DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. CLARINEX-D 12 HOUR Extended Release Tablets are oval shaped, blue and white bilayer tablets with D12 embossed in the blue layer. Each tablet contains 2.5 mg desloratadine in the blue immediate-release layer and 120 mg of pseudoephedrine sulfate USP in the white extended-release layer. Desloratadine 2.5 mg/Pseudoephedrine sulfate 120 mg tablets. (3).

DRUG ABUSE AND DEPENDENCE SECTION.


9 DRUG ABUSE AND DEPENDENCE. There is no information to indicate that abuse or dependency occurs with CLARINEX or CLARINEX-D 12 HOUR Extended Release Tablets.

SPL UNCLASSIFIED SECTION.


1.1Seasonal Allergic Rhinitis. CLARINEX-D(R) 12 HOUR Extended Release Tablets is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in adults and adolescents 12 years of age and older. CLARINEX-D 12 HOUR Extended Release Tablets should be administered when the antihistaminic properties of desloratadine and the nasal decongestant properties of pseudoephedrine are desired [see Clinical Pharmacology (12)].

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the label:Cardiovascular and Central Nervous System effects [see Warnings and Precautions (5.1)] Increased Intraocular pressure [see Warnings and Precautions (5.2)] Urinary retention in patients with prostatic hypertrophy [see Warnings and Precautions (5.2)] Hypersensitivity reactions [see Warnings and Precautions (5.4)]. Cardiovascular and Central Nervous System effects [see Warnings and Precautions (5.1)] Increased Intraocular pressure [see Warnings and Precautions (5.2)] Urinary retention in patients with prostatic hypertrophy [see Warnings and Precautions (5.2)] Hypersensitivity reactions [see Warnings and Precautions (5.4)]. The most common adverse reactions (reported in >=2% of patients) were insomnia, headache, mouth dry, fatigue, somnolence, pharyngitis, dizziness, nausea, insomnia and anorexia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation at 800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions (reported in >=2% of patients) were insomnia, headache, mouth dry, fatigue, somnolence, pharyngitis, dizziness, nausea, insomnia and anorexia. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The safety data described below are from clinical trials with CLARINEX-D 12 HOUR Extended Release Tablets that included 1248 patients with seasonal allergic rhinitis, of which 414 patients received CLARINEX-D 12 HOUR Extended Release Tablets twice daily for up to weeks. The majority of patients were between 18 and <65 years of age with mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82 Caucasian, 9% Black, % Hispanic and 3% Asian/other ethnicity. The percentage of subjects receiving CLARINEX-D 12 HOUR Extended Release Tablets and who discontinued from the clinical trials because of an adverse event was 3.6%. Adverse reactions that were reported by >=2% of subjects receiving CLARINEX-D 12 HOUR Extended Release Tablets are shown in Table 1.TABLE 1: Incidence of Adverse Reactions Reported by >=2% of Subjects Receiving CLARINEX-D 12 HOUR Extended Release TabletsAdverse ReactionCLARINEX-D(R) 12 HOUR BID (N 414)Desloratadine mg QD (N 412)Pseudoephedrine 120 mg BID (N 422)Gastrointestinal Disorders Mouth Dry8%2%8%Nausea2%1%3%General Disorders and Administration Site ConditionsFatigue4%2%2%Metabolism and Nutrition DisordersAnorexia2%0%2%Nervous System DisordersHeadache8%8%9%Somnolence3%4%2%Dizziness3%2%2%Psychiatric DisordersInsomnia10%3%13%Respiratory, Thoracic and Mediastinal DisordersPharyngitis3%3%3%There were no relevant differences in adverse reactions for subgroups of patients as defined by gender, age, or race.. 6.2Post-Marketing Experience. In addition to the adverse reactions reported during clinical trials and listed above, adverse events have been identified during post approval use of CLARINEX-D 12 HOUR Extended Release Tablets. Because these events are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Adverse events identified from post-marketing surveillance on the use of CLARINEX-D 12 HOUR Extended Release Tablets include tachycardia, palpitations, dyspnea, rash and pruritis.In addition to these events, the following spontaneous adverse events have been reported during the marketing of desloratadine as single ingredient product: headache, somnolence, dizziness and rarely hypersensitivity reactions (such as urticaria, edema and anaphylaxis), and elevated liver enzymes including bilirubin and very rarely, hepatitis.

STORAGE AND HANDLING SECTION.


