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Clarinex-D

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Clarinex-D uses


1 INDICATIONS AND USAGE

Clarinex-D is a combination product containing an H1-receptor antagonist and a sympathomimetic amine indicated for:

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 Extended Release Tablets should be administered when the antihistaminic properties of Clarinex-D and the nasal decongestant properties of pseudoephedrine are desired .

2 DOSAGE AND ADMINISTRATION

Administer Clarinex-D Extended Release Tablet by the oral route only. Do not break, chew, or crush the tablet. Swallow the tablet whole.

For oral use only

Adults and adolescents 12 years of age and over: The recommended dose of Clarinex-D Extended Release Tablets is one tablet twice a day. (2.1)

2.1 Adults and Adolescents 12 years of Age and Over

The recommended dose of Clarinex-D Extended Release Tablets is 1 tablet twice a day, administered approximately 12 hours apart and with or without a meal. Higher doses or increased dosing frequency of Clarinex-D Extended Release Tablets have not demonstrated increased effectiveness. Do not exceed the recommended dose as Clarinex-D and pseudoephedrine, the active components of Clarinex-D Extended Release Tablets have been associated with adverse effects at higher doses .

3 DOSAGE FORMS AND STRENGTHS

Clarinex-D Extended Release Tablets are oval shaped, blue and white bilayer tablets with "D12" embossed in the blue layer. Each tablet contains 2.5 mg Clarinex-D in the blue immediate-release layer and 120 mg of pseudoephedrine sulfate USP in the white extended-release layer.

Clarinex-D 2.5 mg/Pseudoephedrine sulfate 120 mg tablets. (3)

4 CONTRAINDICATIONS

Clarinex-D Extended Release Tablets are contraindicated in:

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular and Central Nervous System Effects

The pseudoephedrine sulfate contained in Clarinex-D 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 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 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 .

5.3 Co-Administration with Monoamine Oxidase (MAO) Inhibitors

Clarinex-D 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 .

5.4 Hypersensitivity Reactions

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of Clarinex-D a component of Clarinex-D Extended Release Tablets. If such a reaction occurs, therapy with Clarinex-D Extended Release Tablets should be stopped and alternative treatment should be considered .

5.5 Renal Impairment

Clarinex-D Extended Release Tablets should generally be avoided in patients with renal impairment .

5.6 Hepatic Impairment

Clarinex-D Extended Release Tablets should generally be avoided in patients with hepatic impairment .

6 ADVERSE REACTIONS

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


To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 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 Extended Release Tablets that included 1248 patients with seasonal allergic rhinitis, of which 414 patients received Clarinex-D 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 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 Extended Release Tablets are shown in Table 1.

Adverse Reaction CLARINEX-D

12 HOUR BID

(N=414)

 Clarinex-D

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 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 Extended Release Tablets include tachycardia, palpitations, dyspnea, rash and pruritus.

In addition to these events, the following spontaneous adverse events have been reported during the marketing of Clarinex-D as a single ingredient product: headache, somnolence, dizziness and rarely hypersensitivity reactions (such as urticaria, edema and anaphylaxis), psychomotor hyperactivity, movement disorders (including dystonia, tics, and extrapyramidal symptoms), seizures, and elevated liver enzymes including bilirubin and, very rarely, hepatitis.

7 DRUG INTERACTIONS

No specific interaction studies have been conducted with Clarinex-D Extended Release Tablets.

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

7.1 Monoamine Oxidase Inhibitors

Clarinex-D 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 Extended Release tablets on the vascular system may be potentiated by these agents .

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 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 Extended Release Tablets with these agents.

7.4 Inhibitors of Cytochrome P450 3A4

In controlled clinical studies co-administration of Clarinex-D with ketoconazole, erythromycin, or azithromycin resulted in increased plasma concentrations of Clarinex-D and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of Clarinex-D .

7.5 Fluoxetine

In controlled clinical studies co-administration of Clarinex-D with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), resulted in increased plasma concentrations of Clarinex-D and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of Clarinex-D .

7.6 Cimetidine

In controlled clinical studies co-administration of Clarinex-D with cimetidine a histamine H2-receptor antagonist resulted in increased plasma concentrations of Clarinex-D and 3-hydroxydesloratadine but there were no clinically relevant changes in the safety profile of Clarinex-D .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies of Clarinex-D and pseudoephedrine in combination in pregnant women. Neither are there animal reproduction studies conducted with the combination of Clarinex-D and pseudoephedrine. Clarinex-D 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 Extended Release Tablets should be used during pregnancy only if clearly needed.

