Nucope

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Nucope uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Nucope reviews

1 INDICATIONS AND USAGE

Nucope Tablets are indicated for:

• Seasonal Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 12 years of age and older.
• Perennial Allergic Rhinitis: relief of nasal and non-nasal symptoms in patients 12 years of age and older. (1.2)
• Chronic Idiopathic Urticaria: symptomatic relief of pruritus reduction in the number of hives, and size of hives in patients 12 years of age and older. (1.3)

1.1 Seasonal Allergic Rhinitis

Nucope Tablets are indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 12 years of age and older.

1.2 Perennial Allergic Rhinitis

Nucope Tablets are indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 12 years of age and older.

1.3 Chronic Idiopathic Urticaria

Nucope Tablets are indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

Nucope Tablets may be taken without regard to meals.

Dosage :

Adults and adolescents 12 years of age and over:

• Nucope Tablets - one 5 mg tablet once daily

2.1 Adults and adolescents 12 years of age and over

The recommended dose of Nucope Tablets is one 5 mg tablet once daily.

2.5 Adults with Hepatic or Renal Impairment

In adult patients with liver or renal impairment, a starting dose of one 5 mg tablet every other day is recommended based on pharmacokinetic data. Dosing recommendation for children with liver or renal impairment cannot be made due to lack of data [see Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

Nucope Tablets are light blue round tablets debossed with "5" containing 5 mg Nucope.

• Nucope Tablets - 5 mg (3)

4 CONTRAINDICATIONS

Nucope Tablets are contraindicated in patients who are hypersensitive to this medication or to any of its ingredients or to loratadine [see Warnings and Precautions (5.1) and Adverse Reactions (6.2) ].

• Hypersensitivity (4, 6.2)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported. In such cases, stop Nucope Tablets at once and consider alternative treatments.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions including rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis have been reported after administration of Nucope. If such a reaction occurs, therapy with Nucope Tablets should be stopped and alternative treatment should be considered. [See Adverse Reactions (6.2) .]

6 ADVERSE REACTIONS

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

• Hypersensitivity reactions. [See Warnings and Precautions .]

• The most common adverse reactions (reported in ≥2% of adult and adolescent patients with allergic rhinitis and greater than placebo) were pharyngitis, dry mouth, myalgia, fatigue, somnolence, dysmenorrhea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Virtus Pharmaceuticals at 813-283-1344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults and Adolescents

Allergic Rhinitis: In multiple-dose placebo-controlled trials, 2,834 patients ages 12 years or older received Nucope Tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between Nucope and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the Nucope group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving Nucope. All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of Nucope Tablets (5 mg once daily), and that were more common with Nucope Tablets than placebo, are listed in Table 1.

Adverse Event	Nucope Tablets 5 mg (n=1,655)	Placebo (n=1,652)
Infections and Infestations Pharyngitis	4.1%	2.0%
Nervous System Disorders Somnolence	2.1%	1.8%
Gastrointestinal Disorders Dry Mouth	3.0%	1.9%
Musculoskeletal and Connective Tissue Disorders Myalgia	2.1%	1.8%
Reproductive System and Breast Disorders Dysmenorrhea	2.1%	1.6%
General Disorders and Administration Site Conditions Fatigue	2.1%	1.2%

The frequency and magnitude of laboratory and electrocardiographic abnormalities were similar in Nucope and placebo-treated patients. There were no differences in adverse events for subgroups of patients as defined by gender, age, or race.

Chronic Idiopathic Urticaria: In multiple-dose, placebo-controlled trials of chronic idiopathic urticaria, 211 patients ages 12 years or older received Nucope Tablets and 205 received placebo. Adverse events that were reported by greater than or equal to 2% of patients who received Nucope Tablets and that were more common with Nucope than placebo were (rates for Nucope and placebo, respectively): headache (14%, 13%), nausea (5%, 2%), fatigue (5%, 1%), dizziness (4%, 3%), pharyngitis (3%, 2%), dyspepsia (3%, 1%), and myalgia (3%, 1%).

Pediatrics: Two hundred and forty-six pediatric subjects 6 months to 11 years of age received Nucope Oral Solution for 15 days in three placebo controlled clinical trials. Pediatric subjects aged 6 to 11 years received 2.5 mg once a day, subjects aged 1 to 5 years received 1.25 mg once a day, and subjects 6 to 11 months of age received 1.0 mg once a day.