Storage:Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Avoid exposure at or above 30C (86F). Protect from excessive moisture. Protect from light.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. There are no animal or laboratory studies on the combination product of desloratadine and pseudoephedrine sulfate to evaluate carcinogenesis, mutagenesis, or impairment of fertility.. Carcinogenicity Studies:The carcinogenic potential of desloratadine was assessed using loratadine study in rats and desloratadine study in mice. In 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). 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 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 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.. Genotoxicity Studies:In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).. Impairment of Fertility: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). 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 (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 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately times the AUC in humans at the recommended daily oral dose).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Desloratadine is long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicate that at concentration of to ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H1 receptor. Desloratadine inhibited histamine release from human mast cells in vitro. Results of radiolabeled tissue distribution study in rats and radioligand H1-receptor-binding study in guinea pigs showed that desloratadine does not readily cross the blood brain barrier. The clinical significance of this finding is unknown.Pseudoephedrine sulfate is an orally active sympathomimetic amine and exerts decongestant action on the nasal mucosa. Pseudoephedrine sulfate is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.. 12.2 Pharmacodynamics. Wheal and Flare: Human histamine skin wheal studies following single and repeated mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5mg group over the 28 day treatment period. The clinical relevance of histamine wheal skin testing is unknown.. Effects on QTc In clinical trials for CLARINEX-D 12 HOUR Extended Release Tablets, ECGs were recorded at baseline and endpoint within to hours after the last dose. The majority of ECGs were normal at both baseline and endpoint. No clinically meaningful changes were observed following treatment with CLARINEX-D 12 HOUR Extended Release Tablets for any ECG parameter, including the QTc interval. An increase in the ventricular rate of 7.1 and 6.4 bpm was observed in the CLARINEX-D 12 HOUR Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in subjects receiving desloratadine alone. Single daily doses of CLARINEX 45 mg were given to normal male and female volunteers for 10 days.All ECGs obtained in this study were manually read in blinded fashion by cardiologist. In the CLARINEX-treated subjects, there was mean increase in the maximum heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both Bazetts and Fridericia methods. Using the QTc (Bazett) there was mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo. Using QTc (Fridericia) there was mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.. 12.3 Pharmacokinetics. Absorption:In single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately to hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6 nghr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (Cmax and AUC) of desloratadine. For pseudoephedrine, the mean Tmax occurred at to hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 nghr/mL, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of pseudoephedrine.Following oral administration of CLARINEX-D 12 HOUR Extended Release Tablets twice daily for 14 days in healthy volunteers, steady-state conditions were reached on Day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean steady-state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC 0-12 h) of approximately 1.7 ng/mL and 16 nghr/mL were observed, respectively. For pseudoephedrine, mean steady state peak plasma concentrations (Cmax) and AUC (0-12 h) of 459 ng/mL and 4658 nghr/mL were observed.. Distribution: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.. Metabolism: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 with desloratadine indicate that subset of the general population has 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 subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or subject with desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of and 70 years, including 977 subjects aged to years, 1575 subjects aged 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=1462) and Hispanics (2%, n=1063). 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 prospectively identified, total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with CLARINEX Syrup for 15 to 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.Pseudoephedrine alone is incompletely metabolized (less than 1%) in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in the urine. About 55% to 96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.. Elimination:Following single dose administration of CLARINEX-D 12 HOUR Extended Release Tablets, the mean plasma elimination half-life of desloratadine was approximately 27 hours. In another study, following administration of single oral doses of desloratadine mg, Cmax and AUC values increased in dose proportional manner following single oral doses between and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. human mass balance study documented 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.The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately to or to 16 hours when the urinary pH is or 8, respectively.. Geriatric Subjects: Following multiple-dose administration of CLARINEX Tablets, the mean Cmax and AUC values for desloratadine 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 age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects >=65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older vs. younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly patients.. Pediatric Subjects: CLARINEX-D 12 HOUR Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age. Renally Impaired: Following single dose of desloratadine 7.5 mg pharmacokinetics were characterized in subjects with mild (n=7; creatinine clearance 51-69 mL/min/1.73m2), moderate (n=6; creatinine clearance 34-43 mL/min/1.73m2) and severe (n=6; creatinine clearance 5-29 mL/min/1.73m2) renal impairment or hemodialysis dependent (n=6) subjects. In subjects 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 subjects 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. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment.Pseudoephedrine is primarily excreted unchanged in the urine as unchanged drug with the remainder apparently being metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal impairment.. Hepatically Impaired: Following single oral dose of desloratadine, pharmacokinetics were characterized in subjects with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic impairment and subjects with normal hepatic function. Subjects with hepatic impairment, regardless of severity, had approximately 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in subjects 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 desloratadine in subjects with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for subjects with hepatic impairment combined were not statistically significantly different from subjects with normal hepatic function.. Gender: Female subjects treated for 14 days with CLARINEX Tablets had 10% and 3% higher desloratadine 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 considered to be clinically relevant.. Race: Following 14 days of treatment with CLARINEX Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not considered to be clinically relevant.. Drug interaction: In controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) subjects, desloratadine 7.5 mg (1.5 times the daily dose) once daily was co-administered with erythromycin 500 mg every hours or ketoconazole 200 mg every 12 hours for 10 days. In separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for days (n=18) or with fluoxetine 20 mg once daily for days after 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 healthy male and female subjects. Although increased plasma concentrations (Cmax and AUC 0-24 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 Changes in Desloratadine and 3-hydroxydesloratadine Pharmacokinetics in Healthy Male and Female SubjectsDesloratadine3-hydroxydesloratadineCmax AUC0-24 hrsCmax AUC0-24 hrsErythromycin(500 mg Q8h)+24%+14%+43%+40%Ketoconazole(200 mg Q12h)+45%+39%+43%+72%Azithromycin(500 mg Day 1, 250 mg QD 4 days)+15%+5%+15%+4%Fluoxetine(20 mg QD)+15%+0%+17%+13%Cimetidine(600 mg Q12h)+12%+19%-11%-3%.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1Seasonal Allergic Rhinitis. The clinical efficacy and safety of CLARINEX-D 12 HOUR Extended Release Tablets was evaluated in two 2-week multicenter, randomized parallel group clinical trials involving 1248 subjects 12 to 78 years of age with seasonal allergic rhinitis, 414 of whom received CLARINEX-D 12 HOUR Extended Release Tablets. In the trials, subjects were randomized to receive CLARINEX-D 12 HOUR Extended Release Tablets twice daily, CLARINEX Tablets mg once daily, or sustained-release pseudoephedrine tablet 120 mg twice daily for weeks. The majority of patients were between 18 and <65 years of age with mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82 Caucasian, 9% Black, % Hispanic and 3% Asian/other ethnicity. Primary efficacy variable was twice-daily reflective patient scoring of nasal symptoms (rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and four non-nasal symptoms (itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate) on 4 point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic efficacy of CLARINEX-D 12 HOUR Extended Release Tablets, as measured by total symptom score excluding nasal congestion, was significantly greater than pseudoephedrine alone over the 2-week treatment period; and the decongestant efficacy of CLARINEX-D 12 HOUR Extended Release Tablets, as measured by nasal stuffiness/congestion, was significantly greater than CLARINEX (desloratadine alone) over the 2-week treatment period. Primary efficacy variable results from of trials are shown in Table 3.TABLE 3: Changes in Symptoms in 2-Week Clinical Trial in Subjects With Seasonal Allergic Rhinitis Treatment Group (n)Mean BaselineTo qualify at Baseline, the sum of the twice-daily diary reflective scores for the days prior to Baseline and the morning of the Baseline visit were to total >=42 for total nasal symptom score (sum of nasal symptoms of rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and total of >=35 for total non-nasal symptoms score (sum of non-nasal symptoms of itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate), and score of >=14 for each of the individual symptoms of nasal stuffiness/congestion and rhinorrhea. Each symptom was scored on 4-point severity scale (0=none, 1=mild, 2=moderate, 3=severe). (sem)Change (% Change) from BaselineMean reduction in score averaged over the 2-week treatment period. (sem)CLARINEX-D(R) 12 HOUR Comparison to ComponentsThe comparison of interest is shown bolded. (P-value)Sem=Standard Error of the MeanTotal Symptom Score (Excluding Nasal Congestion)CLARINEX-D 12 HOUR Extended Release Tablets BID(199)14.18 (0.21)-6.54 (-46.0) (0.30)- Pseudoephedrine tablet 120 mg BID(197)14.06 (0.21)-5.07 (-35.9) (0.30)P<0.001CLARINEX(R) mg Tablets QD(197)14.82 (0.21)-5.09 (-33.5) (0.30)P<0.001Nasal Stuffiness/CongestionCLARINEX-D 12 HOUR Extended Release Tablets BID(199)2.47 (0.027)-0.93 (-37.4) (0.046)- Pseudoephedrine tablet 120 mg BID (197)2.46 (0.027)-0.75 (-31.2) (0.046)P=0.006CLARINEX(R) mg Tablets QD(197)2.50 (0.027)-0.66 (-26.7) (0.046)P<0.001There were no significant differences in the efficacy of CLARINEX-D 12 HOUR Extended Release Tablets across subgroups of subjects defined by gender, age, or race.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. 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 Post-Marketing Experience (6.2)] Patients with narrow angle glaucomaPatients with urinary retentionPatients 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. Patients with hypersensitivity to any of its ingredients, or to loratadine [see Warnings and Precautions (5.4) and Post-Marketing Experience (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). 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).