Clarinex-D 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 a decreased number of implantations and fetuses were noted, however, in a separate study in female rats at approximately 120 times the AUC in humans at the recommended daily oral dose. Reduced body weight and slow righting reflex were reported in pups at approximately 50 times or greater than the AUC in humans at the recommended daily oral dose. Clarinex-D had no effect on pup development at approximately 7 times the AUC in humans at the recommended daily oral dose. The AUCs in comparison referred to the Clarinex-D exposure in rabbits and the sum of Clarinex-D and its metabolites exposures in rats, respectively .

8.3 Nursing Mothers

Clarinex-D and pseudoephedrine both pass into breast milk; therefore, a decision should be made whether to discontinue nursing or to discontinue Clarinex-D 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 Extended Release Tablets are not indicated for use in pediatric patients under 12 years of age.

8.5 Geriatric Use

The number of subjects ≥65 years old treated with Clarinex-D 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 .

Pseudoephedrine, Clarinex-D, 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 .

8.6 Renal Impairment

No studies with Clarinex-D Extended Release Tablets were conducted in subjects with renal impairment.

Clarinex-D Extended Release Tablets should generally be avoided in patients with renal impairment .

8.7 Hepatic Impairment

No studies with Clarinex-D Extended Release Tablets or pseudoephedrine were conducted in subjects with hepatic impairment.

Clarinex-D Extended Release Tablets should generally be avoided in patients with hepatic impairment .

8.8 Gender

No clinically significant gender-related differences were observed in the pharmacokinetic parameters of Clarinex-D, 3-hydroxydesloratadine or pseudoephedrine following administration of Clarinex-D Extended Release Tablets.

8.9 Race

No studies have been conducted to evaluate the effect of race on the pharmacokinetics of Clarinex-D Extended Release Tablets.

9 DRUG ABUSE AND DEPENDENCE

There is no information to indicate that abuse or dependency occurs with CLARINEX or Clarinex-D Extended Release Tablets.

10 OVERDOSAGE

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

10.1 Clarinex-D

Information regarding acute overdosage with Clarinex-D is limited to experience from post-marketing 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 Clarinex-D. In a dose-ranging trial, at doses of 10 mg and 20 mg/day, somnolence was reported.

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

Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated Clarinex-D and Clarinex-D 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 Clarinex-D 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 Clarinex-D exposure was approximately 810 times the human daily oral dose on an mg/m2 basis).

10.2 Sympathomimetics

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 a toxic psychosis with delusions and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure.

11 DESCRIPTION

Clarinex-D Extended Release Tablets are oval-shaped blue and white bilayer tablets containing 2.5 mg Clarinex-D 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 Extended Release Tablets are hypromellose USP, microcrystalline cellulose NF, povidone USP, silicon dioxide NF, magnesium stearate NF, corn starch NF, edetate disodium USP, citric acid anhydrous USP, stearic acid NF, and FD&C Blue No. 2 aluminum lake dye.

Clarinex-D, 1 of the 2 active ingredients of Clarinex-D Extended Release Tablets, is a white to off-white powder that is slightly soluble in water, but very soluble in ethanol and propylene glycol. It has an empirical formula: C19H19ClN2 and a 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 Extended Release Tablets, is the synthetic salt of one of the naturally occurring dextrorotatory diastereomers of ephedrine and is classified as an indirect sympathomimetic amine. Pseudoephedrine sulfate is a colorless hygroscopic crystal or white, hygroscopic crystalline powder, practically odorless, with a bitter taste. It is very soluble in water, freely soluble in alcohol, and sparingly soluble in ether. The empirical formula for pseudoephedrine sulfate is (C10H15NO)2 - H2SO4; the chemical name is benzenemethanol, α-[1-(methylamino) ethyl]-,[S-(R*,R*)]-, sulfate (2:1)(salt); and the chemical structure is:

Chemical Structure Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clarinex-D is a long acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Receptor binding data indicate that at a concentration of 2 to 3 ng/mL, Clarinex-D shows significant interaction with the human histamine H1 receptor. Clarinex-D inhibited histamine release from human mast cells in vitro. Results of a radiolabeled tissue distribution study in rats and a radioligand H1-receptor-binding study in guinea pigs showed that Clarinex-D 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.