In subjects 6 to 11 years of age, no individual adverse event was reported by 2 percent or more of the subjects.

In subjects 2 to 5 years of age, adverse events reported for Nucope and placebo in at least 2 percent of subjects receiving Nucope Oral Solution and at a frequency greater than placebo were fever (5.5%, 5.4%), urinary tract infection (3.6%, 0%) and varicella (3.6%, 0%).

In subjects 12 months to 23 months of age, adverse events reported for the Nucope product and placebo in at least 2 percent of subjects receiving Nucope Oral Solution and at a frequency greater than placebo were fever (16.9%, 12.9%), diarrhea (15.4%, 11.3%), upper respiratory tract infections (10.8%, 9.7%), coughing (10.8%, 6.5%), appetite increased (3.1%, 1.6%), emotional lability (3.1%, 0%), epistaxis (3.1%, 0%), parasitic infection (3.1%, 0%), pharyngitis (3.1%, 0%), rash maculopapular (3.1%, 0%).

In subjects 6 months to 11 months of age, adverse events reported for Nucope and placebo in at least 2 percent of subjects receiving Nucope Oral Solution and at a frequency greater than placebo were upper respiratory tract infections (21.2%, 12.9%), diarrhea (19.7%, 8.1%), fever (12.1%, 1.6%), irritability (12.1%, 11.3%), coughing (10.6%, 9.7%), somnolence (9.1%, 8.1%), bronchitis (6.1%, 0%), otitis media (6.1%, 1.6%), vomiting (6.1%, 3.2%), anorexia (4.5%, 1.6%), pharyngitis (4.5%, 1.6%), insomnia (4.5%, 0%), rhinorrhea (4.5%, 3.2%), erythema (3.0%, 1.6%), and nausea (3.0%, 0%). There were no clinically meaningful changes in any electrocardiographic parameter, including the QTc interval. Only one of the 246 pediatric subjects receiving Nucope Oral Solution in the clinical trials discontinued treatment because of an adverse event.

6.2 Post-Marketing Experience

Because adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following spontaneous adverse events have been reported during the marketing of Nucope: tachycardia, palpitations, rare cases of hypersensitivity reactions (such as rash, pruritus, urticaria, edema, dyspnea, and anaphylaxis), psychomotor hyperactivity, seizures, and elevated liver enzymes including bilirubin, and very rarely, hepatitis.

7 DRUG INTERACTIONS

7.1 Inhibitors of Cytochrome P450 3A4

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

7.2 Fluoxetine

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

7.3 Cimetidine

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

8 USE IN SPECIFIC POPULATIONS

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

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Nucope should be used during pregnancy only if clearly needed. Nucope was not teratogenic in rats or rabbits at approximately 210 and 230 times, respectively, the area under the concentration-time curve (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. Nucope 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 Nucope exposure in rabbits and the sum of Nucope and its metabolites exposures in rats, respectively. [See Nonclinical Toxicology (13.2).]

8.3 Nursing Mothers

Nucope passes into breast milk; therefore, a decision should be made whether to discontinue nursing or to discontinue Nucope, taking into account the benefit of the drug to the nursing mother and the possible risk to the child.

8.4 Pediatric Use

The recommended dose of Nucope Oral Solution in the pediatric population is based on cross-study comparison of the plasma concentration of Nucope in adults and pediatric subjects. The safety of Nucope Oral Solution has been established in 246 pediatric subjects aged 6 months to 11 years in three placebo-controlled clinical studies. Since the course of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria and the effects of Nucope are sufficiently similar in the pediatric and adult populations, it allows extrapolation from the adult efficacy data to pediatric patients. The effectiveness of Nucope Oral Solution in these age groups is supported by evidence from adequate and well-controlled studies of Nucope Tablets in adults. The safety and effectiveness of Nucope Tablets or Nucope Oral Solution have not been demonstrated in pediatric patients less than 6 months of age. [See Clinical Pharmacology.]

8.5 Geriatric Use

Clinical studies of Nucope did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. [See Clinical Pharmacology (12.3).]

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

9 DRUG ABUSE AND DEPENDENCE

There is no information to indicate that abuse or dependency occurs with Nucope Tablets.

10 OVERDOSAGE

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

Information regarding acute overdosage is limited to experience from post-marketing adverse event reports and from clinical trials conducted during the development of the Nucope product. 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 Nucope 45 mg for 10 days [see Clinical Pharmacology (12.2) ].