DESCRIPTION SECTION.


11 DESCRIPTION. 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. aluminum lake dye.Desloratadine, of the active ingredients of CLARINEX-D 12 HOUR Extended Release Tablets, is white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It has an empirical formula: C19H19ClN2 and molecular weight of 310.8. The chemical name is 8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-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 colorless hygroscopic crystal or white, hygroscopic crystalline powder, practically odorless, with bitter taste. It is very soluble in water, freely soluble in alcohol, and sparingly soluble in ether. The empirical formula for pseudoephedrine sulfate is (C10H15NO)2 H2SO4; the chemical name is benzenemethanol, -[1-(methylamino) ethyl]-,[S-(R,R)]-, sulfate (2:1)(salt); and the chemical structure is:. Chemical Structure. Chemical Structure. Logo.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Administer CLARINEX-D 12 HOUR Extended Release Tablet by the oral route only. Do not break, chew or crush the tablet. Swallow the tablet whole.. For oral use onlyAdults and adolescents 12 years of age and over: The recommended dose of CLARINEX-D 12 HOUR Extended Release Tablets is one tablet twice day. (2). 2.1Adults and Adolescents 12 years of Age and Over. The recommended dose of CLARINEX-D 12 HOUR Extended Release Tablets is tablet twice day, administered approximately 12 hours apart and with or without meal. Higher doses or increased dosing frequency of CLARINEX-D 12 HOUR Extended Release Tablets have not demonstrated increased effectiveness. Do not exceed the recommended dose as desloratadine and pseudoephedrine, the active components of CLARINEX-D 12 HOUR Extended Release Tablets have been associated with adverse effects at higher doses [see Overdosage (10.1) and (10.2)].