12.2 Pharmacodynamics

Wheal and Flare: Human histamine skin wheal studies following single and repeated 5 mg doses of Clarinex-D have shown that the drug exhibits an antihistaminic effect by 1 hour; this activity may persist for as long as 24 hours. There was no evidence of histamine-induced skin wheal tachyphylaxis within the Clarinex-D 5 mg 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 Extended Release Tablets, ECGs were recorded at baseline and endpoint within 1 to 3 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 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 Extended Release Tablets and pseudoephedrine groups, respectively, compared to an increase of 3.2 bpm in subjects receiving Clarinex-D 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 a blinded fashion by a cardiologist. In the CLARINEX-treated subjects, there was a 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 Bazett's and Fridericia methods. Using the QTc (Bazett), there was a mean increase of 8.1 msec in the CLARINEX-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in CLARINEX-treated subjects relative to placebo. No clinically relevant adverse events were reported.

12.3 Pharmacokinetics

Absorption: In a single dose pharmacokinetic study, the mean time to maximum plasma concentrations (Tmax) for Clarinex-D occurred at approximately 4 to 5 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 ng∙hr/mL, respectively, were observed. In another pharmacokinetic study, food and grapefruit juice had no effect on the bioavailability (Cmax and AUC) of Clarinex-D.

For pseudoephedrine, the mean Tmax occurred at 6 to 7 hours post dose and mean peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of approximately 263 ng/mL and 4588 ng∙hr/mL, respectively, were observed. Food had no effect on the bioavailability (Cmax and AUC) of pseudoephedrine.

Following oral administration of Clarinex-D Extended Release Tablets twice daily for 14 days in healthy volunteers, steady-state conditions were reached on Day 10 for Clarinex-D, 3-hydroxydesloratadine and pseudoephedrine. For Clarinex-D, mean steady-state peak plasma concentrations (Cmax) and area under the concentration-time curve AUC 0-12 hrs of approximately 1.7 ng/mL and 16 ng∙hr/mL were observed, respectively. For pseudoephedrine, mean steady-state peak plasma concentrations (Cmax) and AUC 0-12 hrs of 459 ng/mL and 4658 ng∙hr/mL were observed.

Distribution: Clarinex-D and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound to plasma proteins, respectively. Protein binding of Clarinex-D and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism: Clarinex-D (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 Clarinex-D indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of Clarinex-D. In pharmacokinetic studies (n=3748), approximately 6% of subjects were poor metabolizers of Clarinex-D (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to Clarinex-D less than 0.1, or a subject with a Clarinex-D half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2 to 5 years, 1575 subjects aged 6 to 11 years, and 1196 subjects aged 12 to 70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to Clarinex-D in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of Clarinex-D cannot be prospectively identified and will be exposed to higher levels of Clarinex-D following dosing with the recommended dose of Clarinex-D. In multidose clinical safety studies, where metabolizer status was prospectively identified, a 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 Extended Release Tablets, the mean plasma elimination half-life of Clarinex-D was approximately 27 hours. In another study, following administration of single oral doses of Clarinex-D 5 mg, Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to Clarinex-D.

The mean elimination half-life of pseudoephedrine is dependent on urinary pH. The elimination half-life is approximately 3 to 6 or 9 to 16 hours when the urinary pH is 5 or 8, respectively.

Geriatric Subjects: Following multiple-dose administration of CLARINEX Tablets, the mean Cmax and AUC values for Clarinex-D 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 2 age groups. The mean plasma elimination half-life of Clarinex-D 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 Extended Release Tablets are not an appropriate dosage form for use in pediatric patients below 12 years of age.

Renally Impaired: Following a single dose of Clarinex-D 7.5 mg, pharmacokinetics were characterized in subjects with mild (n=7; creatinine clearance 51–69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34–43 mL/min/1.73 m2) and severe (n=6; creatinine clearance 5–29 mL/min/1.73 m2) 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. Clarinex-D and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of Clarinex-D 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 a single oral dose of Clarinex-D, 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 8 subjects with normal hepatic function. Subjects with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of Clarinex-D 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 Clarinex-D 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 Clarinex-D 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 Clarinex-D were 18% and 32% higher, respectively in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a 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 2 controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) subjects, Clarinex-D 7.5 mg (1.5 times the daily dose) once daily was co-administered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In 3 separate controlled, parallel group clinical pharmacology studies, Clarinex-D at the clinical dose of 5 mg has been co-administered with azithromycin 500 mg followed by 250 mg once daily for 4 days (n=18) or with fluoxetine 20 mg once daily for 7 days after a 23-day pretreatment period with fluoxetine (n=18) or with cimetidine 600 mg every 12 hours for 14 days (n=18) under steady state conditions to healthy male and female subjects. Although increased plasma concentrations (Cmax and AUC 0-24 hrs) of Clarinex-D and 3-hydroxydesloratadine were observed (see Table 2 ), there were no clinically relevant changes in the safety profile of Clarinex-D, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs and adverse events.