Lethality occurred in rats at oral doses of 250 mg/kg or greater (estimated Nucope and Nucope 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 Nucope exposures were approximately 290 times the human daily oral dose on a mg/m² basis). No deaths occurred at oral doses up to 250 mg/kg in monkeys (estimated Nucope exposures were approximately 810 times the human daily oral dose on a mg/m² basis).

11 DESCRIPTION

Nucope Tablets are light blue, round, tablets containing 5 mg Nucope, an antihistamine, to be administered orally. Nucope Tablets also contain the following inactive ingredients: microcrystalline cellulose NF, pregelatinized starch NF, croscarmellose sodium NF, talc USP, zinc stearate, USP and FD&C Blue #2 HT 11-14%.

Nucope 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:

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nucope is a long-acting tricyclic histamine antagonist with selective H₁-receptor histamine antagonist activity. Receptor binding data indicates that at a concentration of 2-3 ng/mL, Nucope shows significant interaction with the human histamine H₁-receptor. Nucope 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 Nucope did not readily cross the blood brain barrier. The clinical significance of this finding is unknown.

12.2 Pharmacodynamics

Wheal and Flare: Human histamine skin wheal studies following single and repeated 5 mg doses of Nucope 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 Nucope 5 mg group over the 28-day treatment period. The clinical relevance of histamine wheal skin testing is unknown.

Effects on QTc: Single daily doses of 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 Nucope - treated subjects, there was an increase in mean heart rate of 9.2 bpm relative to placebo. The QT interval was corrected for heart rate (QTc) by both the Bazett and Fridericia methods. Using the QTc (Bazett) there was a mean increase of 8.1 msec in Desloratadine-treated subjects relative to placebo. Using QTc (Fridericia) there was a mean increase of 0.4 msec in Nucope treated subjects relative to placebo. No clinically relevant adverse events were reported.

12.3 Pharmacokinetics

Absorption

Following oral administration of a Nucope 5 mg tablet once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (T_max) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (C_max) and AUC of 4 ng/mL and 56.9 ng∙hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (C_max and AUC) of Nucope.

The pharmacokinetic profile of Nucope Oral Solution was evaluated in a three-way crossover study in 30 adult volunteers. A single dose of 10 mL of Nucope Oral Solution containing 5 mg of Nucope was bioequivalent to a single dose of 5 mg Nucope Tablet. Food had no effect on the bioavailability (AUC and C_max) of Nucope Oral Solution.

Distribution

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

Metabolism

Nucope (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 indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of Nucope. In pharmacokinetic studies (n=3,748), approximately 6% of subjects were poor metabolizers of Nucope (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to Nucope less than 0.1, or a subject with a Nucope 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, 1,575 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=1,462) and Hispanics (2%, n=1,063). The median exposure (AUC) to Nucope in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of Nucope cannot be prospectively identified and will be exposed to higher levels of Nucope following dosing with the recommended dose of Nucope. In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with Nucope Oral Solution for 15-35 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.

Elimination

The mean plasma elimination half-life of Nucope was approximately 27 hours. C_max 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 T_max and half-life values compared to Nucope.

Special Populations

Geriatric Subjects: In older subjects (≥65 years old; n=17) following multiple-dose administration of Nucope Tablets, the mean C_max and AUC values for Nucope 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 two age groups. The mean plasma elimination half-life of Nucope was 33.7 hr in subjects ≥65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects: In subjects 6 to 11 years old, a single dose of 5 mL of Nucope Oral solution containing 2.5 mg of Nucope, resulted in Nucope plasma concentrations similar to those achieved in adults administered a single 5 mg Nucope Tablet. In subjects 2 to 5 years old, a single dose of 2.5 mL of Nucope Oral solution containing 1.25 mg of Nucope, resulted in Nucope plasma concentrations similar to those achieved in adults administered a single 5-mg Nucope Tablet. However, the C_max and AUC of the metabolite (3-hydroxydesloratadine) were 1.27 and 1.61 times higher for the 5 mg dose of Oral solution administered in adults compared to the C_max and AUC obtained in children 2 to 11 years of age receiving 1.25-2.5 mg of Nucope Oral solution. A single dose of either 2.5 mL or 1.25 mL of Nucope Oral solution containing 1.25 mg or 0.625 mg, respectively, of Nucope was administered to subjects 6 to 11 months of age and 12 to 23 months of age. The results of a population pharmacokinetic analysis indicated that a dose of 1 mg for subjects aged 6 to 11 months and 1.25 mg for subjects 12 to 23 months of age is required to obtain Nucope plasma concentrations similar to those achieved in adults administered a single 5 mg dose of Nucope Oral solution.