DRUG INTERACTIONS SECTION.


7 DRUG 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). 7.1Monoamine 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 component of CLARINEX-D 12 HOUR Extended Release tablets on the vascular system may be potentiated by these agents. (see Contraindications (4) and Warnings and Precautions 5.3) 7.2Beta-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.. 7.3Digitalis. 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.. 7.4Inhibitors 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)] 7.5Fluoxetine. In controlled clinical studies co-administration of desloratadine with fluoxetine, 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)] 7.6Cimetidine. In controlled clinical studies co-administration of desloratadine with cimetidine 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)].

GERIATRIC USE SECTION.


8.5 Geriatric Use. The number of subjects (n=10) >=65 years old treated with CLARINEX-D 12 HOUR Extended Release Tablets was too limited to make any formal statistical comparison regarding the efficacy or safety of this drug product in this age group, or to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients, although the elderly are more likely to have adverse reactions to sympathomimetic amines. 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)].Pseudoephedrine, desloratadine, and their metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor the patient for adverse events [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. CLARINEX-D 12 HOUR Extended Release Tablets are oval-shaped, blue and white bilayer tablets with D12 embossed in the blue layer, containing 2.5 mg desloratadine in the blue immediate-release layer and 120 mg of pseudoephedrine sulfate USP in the white extended-release layer. CLARINEX-D 12 HOUR Extended Release Tablets are supplied in Bottles of 10 NDC 54868-5708-0 Bottles of 30 NDC 54868-5708-1 . Storage:Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Avoid exposure at or above 30C (86F). Protect from excessive moisture. Protect from light.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. CLARINEX-D 12 HOUR is combination product containing an H1-receptor antagonist and sympathomimetic amine indicated for: Relief of nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in adults and adolescents 12 years of age and older. (1). Relief of nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in adults and adolescents 12 years of age and older. (1). 1.1Seasonal Allergic Rhinitis. CLARINEX-D(R) 12 HOUR Extended Release Tablets is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, including nasal congestion, in adults and adolescents 12 years of age and older. CLARINEX-D 12 HOUR Extended Release Tablets should be administered when the antihistaminic properties of desloratadine and the nasal decongestant properties of pseudoephedrine are desired [see Clinical Pharmacology (12)].

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. [see FDA Approved Patient Labeling]. 17.1Cardiovascular and Central Nervous System Effects. Patients should be informed that pseudoephedrine, on of the active ingredients in CLARINEX-D 12 HOUR Extended Release Tablets may cause cardiovascular or central nervous system effects such as insomnia, dizziness, tremor, or arrhythmia.. 17.2Dosing. Patients should be advised not to increase the dose or dosing frequency of CLARINEX-D 12 HOUR Extended Release Tablets.. 17.3Additional Antihistamines and/or Decongestants. Patients should be advised against the concurrent use of CLARINEX-D 12 HOUR Extended Release Tablets with other antihistamines and/or decongestants.. 17.4Monoamine Oxidase (MAO) Inhibitors. Patients should be informed that due to its pseudoephedrine component, they should not use CLARINEX-D 12 HOUR with monoamine oxidase (MAO) inhibitor or within 14 days of stopping use of an MAO inhibitor.. 17.5Coexisting Conditions. Patients with severe hypertension or severe coronary artery disease, narrow-angle glaucoma, or urinary retention should be advised not to use CLARINEX-D 12 HOUR Extended Release Tablets.. 17.6Instructions for Use. Patients should be instructed not to break, crush or chew the tablet; the tablet should be swallowed whole, and can be taken without regard to meals.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Desloratadine is long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicate that at concentration of to ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H1 receptor. Desloratadine inhibited histamine release from human mast cells in vitro. Results of radiolabeled tissue distribution study in rats and radioligand H1-receptor-binding study in guinea pigs showed that desloratadine does not readily cross the blood brain barrier. The clinical significance of this finding is unknown.Pseudoephedrine sulfate is an orally active sympathomimetic amine and exerts decongestant action on the nasal mucosa. Pseudoephedrine sulfate is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. There are no animal or laboratory studies on the combination product of desloratadine and pseudoephedrine sulfate to evaluate carcinogenesis, mutagenesis, or impairment of fertility.. Carcinogenicity Studies:The carcinogenic potential of desloratadine was assessed using loratadine study in rats and desloratadine study in mice. In 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). 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 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 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.. Genotoxicity Studies:In genotoxicity studies with desloratadine, there was no evidence of genotoxic potential in reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).. Impairment of Fertility: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). 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 (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 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately times the AUC in humans at the recommended daily oral dose).. 13.2Animal Toxicology and/or Pharmacology. Reproductive Toxicology Studies:Desloratadine was not teratogenic in rats at doses up to 48 mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately 210 times the AUC in humans at the recommended daily oral dose) or in rabbits at doses up to 60 mg/kg/day (estimated desloratadine exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). In separate study, an increase in pre-implantation loss and decreased number of implantations and fetuses were noted in female rats at 24 mg/kg (estimated desloratadine and desloratadine metabolite exposures were 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 doses of mg/kg/day or greater (estimated desloratadine and desloratadine metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Desloratadine had no effect on pup development at an oral dose of mg/kg/day (estimated desloratadine and desloratadine metabolite exposures were approximately times the AUC in humans at the recommended daily oral dose).

