets with these agents.

7.4 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

7.5 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

7.6 Cimetidine In controlled clinical studies co-administration of desloratadine with cimetidine a histamine H 2 -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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.