Renally Impaired: Nucope pharmacokinetics following a single dose of 7.5 mg were characterized in patients 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) patients. In patients with mild and moderate renal impairment, median C_max and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who were hemodialysis dependent, C_max and AUC values increased by approximately 1.7- and 2.5-fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Nucope and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of Nucope and 3-hydroxydesloratadine was unaltered by renal impairment. Dosage adjustment for patients with renal impairment is recommended [see Dosage and Administration (2.5) ].

Hepatically Impaired: Nucope pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients 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 Nucope in patients 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 Nucope in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean C_max and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Dosage adjustment for patients with hepatic impairment is recommended [see Dosage and Administration (2.5) ].

Gender: Female subjects treated for 14 days with Nucope Tablets had 10% and 3% higher Nucope C_max and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine C_max and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race: Following 14 days of treatment with Nucope Tablets, the C_max and AUC values for Nucope were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in C_max and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

Drug Interactions: In two controlled crossover clinical pharmacology studies in healthy male (n=12 in each study) and female (n=12 in each study) volunteers, Nucope 7.5 mg (1.5 times the daily dose) once daily was coadministered with erythromycin 500 mg every 8 hours or ketoconazole 200 mg every 12 hours for 10 days. In three separate controlled, parallel group clinical pharmacology studies, Nucope at the clinical dose of 5 mg has been coadministered 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 normal healthy male and female volunteers. Although increased plasma concentrations (C_max and AUC 0-24 hrs) of Nucope and 3-hydroxydesloratadine were observed, there were no clinically relevant changes in the safety profile of Nucope, as assessed by electrocardiographic parameters (including the corrected QT interval), clinical laboratory tests, vital signs, and adverse events.

	Nucope		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

Carcinogenicity Studies:

The carcinogenic potential of Nucope was assessed using a loratadine study in rats and a Nucope 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 Nucope and Nucope 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 Nucope 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 Nucope, respectively, did not show significant increases in the incidence of any tumors. The estimated Nucope and Nucope 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 Nucope, 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 Nucope doses up to 24 mg/kg/day (estimated Nucope and Nucope 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 Nucope dose of 12 mg/kg in rats (estimated Nucope and Nucope metabolite exposures were approximately 45 times the AUC in humans at the recommended daily oral dose). Nucope had no effect on fertility in rats at an oral dose of 3 mg/kg/day (estimated Nucope and Nucope 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:

Nucope was not teratogenic in rats at doses up to 48 mg/kg/day (estimated Nucope and Nucope 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 Nucope 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 Nucope and Nucope 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 Nucope and Nucope metabolite exposures were approximately 50 times or greater than the AUC in humans at the recommended daily oral dose). Nucope had no effect on pup development at an oral dose of 3 mg/kg/day (estimated Nucope and Nucope 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 Nucope Tablets were evaluated in over 2,300 patients 12 to 75 years of age with seasonal allergic rhinitis. A total of 1,838 patients received 2.5 to 20 mg/day of Nucope in 4 double-blind, randomized, placebo-controlled clinical trials of 2 to 4 weeks' duration conducted in the United States. The results of these studies demonstrated the efficacy and safety of Nucope 5 mg in the treatment of adult and adolescent patients with seasonal allergic rhinitis. In a dose-ranging trial, Nucope 2.5 to 20 mg/day was studied. Doses of 5, 7.5, 10, and 20 mg/day were superior to placebo; and no additional benefit was seen at doses above 5.0 mg. In the same study, an increase in the incidence of somnolence was observed at doses of 10 mg/day and 20 mg/day, compared to placebo (2.3%).

In two 4-week studies of 924 patients (aged 15 to 75 years) with seasonal allergic rhinitis and concomitant asthma, Nucope Tablets 5 mg once daily improved rhinitis symptoms, with no decrease in pulmonary function. This supports the safety of administering Nucope Tablets to adult patients with seasonal allergic rhinitis with mild to moderate asthma.

Nucope Tablets 5 mg once daily significantly reduced the Total Symptom Score (the sum of individual scores of nasal and non-nasal symptoms) in patients with seasonal allergic rhinitis. See Table 3.