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. Desloratadine and pseudoephedrine both pass into breast milk; therefore, decision should be made whether to discontinue nursing or to discontinue CLARINEX-D 12 HOUR Extended Release Tablets, taking into account the benefit of the drug to the nursing mother and the possible risk to the child.

OVERDOSAGE SECTION.


10 OVERDOSAGE. 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.. 10.1 Desloratadine. Information regarding acute overdosage with desloratadine is limited to experience from postmarketing adverse event reports and from clinical trials conducted during the development of the CLARINEX product. In the reported cases of overdose, there were no significant adverse events that were attributed to desloratadine. In 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 [see Clinical Pharmacology (12.2)]. 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 exposure was approximately 290 times the human daily oral dose on an mg/m2 basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated desloratadine exposure was approximately 810 times the human daily oral dose on an mg/m2 basis).. 10.2Sympathomimetics. In large doses, sympathomimetics such as pseudoephedrine may give rise to giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscle weakness and tenseness, anxiety, restlessness, and insomnia. Many patients can present toxic psychosis with delusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL CLARINEX-D(R) 12 HOUR (desloratadine 2.5 mg/pseudoephedrine sulfate, USP 120 mg)EXTENDED RELEASE TABLETSRx only. image of package label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. CLARINEX-D 12 HOUR Extended Release Tablets are not indicated for use in pediatric patients under 12 years of age.

PHARMACODYNAMICS SECTION.


12.2 Pharmacodynamics. Wheal and Flare: Human histamine skin wheal studies following single and repeated mg doses of desloratadine have shown that the drug exhibits an antihistaminic effect by hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the desloratadine 5mg group over the 28 day treatment period. The clinical relevance of histamine wheal skin testing is unknown.. Effects on QTc In clinical trials for CLARINEX-D 12 HOUR Extended Release Tablets, ECGs were recorded at baseline and endpoint within to hours after the last dose. The majority of ECGs were normal at both baseline and endpoint. No clinically meaningful changes were observed following treatment with CLARINEX-D 12 HOUR Extended Release Tablets for any ECG parameter, including the QTc interval. An increase in the ventricular rate of 7.1 and 6.4 bpm was observed in the CLARINEX-D 12 HOUR Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in subjects receiving desloratadine alone. Single daily doses of CLARINEX 45 mg were given to normal male and female volunteers for 10 days.All ECGs obtained in this study were manually read in blinded fashion by cardiologist. In the CLARINEX-treated subjects, there was mean increase in the maximum heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both Bazetts and Fridericia methods. Using the QTc (Bazett) there was mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo. Using QTc (Fridericia) there was mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Absorption:In single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for desloratadine occurred at approximately to hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 1.09 ng/mL and 31.6 nghr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (Cmax and AUC) of desloratadine. For pseudoephedrine, the mean Tmax occurred at to hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 nghr/mL, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of pseudoephedrine.Following oral administration of CLARINEX-D 12 HOUR Extended Release Tablets twice daily for 14 days in healthy volunteers, steady-state conditions were reached on Day 10 for desloratadine, 3-hydroxydesloratadine and pseudoephedrine. For desloratadine, mean steady-state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC 0-12 h) of approximately 1.7 ng/mL and 16 nghr/mL were observed, respectively. For pseudoephedrine, mean steady state peak plasma concentrations (Cmax) and AUC (0-12 h) of 459 ng/mL and 4658 nghr/mL were observed.. Distribution: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.. Metabolism: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 with desloratadine indicate that subset of the general population has 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 subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or subject with desloratadine half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of and 70 years, including 977 subjects aged to years, 1575 subjects aged 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=1462) and Hispanics (2%, n=1063). 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 prospectively identified, total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with CLARINEX Syrup for 15 to 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.Pseudoephedrine alone is incompletely metabolized (less than 1%) in the liver by N-demethylation to an inactive metabolite. The drug and its metabolite are excreted in the urine. About 55% to 96% of an administered dose of pseudoephedrine hydrochloride is excreted unchanged in the urine.. Elimination:Following single dose administration of CLARINEX-D 12 HOUR Extended Release Tablets, the mean plasma elimination half-life of desloratadine was approximately 27 hours. In another study, following administration of single oral doses of desloratadine mg, Cmax and AUC values increased in dose proportional manner following single oral doses between and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. human mass balance study documented 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.The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately to or to 16 hours when the urinary pH is or 8, respectively.. Geriatric Subjects: Following multiple-dose administration of CLARINEX Tablets, the mean Cmax and AUC values for desloratadine 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 age groups. The mean plasma elimination half-life of desloratadine was 33.7 hr in subjects >=65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older vs. younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly patients.. Pediatric Subjects: CLARINEX-D 12 HOUR Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age. Renally Impaired: Following single dose of desloratadine 7.5 mg pharmacokinetics were characterized in subjects with mild (n=7; creatinine clearance 51-69 mL/min/1.73m2), moderate (n=6; creatinine clearance 34-43 mL/min/1.73m2) and severe (n=6; creatinine clearance 5-29 mL/min/1.73m2) renal impairment or hemodialysis dependent (n=6) subjects. In subjects 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 subjects 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. Desloratadine and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxydesloratadine was unaltered by renal impairment.Pseudoephedrine is primarily excreted unchanged in the urine as unchanged drug with the remainder apparently being metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal impairment.. Hepatically Impaired: Following single oral dose of desloratadine, pharmacokinetics were characterized in subjects with mild (n=4), moderate (n=4) and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic impairment and subjects with normal hepatic function. Subjects with hepatic impairment, regardless of severity, had approximately 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of desloratadine in subjects 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 desloratadine in subjects with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for subjects with hepatic impairment combined were not statistically significantly different from subjects with normal hepatic function.. Gender: Female subjects treated for 14 days with CLARINEX Tablets had 10% and 3% higher desloratadine 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 considered to be clinically relevant.. Race: Following 14 days of treatment with CLARINEX Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not considered to be clinically relevant.. Drug interaction: In controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) subjects, desloratadine 7.5 mg (1.5 times the daily dose) once daily was co-administered with erythromycin 500 mg every hours or ketoconazole 200 mg every 12 hours for 10 days. In separate controlled, parallel group clinical pharmacology studies, desloratadine at the clinical dose of mg has been coadministered with azithromycin 500 mg followed by 250 mg once daily for days (n=18) or with fluoxetine 20 mg once daily for days after 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 healthy male and female subjects. Although increased plasma concentrations (Cmax and AUC 0-24 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 Changes in Desloratadine and 3-hydroxydesloratadine Pharmacokinetics in Healthy Male and Female SubjectsDesloratadine3-hydroxydesloratadineCmax AUC0-24 hrsCmax AUC0-24 hrsErythromycin(500 mg Q8h)+24%+14%+43%+40%Ketoconazole(200 mg Q12h)+45%+39%+43%+72%Azithromycin(500 mg Day 1, 250 mg QD 4 days)+15%+5%+15%+4%Fluoxetine(20 mg QD)+15%+0%+17%+13%Cimetidine(600 mg Q12h)+12%+19%-11%-3%.