Clarinex-D 3-hydroxydesloratadine
Cmax AUC 0-24hrs Cmax AUC 0-24hrs
Erythromycin

(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%

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or laboratory studies on the combination product of Clarinex-D and pseudoephedrine sulfate to evaluate carcinogenesis, mutagenesis, or impairment of fertility.

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

In a 2-year dietary study in mice, males and females given up to 16 mg/kg/day and 32 mg/kg/day Clarinex-D, respectively, did not show significant increases in the incidence of any tumors. The estimated Clarinex-D and Clarinex-D 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 Clarinex-D, there was no evidence of genotoxic potential in a reverse mutation assay (Salmonella/E. coli mammalian microsome bacterial mutagenicity assay) or in 2 assays for chromosomal aberrations (human peripheral blood lymphocyte clastogenicity assay and mouse bone marrow micronucleus assay).

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

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies: Clarinex-D was not teratogenic in rats at doses up to 48 mg/kg/day (estimated Clarinex-D and Clarinex-D 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 Clarinex-D exposures were approximately 230 times the AUC in humans at the recommended daily oral dose). In a separate study, an increase in pre-implantation loss and a decreased number of implantations and fetuses were noted in female rats at 24 mg/kg (estimated Clarinex-D and Clarinex-D 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 9 mg/kg/day or greater (estimated Clarinex-D and Clarinex-D metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Clarinex-D had no effect on pup development at an oral dose of 3 mg/kg/day (estimated Clarinex-D and Clarinex-D metabolite exposures were approximately 7 times the AUC in humans at the recommended daily oral dose).

14 CLINICAL STUDIES

14.1 Seasonal Allergic Rhinitis

The clinical efficacy and safety of Clarinex-D 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 Extended Release Tablets. In the 2 trials, subjects were randomized to receive Clarinex-D Extended Release Tablets twice daily, CLARINEX Tablets 5 mg once daily, or sustained-release pseudoephedrine tablet 120 mg twice daily for 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. Primary efficacy variable was twice-daily reflective patient scoring of 4 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 a 4 point scale (0=none, 1=mild, 2=moderate, and 3=severe). In both trials, the antihistaminic efficacy of Clarinex-D 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 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 1 of 2 trials are shown in Table 3.

Treatment Group

(n)

 Mean BaselineTo qualify at Baseline, the sum of the twice-daily diary reflective scores for the 3 days prior to Baseline and the morning of the Baseline visit were to total ≥42 for total nasal symptom score (sum of 4 nasal symptoms of rhinorrhea, nasal stuffiness/congestion, nasal itching, and sneezing) and a total of ≥35 for total non-nasal symptoms score (sum of 4 non-nasal symptoms of itching/burning eyes, tearing/watering eyes, redness of eyes, and itching of ears/palate), and a score of ≥14 for each of the individual symptoms of nasal stuffiness/congestion and rhinorrhea. Each symptom was scored on a 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

12 HOUR Comparison to ComponentsThe comparison of interest is shown bolded.

(P-value)
SEM=Standard Error of the Mean
Total Symptom Score (Excluding Nasal Congestion)
Clarinex-D 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 <0.001
CLARINEX 5 mg Tablets QD

(197)

14.82

(0.21)

 -5.09 (-33.5)

(0.30)

 P<0.001
Nasal Stuffiness/Congestion
Clarinex-D 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=0.006
CLARINEX 5 mg Tablets QD

(197)

2.50

(0.027)

 -0.66 (-26.7)

(0.046)

 P <0.001


There were no significant differences in the efficacy of Clarinex-D Extended Release Tablets across subgroups of subjects defined by gender, age, or race.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clarinex-D Extended Release Tablets are oval-shaped, blue and white bilayer tablets with "D12" embossed in the blue layer, containing 2.5 mg Clarinex-D in the blue immediate-release layer and 120 mg of pseudoephedrine sulfate USP in the white extended-release layer. Clarinex-D Extended Release Tablets are supplied in high-density polyethylene bottles of 100 (NDC 0085-1322-01).

Storage: Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). Avoid exposure at or above 30°C (86°F). Protect from excessive moisture. Protect from light.