Treatment Group (n)	Mean BaselineAt baseline, a total nasal symptom score (sum of 4 individual symptoms) of at least 6 and a total non-nasal symptom score (sum of 4 individual symptoms) of at least 5 (each symptom scored 0 to 3 where 0=no symptom and 3=severe symptoms) was required for trial eligibility. TSS ranges from 0=no symptoms to 24=maximal symptoms. (SEM)	Change from BaselineMean reduction in TSS averaged over the 2 - week treatment period. (SEM)	Placebo Comparison (P-value)
SEM = Standard Error of the Mean
Nucope 5.0 mg (171)	14.2 (0.3)	-4.3 (0.3)	P<0.01
Placebo (173)	13.7 (0.3)	-2.5 (0.3)

There were no significant differences in the effectiveness of Nucope Tablets 5 mg across subgroups of patients defined by gender, age, or race.

14.2 Perennial Allergic Rhinitis

The clinical efficacy and safety of Nucope Tablets 5 mg were evaluated in over 1,300 patients 12 to 80 years of age with perennial allergic rhinitis. A total of 685 patients received 5 mg/day of Nucope in two double-blind, randomized, placebo-controlled clinical trials of 4 weeks' duration conducted in the United States and internationally. In one of these studies Nucope Tablets 5 mg once daily was shown to significantly reduce the Total Symptom Score in patients with perennial allergic rhinitis (Table 4).

Treatment Group (n)	Mean BaselineAt baseline, average of total symptom score (sum of 5 individual nasal symptoms and 3 non-nasal symptoms, each symptom scored 0 to 3 where 0=no symptom and 3=severe symptoms) of at least 10 was required for trial eligibility. TSS ranges from 0=no symptoms to 24=maximal symptoms. (SEM)	Change from BaselineMean reduction in TSS averaged over the 4 week treatment period. (SEM)	Placebo Comparison (P-value)
SEM = Standard Error of the Mean
Nucope 5.0 mg (337)	12.37 (0.18)	-4.06 (0.21)	P=0.01
Placebo (337)	12.30 (0.18)	-3.27 (0.21)

14.3 Chronic Idiopathic Urticaria

The efficacy and safety of Nucope Tablets 5 mg once daily was studied in 416 chronic idiopathic urticaria patients 12 to 84 years of age, of whom 211 received Nucope. In two double-blind, placebo-controlled, randomized clinical trials of six weeks duration, at the pre-specified one-week primary time point evaluation, Nucope Tablets significantly reduced the severity of pruritus when compared to placebo (Table 5). Secondary endpoints were also evaluated, and during the first week of therapy Nucope Tablets 5 mg reduced the secondary endpoints, "Number of Hives" and the "Size of the Largest Hive," when compared to placebo.

Treatment Group (n)	Mean Baselinex (SEM)	Change from BaselineMean reduction in Pruritus averaged over the first week of treatment. (SEM)	Placebo Comparison (P-value)
Pruritus scored 0 to 3 where 0=no symptom to 3=maximum symptom
SEM = Standard Error of the Mean
Nucope 5.0 mg (115)	2.19 (0.04)	-1.05 (0.07)	P=0.01
Placebo (110)	2.21 (0.04)	-0.52 (0.07)

16 HOW SUPPLIED/STORAGE AND HANDLING

Nucope Tablets: Debossed "5", light blue, round tablets that are packaged in high-density polyethylene plastic bottles of 30 (NDC 76439-107-30), 100 (NDC 76439-0107-10) and 500 (NDC 76439-107-50).

Storage:

• Nucope Tablets: Store at 25° C (77° F); excursions permitted to 15° C - 30° C (59° F - 86° F) Heat sensitive. Avoid exposure at or above 30° C (86° F).
  

  Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

.

17.1 Information for Patients

• Patients should be instructed to use Nucope Tablets as directed.
• As there are no food effects on bioavailability, patients can be instructed that Nucope Tablets may be taken without regard to meals.
• Patients should be advised not to increase the dose or dosing frequency as studies have not demonstrated increased effectiveness at higher doses and somnolence may occur.

Manufactured by

Belcher Pharmaceuticals, LLC.

12393 Belcher Road, Suite 420

Largo, FL 33773

Manufactured for:

Virtus Pharmaceuticals

Tampa, FL 33619

www.virtusRX.com

MADE IN USA

Rev. 04/12

PATIENT INFORMATION

Nucope Tablets, 5 mg

Read the Patient Information that comes with Nucope 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 are Nucope tablets?