PREGNANCY SECTION.


8.1 Pregnancy. Pregnancy Category C: There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine. Desloratadine was not teratogenic in rats or rabbits but affected implantation in rats. Because animal reproduction studies are not always predictive of human response, CLARINEX-D 12 HOUR Extended Release Tablets 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 AUC in humans at the recommended daily oral dose). An increase in pre-implantation loss and decreased number of implantations and fetuses were noted, however, in 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 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 [see Nonclinical Toxicology (13.2)].

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATIONCLARINEX-D (CLA-RI-NEX) 12 Hour Extended Release Tablets(desloratadine and pseudoephedrine sulfate)Read the Patient Information that comes with CLARINEX-D 12 Hour Extended Release Tablets before you start taking it and each time you get refill. There may be new information. This leaflet is summary of the information for patients. Your doctor or pharmacist can give you additional information. This leaflet does not take the place of talking to your doctor about your medical condition or treatment.What is CLARINEX-D(R) 12 Hour Extended Release TabletsCLARINEX-D 12 Hour Extended Release Tablets is prescription medicine that contains the medicines desloratadine (an antihistamine) and pseudoephedrine (a nasal decongestant). CLARINEX-D 12 Hour Extended Release Tablets is used to help control the symptoms of seasonal allergic rhinitis (sneezing, stuffy nose, runny nose and itching of the nose) in adults and children 12 years and older.CLARINEX-D 12 Hour Extended Release Tablets is not for children under 12 years of age.Who should not take CLARINEX-D(R) 12 Hour Extended Release TabletsDo not take CLARINEX-D 12 Hour Extended Release Tablets if you:are allergic to desloratadine or pseudoephedrine sulfate or any of the ingredients in CLARINEX-D 12 Hour Extended Release Tablets. See the end of this leaflet for complete list of ingredients in CLARINEX-D 12 Hour Extended Release Tablets.are allergic to loratadine (Alavert, Claritin)have narrow angle glaucomahave problems with urination (urinary retention)take Monoamine Oxidase Inhibitor (MAOI) medicine to treat depression, or if you stopped taking an MAOI medicine within the last weeks. Ask your doctor or pharmacist if you are not sure if you take an MAOI medicine.have severe high blood pressurehave severe heart diseaseTalk to your doctor before taking this medicine if you have any of these conditions.What should tell my doctor before taking CLARINEX-D(R) 12 Hour Extended Release TabletsBefore you take CLARINEX-D 12 Hour Extended Release Tablets, tell your doctor if you:have any of the conditions listed in the section Who should not take CLARINEX-D 12 Hour Extended Release Tabletsdiabeteshyperthyroidismhave prostate problemshave liver or kidney problemshave any other medical conditionsare pregnant or plan to become pregnant. It is not known if CLARINEX-D 12 Hour Extended Release Tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.are breast-feeding or plan to breast-feed. CLARINEX-D 12 Hour Extended Release Tablets can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take CLARINEX-D 12 Hour Extended Release Tablets.Tell your doctor about all the medicines your take, including prescription and non-prescription medicines, vitamins and herbal supplements. CLARINEX-D 12 Hour Extended Release Tablets may affect the way other medicines work, and other medicines may affect how CLARINEX-D 12 Hour Extended Release Tablets works. Especially tell your doctor if you take:Monoamine Oxidase Inhibitors (MAOI). You should not use CLARINEX-D 12 Hour Extended Release Tablets if you take MAOI or within weeks of stopping an MAOI.methyldopareserpine (Serpalan)digitalis (Digoxin, Lanoxicaps, Lanoxin) ketoconazole (Nizoral)erythromycin (Ery-tab, Eryc, PCE)azithromycin (Zithromax, Zmax)antihistaminesother decongestant medicinesKnow the medicines you take. Keep list of your medicines and show it to your doctor and pharmacist when you get new medicine.How should take CLARINEX-D(R) 12 Hour Extended Release TabletsTake CLARINEX-D 12 Hour Extended Release Tablets exactly as your doctor tells you to take it.CLARINEX-D 12 Hour Extended Release Tablets can be taken with or without food.Swallow CLARINEX-D 12 Hour Extended Release Tablets whole. Do not break, crush, or chew CLARINEX-D 12 Hour Extended Release Tablets before swallowing. If you cannot swallow CLARINEX-D 12 Hour Extended Release Tablets whole, tell your doctor. You may need different medicine.Take CLARINEX-D 12 Hour Extended Release Tablet times day (every 12 hours).What are the possible side effects of CLARINEX-D(R) 12 Hour Extended Release TabletsCLARINEX-D 12 Hour Extended Release Tablets may cause serious side effects, including:Cardiovascular and central nervous system effects, such as unable to sleep (insomnia)dizzinessweaknesstremorirregular heart beatseizurelow blood pressure Increased sleepiness or tiredness can happen if you take more CLARINEX-D 12 Hour Extended Release Tablets than