Desloratadine and Pseudoephedrine Sulfate

CLARINEX-D 12 HOUR is a combination product containing a histamine-1 (H1) receptor antagonist and an alpha adrenergic agonist 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. ( 1.1 )

1.1 Seasonal Allergic Rhinitis CLARINEX-D ® 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) ].

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 )

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 )

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 [see Contraindications (4) ].

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 [see Contraindications (4) and Drug Interactions (7.1) ].

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 [see Adverse Reactions (6.2) ].

5.5 Renal Impairment CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with renal impairment [see Clinical Pharmacology (12.3) ].

5.6 Hepatic Impairment CLARINEX-D 12 HOUR Extended Release Tablets should generally be avoided in patients with hepatic impairment [see Clinical Pharmacology (12.3) ].

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) ] Severe Skin Reactions The most common adverse reactions (reported in ≥2% of patients) were insomnia, headache, mouth dry, fatigue, somnolence, pharyngitis, dizziness, nausea, and anorexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data described below are from 2 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 2 weeks. The majority of patients were between 18 and <65 years of age with a mean age of 35.8 years and were predominantly women (64%). Patient ethnicity was 82% Caucasian, 9% Black, 6% 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 Tablets Adverse Reaction CLARINEX-D 12 HOUR BID (N=414) Desloratadine 5 mg QD (N=412) Pseudoephedrine 120 mg BID (N=422) Gastrointestinal Disorders Mouth Dry 8% 2% 8% Nausea 2% 1% 3% General Disorders and Administration Site Conditions Fatigue 4% 2% 2% Metabolism and Nutrition Disorders Anorexia 2% 0% 2% Nervous System Disorders Headache 8% 8% 9% Somnolence 3% 4% 2% Dizziness 3% 2% 2% Psychiatric Disorders Insomnia 10% 3% 13% Respiratory, Thoracic, and Mediastinal Disorders Pharyngitis 3% 3% 3% There were no relevant differences in adverse reactions for subgroups of patients as defined by gender, age, or race.

6.2 Post-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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse events identified from post-marketing surveillance on the use of CLARINEX-D 12 HOUR Extended Release Tablets include: Cardiac disorders: tachycardia, palpitations Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: rash, pruritus In addition to these events, the following spontaneous adverse events have been reported during the marketing of desloratadine as a single ingredient product: Nervous system disorders: headache, somnolence, dizziness, 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 Cases of severe skin reactions such as acute generalized exanthematous pustulosis (AGEP) have been reported with pseudoephedrine-containing products.

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 [see Contraindications (4) and Warnings and Precautions (5.3) ].

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 [see Clinical Pharmacology (12.3) ].

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 [see Clinical Pharmacology (12.3) ].

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 [see Clinical Pharmacology (12.3) ].

Renal impairment: Avoid in patients with renal impairment. ( 8.6 ) Hepatic impairment: Avoid in patients with hepatic impairment. ( 8.7 )

8.1 Pregnancy Risk Summary The limited available data with CLARINEX-D 12 HOUR in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are no adequate and well-controlled studies of desloratadine and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of desloratadine and pseudoephedrine or pseudoephedrine alone . Desloratadine given during organogenesis to pregnant rats was not teratogenic at the summed area under the concentration-time curve (AUC)-based exposures of desloratadine and its metabolite approximately 320 times that at the recommended human daily oral dose (RHD) of 5 mg/day. Desloratadine given during organogenesis to pregnant rabbits was not teratogenic at the AUC-based exposures of desloratadine approximately 230 times that at the RHD. Desloratadine given to pregnant rats during organogenesis through lactation resulted in reduced body weight and slow righting reflex of F 1 pups at the summed AUC-based exposures of desloratadine and its metabolite approximately 70 times or greater than that at the RHD [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Pseudoephedrine The majority of studies examining the use of pseudoephedrine in pregnancy did not find an association with an increased risk of congenital anomalies. A few case-control studies conducted reported potential associations with isolated congenital disorders. However, several similar studies did not find statistically significant associations. Methodological limitations of these studies included small sample size, selection bias, recall bias, inadequate adjustment for risk factors, residual confounding, exposure misclassification, and lack of information regarding dose and timing of exposure. Animal Data No animal reproduction studies were conducted with the combination of desloratadine and pseudoephedrine or pseudoephedrine alone. Desloratadine Desloratadine was given orally during organogenesis to pregnant rats at doses of 6, 24 and 48 mg/kg/day (approximately 50, 200 and 320 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). No fetal malformations were present. Reduced fetal weights and skeletal variations noted at doses of 24 and 48 mg/kg/day were likely secondary to the maternal toxicities of reduced body weight gain and food consumption observed at the same doses. Desloratadine was also given orally during organogenesis to pregnant rabbits at doses of 15, 30 and 60 mg/kg/day (approximately 30, 70 and 230 times the AUC-based exposure of desloratadine at the RHD). No adverse effects to the fetus were noted. Reduced maternal body weight gain was noted in rabbits at 60 mg/kg/day. In a peri- and post-natal development study, desloratadine was given to rats orally during the peri-natal (Gestation Day 6) through lactation periods (Postpartum Day 21) at doses of 3, 9 and 18 mg/kg/day. Reduced body weight and slow righting reflex were reported in F 1 pups at doses of 9 mg/kg/day or greater (approximately 70 times or greater than the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Desloratadine had no effect on F 1 pup development at 3 mg/kg/day (approximately 10 times the summed AUC-based exposure of desloratadine and its metabolite at the RHD). Maternal toxicities including reduced body weight gain and food consumption were noted at 18 mg/kg/day for F 0 dams. F 1 offspring were subsequently mated and there was no developmental toxicity for F 2 pups observed.

8.2 Lactation Risk Summary Desloratadine and pseudoephedrine both pass into breast milk. There are not sufficient data on the effects of desloratadine on the breastfed infant or the effects of desloratadine on milk production. Pseudoephedrine has been reported to decrease milk production [see Data ]. Pseudoephedrine has been reported to cause irritability in breastfed infants. The decision should be made whether to discontinue nursing or to discontinue CLARINEX-D 12 HOUR Extended Release Tablets, taking into account the developmental and health benefits of breastfeeding, the nursing mother's clinical need, and any potential adverse effects on the breastfed infant from desloratadine and pseudoephedrine or from the underlying maternal condition. Data Human Data Pseudoephedrine In a study of eight lactating women, who were 8 to 76 weeks postpartum and received a single dose of 60 mg of pseudoephedrine, the mean 24-hour milk production was reduced by 24%. In the same study, the estimated mean relative infant dose from breast milk (assuming mean milk consumption of 150 mL/kg/day and a maternal dosing regimen of 60 mg pseudoephedrine four times per day) was calculated to be 4.3% of the weight-adjusted maternal dose.

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

8.4 Pediatric Use 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) ].

8.6 Renal 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) ].

8.7 Hepatic 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) ]. […]

Desloratadine is a long acting tricyclic histamine antagonist with selective H 1 -receptor histamine antagonist activity. Receptor binding data indicate that at a concentration of 2 to 3 ng/mL (7 nanomolar), desloratadine shows significant interaction with the human histamine H 1 receptor. Desloratadine inhibited histamine release from human mast cells in vitro . Results of a radiolabeled tissue distribution study in rats and a radioligand H 1 -receptor-binding study in guinea pigs showed that desloratadine 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 a 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.