Nucope tablets are a prescription medicine that contains the medicine Nucope (an antihistamine).

Nucope tablets are used to help control the symptoms of:

• seasonal allergic rhinitis (sneezing, stuffy nose, runny nose and itching of the nose) in people 12 years of age and older.
• perennial allergic rhinitis (sneezing, stuffy nose, runny nose and itching of the nose) in people 12 years of age and older.
• Chronic idiopathic urticaria (long term itching) and to reduce the number and size of hives in people 12 years of age and older.

Nucope Tablets, 5 mg is not for children younger than 12 years of age.

Who should not take Nucope tablets?

Do not take Nucope tablets if you:

• are allergic to Nucope or any of the ingredients in Nucope Tablets. See the end of this leaflet for a complete list of ingredients.
• are allergic to loratadine (Alavert, Claritin).

Talk to your doctor before taking this medicine if you have any questions about whether or not to take this medicine.

What should I tell my doctor before taking Nucope tablets?

Before you take Nucope Tablets, tell your doctor if you:

• have liver or kidney problems.
• have any other medical conditions.
• are pregnant or plan to become pregnant. It is not known if Nucope 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. Nucope can pass into your breast milk.

Talk to your doctor about the best way to feed your baby if you take Nucope tablets.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Nucope may affect the way other medicines work, and other medicines may affect how Nucope works. Especially tell your doctor if you take:

• ketoconazole (Nizoral)
• erythromycin (Ery-tab, Eryc, PCE)
• azithromycin (Zithromax, Zmax)
• antihistamines
• fluoxetine (Prozac)
• cimetidine (Tagamet)

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 Nucope Tablets?

• Take Nucope tablets exactly as your doctor tells you to take it.
• Do not change your dose of Nucope tablets or take more often than prescribed.
• Nucope tablets can be taken with or without food.
• If you take too much Nucope tablets, call your doctor or get medical attention right away.

What are the possible side effects of Nucope Tablets?

Nucope tablets may cause serious side effects, including:

Allergic reactions. Stop taking Nucope tablets and call your doctor right away or get emergency help if you have any of these symptoms:

• rash
• itching
• hives
• swelling of your lips, tongue, face, and throat
• shortness of breath or trouble breathing

The most common side effects of Nucope tablets in adults and children 12 years of age and older with allergic rhinitis include:

• sore throat
• dry mouth
• muscle pain
• tiredness
• sleepiness
• menstrual pain

Increased sleepiness or tiredness can happen if you take more Nucope Tablets than your doctor prescribed to you.

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 Nucope Tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Virtus Pharmaceuticals at 813-283-1344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

How should I store Nucope Tablets?

• Store Nucope Tablets between 59°F to 86°F (15°C to 30°C).
• Nucope Tablets are sensitive to heat. Do not store above 86°F (30°C).
• Protect Nucope Tablets from moisture.

Keep Nucope Tablets, and all medicines out of the reach of children.

General information about Nucope Tablets

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Nucope Tablets for a condition for which it was not prescribed. Do not give Nucope 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 Nucope tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Nucope Tablets that is written for health professionals.

What are the ingredients in Nucope Tablets?

Active ingredient: Nucope

Inactive ingredients in Nucope Tablets: microcrystalline cellulose NF, pregelatinized starch NF, croscarmellose sodium NF, talc USP, zinc stearate, USP and FD&C Blue #2 HT 11-14%.

Manufactured by

Belcher Pharmaceuticals, LLC.

12393 Belcher Road, Suite 420

Largo, FL 33773

Manufactured for:

Virtus Pharmaceuticals

Tampa, FL 33619

www.virtusRX.com

MADE IN USA

April 2012

L05I-VIR

R-1204

Nucope 5mg tablet

Chemical Structure

Nucope pharmaceutical active ingredients containing related brand and generic drugs:

• Desloratadine

Nucope available forms, composition, doses:

• Tablets; Oral; Desloratadine 5 mg

Nucope destination | category:

• Human:
• Antihistamines and antiallergics

Nucope Anatomical Therapeutic Chemical codes:

• R06AX27 - Desloratadine

Nucope pharmaceutical companies:

• Mankind Pharma

References

1. Dailymed."DESLORATADINE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. 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).
3. "Desloratadine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Nucope?

Depending on the reaction of the Nucope after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Nucope 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 Nucope 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.

Review

sdrugs.com conducted a study on Nucope, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Nucope consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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