your doctor prescribed to you.Allergic reactions. Stop taking CLARINEX-D 12 Hour Extended Release Tablets and call your doctor right away or get emergency help if you have any of these symptoms: rashitchinghivesswelling of your lips, tongue, face, and throatshortness of breath or trouble breathing The most common side effects of CLARINEX-D 12 HOUR Extended Release Tablets include:unable to sleep (insomnia)sore throatheadachedizzinessdry mouthnauseatirednessloss of appetitesleepinessTell your doctor if you have any side effect that bothers you or that does not go away.These are not all of the possible side effects of CLARINEX-D 12 Hour Extended Release Tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store CLARINEX-D(R) 12 Hour Extended Release TabletsStore CLARINEX-D 12 Hour Extended Release Tablets at 59F to 86F (15C to 30C)Keep CLARINEX-D 12 Hour Extended Release Tablets dry and out of the light.Keep CLARINEX-D 12 Hour Extended Release Tablets and all medicines out of the reach of children.General information CLARINEX-D(R) 12 Hour Extended Release TabletsMedicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use CLARINEX-D 12 Hour Extended Release Tablets for condition for which it was not prescribed. Do not give CLARINEX-D 12 Hour Extended Release Tablets to other people, even if they have the same condition you have. It may harm them.This patient information leaflet summarizes the most important information about CLARINEX-D 12 Hour Extended Release Tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about CLARINEX-D 12 Hour Extended Release Tablets that is written for health professionals.For more information, go to www. CLARINEX.com What are the ingredients in CLARINEX-D(R) 12 Hour Extended Release TabletsActive ingredients: desloratadine and pseudoephedrine sulfateInactive ingredients: 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. aluminum lake dye.Manufactured by Schering Corporation, subsidiary of Schering-Plough Corporation,Kenilworth, NJ 07033 USA.Rev: Month/Year(C) 2006, 2009, Schering Corporation. All rights reserved.U.S. Patent Nos. 4,659,716; 4,863,931; 5,595,997; and 6,100,274. are allergic to desloratadine or pseudoephedrine sulfate or any of the ingredients in CLARINEX-D 12 Hour Extended Release Tablets. See the end of this leaflet for complete list of ingredients in CLARINEX-D 12 Hour Extended Release Tablets.. are allergic to loratadine (Alavert, Claritin). have narrow angle glaucoma. have problems with urination (urinary retention). take Monoamine Oxidase Inhibitor (MAOI) medicine to treat depression, or if you stopped taking an MAOI medicine within the last weeks. Ask your doctor or pharmacist if you are not sure if you take an MAOI medicine.. have severe high blood pressure. have severe heart disease. have any of the conditions listed in the section Who should not take CLARINEX-D 12 Hour Extended Release Tablets. diabetes. hyperthyroidism. have prostate problems. have liver or kidney problems. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if CLARINEX-D 12 Hour Extended Release Tablets will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.. are breast-feeding or plan to breast-feed. CLARINEX-D 12 Hour Extended Release Tablets can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take CLARINEX-D 12 Hour Extended Release Tablets.. Monoamine Oxidase Inhibitors (MAOI). You should not use CLARINEX-D 12 Hour Extended Release Tablets if you take MAOI or within weeks of stopping an MAOI.. methyldopa. reserpine (Serpalan). digitalis (Digoxin, Lanoxicaps, Lanoxin) ketoconazole (Nizoral). erythromycin (Ery-tab, Eryc, PCE). azithromycin (Zithromax, Zmax). antihistamines. other decongestant medicines. CLARINEX-D 12 Hour Extended Release Tablets can be taken with or without food.. Swallow CLARINEX-D 12 Hour Extended Release Tablets whole. Do not break, crush, or chew CLARINEX-D 12 Hour Extended Release Tablets before swallowing. If you cannot swallow CLARINEX-D 12 Hour Extended Release Tablets whole, tell your doctor. You may need different medicine.. Take CLARINEX-D 12 Hour Extended Release Tablet times day (every 12 hours).. Cardiovascular and central nervous system effects, such as unable to sleep (insomnia)dizzinessweaknesstremorirregular heart beatseizurelow blood pressure unable to sleep (insomnia). dizziness. weakness. tremor. irregular heart beat. seizure. low blood pressure. Increased sleepiness or tiredness can happen if you take more CLARINEX-D 12 Hour Extended Release Tablets than your doctor prescribed to you.. Allergic reactions. Stop taking CLARINEX-D 12 Hour Extended Release Tablets and call your doctor right away or get emergency help if you have any of these symptoms: rashitchinghivesswelling of your lips, tongue, face, and throatshortness of breath or trouble breathing rash. itching. hives. swelling of your lips, tongue, face, and throat. shortness of breath or trouble breathing. unable to sleep (insomnia). sore throat. headache. dizziness. dry mouth. nausea. tiredness. loss of appetite. sleepiness. Store CLARINEX-D 12 Hour Extended Release Tablets at 59F to 86F (15C to 30C). Keep CLARINEX-D 12 Hour Extended Release Tablets dry and out of the light.