17 PATIENT COUNSELING INFORMATION

17.1 Cardiovascular and Central Nervous System Effects

Patients should be informed that pseudoephedrine, one of the active ingredients in Clarinex-D Extended Release Tablets may cause cardiovascular or central nervous system effects such as insomnia, dizziness, tremor, or arrhythmia.

17.2 Dosing

Patients should be advised not to increase the dose or dosing frequency of Clarinex-D Extended Release Tablets.

17.3 Additional Antihistamines and/or Decongestants

Patients should be advised against the concurrent use of Clarinex-D Extended Release Tablets with other antihistamines and/or decongestants.

17.4 Monoamine Oxidase Inhibitors

Patients should be informed that due to its pseudoephedrine component, they should not use Clarinex-D with a monoamine oxidase (MAO) inhibitor or within 14 days of stopping use of an MAO inhibitor.

17.5 Coexisting Conditions

Patients with severe hypertension or severe coronary artery disease, narrow-angle glaucoma, or urinary retention should be advised not to use Clarinex-D Extended Release Tablets.

17.6 Instructions 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.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:

Patheon Inc., Whitby, Ontario

L1N 5Z5, Canada

For patent information: www.merck.com/product/patent/home.html

Copyright © 2006, 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

uspi-mk4117a-t-d12-1403r005

PATIENT INFORMATION

CLARINEX-D® (CLA-RI-NEX) 12 Hour Extended Release Tablets

(desloratadine and pseudoephedrine sulfate)

Read the Patient Information that comes with Clarinex-D Extended Release Tablets before you start taking it and each time you get a refill. There may be new information. This leaflet is a 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® 12 Hour Extended Release Tablets?

Clarinex-D Extended Release Tablets is a prescription medicine that contains the medicines Clarinex-D (an antihistamine) and pseudoephedrine (a nasal decongestant). Clarinex-D 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 Extended Release Tablets is not for children under 12 years of age.

Who should not take CLARINEX-D® 12 Hour Extended Release Tablets?

Do not take Clarinex-D Extended Release Tablets if you:


Talk to your doctor before taking this medicine if you have any of these conditions.

What should I tell my doctor before taking CLARINEX-D® 12 Hour Extended Release Tablets?

Before you take Clarinex-D Extended Release Tablets, tell your doctor if you:


Tell your doctor about all the medicines you take, including prescription and nonprescription 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 Extended Release Tablets works. Especially tell your doctor if you take:


Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take CLARINEX-D® 12 Hour Extended Release Tablets?

Take Clarinex-D Extended Release Tablets exactly as your doctor tells you to take it.


What are the possible side effects of CLARINEX-D® 12 Hour Extended Release Tablets?

Clarinex-D Extended Release Tablets may cause serious side effects, including:


The most common side effects of Clarinex-D Extended Release Tablets include:


Tell 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 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 I store CLARINEX-D® 12 Hour Extended Release Tablets?


Keep Clarinex-D Extended Release Tablets and all medicines out of the reach of children.

General information about CLARINEX-D® 12 Hour Extended Release Tablets

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Clarinex-D Extended Release Tablets for a condition for which it was not prescribed. Do not give Clarinex-D 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 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 Extended Release Tablets that is written for health professionals.

For more information, go to www. CLARINEX.com

What are the ingredients in CLARINEX-D® 12 Hour Extended Release Tablets?

Active ingredients: Clarinex-D and pseudoephedrine sulfate

Inactive 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. 2 aluminum lake dye.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by:

Patheon Inc., Whitby, Ontario

L1N 5Z5, Canada

For patent information: www.merck.com/product/patent/home.html

Copyright © 2006, 2009 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

Revised: 03/2014

usppi-mk4117a-t-d12-1403r004

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label

NDC 0085-1322-01

100 Tablets

CLARINEX-D ®

12 HOUR

(desloratadine 2.5 mg/

pseudoephedrine sulfate, USP 120 mg)

EXTENDED RELEASE TABLETS

Rx only

actual size

Clarinex-D pharmaceutical active ingredients containing related brand and generic drugs:


Clarinex-D available forms, composition, doses:


Clarinex-D destination | category:


Clarinex-D Anatomical Therapeutic Chemical codes:


Clarinex-D pharmaceutical companies:


References

  1. Dailymed."DESLORATADINE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."PSEUDOEPHEDRINE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."DESLORATADINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Clarinex-D?

Depending on the reaction of the Clarinex-D after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Clarinex-D not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Clarinex-D addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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