TERATOGENIC EFFECTS SECTION.


Pregnancy Category C: There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine. Desloratadine was not teratogenic in rats or rabbits but affected implantation in rats. Because animal reproduction studies are not always predictive of human response, CLARINEX-D 12 HOUR Extended Release Tablets 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 AUC in humans at the recommended daily oral dose). An increase in pre-implantation loss and decreased number of implantations and fetuses were noted, however, in 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 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 [see Nonclinical Toxicology (13.2)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Renal impairment: Avoid in patients with renal impairment (8.6)Hepatic impairment: Avoid in patients with hepatic impairment (8.7). Renal impairment: Avoid in patients with renal impairment (8.6). Hepatic impairment: Avoid in patients with hepatic impairment (8.7). 8.1 Pregnancy. Pregnancy Category C: There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine. Desloratadine was not teratogenic in rats or rabbits but affected implantation in rats. Because animal reproduction studies are not always predictive of human response, CLARINEX-D 12 HOUR Extended Release Tablets 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 AUC in humans at the recommended daily oral dose). An increase in pre-implantation loss and decreased number of implantations and fetuses were noted, however, in 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 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 [see Nonclinical Toxicology (13.2)].. 8.3 Nursing Mothers. Desloratadine and pseudoephedrine both pass into breast milk; therefore, decision should be made whether to discontinue nursing or to discontinue CLARINEX-D 12 HOUR Extended Release Tablets, taking into account the benefit of the drug to the nursing mother and the possible risk to the child. 8.4 Pediatric Use. CLARINEX-D 12 HOUR Extended Release Tablets are not indicated for use in pediatric patients under 12 years of age.. 8.5 Geriatric Use. The number of subjects (n=10) >=65 years old treated with CLARINEX-D 12 HOUR Extended Release Tablets was too limited to make any formal statistical comparison regarding the efficacy or safety of this drug product in this age group, or to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients, although the elderly are more likely to have adverse reactions to sympathomimetic amines. 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)].Pseudoephedrine, desloratadine, and their metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor the patient for adverse events [see Clinical Pharmacology (12.3)].. 8.6Renal Impairment. No studies with CLARINEX-D 12 HOUR Extended Release Tablets were conducted in subjects with renal impairment.CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with renal impairment [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. No studies with CLARINEX-D 12 HOUR Extended Release Tablets or pseudoephedrine were conducted in subjects with hepatic impairment.CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with hepatic impairment [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].. 8.8Gender. No clinically significant gender-related differences were observed in the pharmacokinetic parameters of desloratadine, 3-hydroxydesloratadine or pseudoephedrine following administration of CLARINEX-D 12 HOUR Extended Release Tablets.. 8.9Race. No studies have been conducted to evaluate the effect of race on the pharmacokinetics of CLARINEX-D 12 HOUR Extended Release Tablets.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS 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).. 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).. 5.1Cardiovascular 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.. 5.2Coexisting Conditions. CLARINEX-D 12 HOUR Extended Release Tablets contain pseudoephedrine sulfate 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 [see Contraindications (4)]. 5.3Co-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 [see Contraindications (4) and Drug Interactions (7.1)]. 5.4Hypersensitivity Reactions. Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of desloratadine component of CLARINEX-D 12 HOUR Extended Release Tablets. If such reaction occurs, therapy with CLARINEX-D 12 HOUR Extended Release Tablets should be stopped and alternative treatment should be considered [see Post-marketing (6.2)]. 5.5Renal Impairment. CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with renal impairment [see Clinical Pharmacology (12)]. 5.6Hepatic Impairment. CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with hepatic impairment [see Clinical Pharmacology (12)].