Vesigard

Vesigard uses

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

1 INDICATIONS AND USAGE

Vesigard (darifenacin) is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency.

Vesigard is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency (1)

2 DOSAGE AND ADMINISTRATION

The recommended starting dose of Vesigard is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy.

Vesigard should be taken once daily with water. Vesigard may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone), the daily dose of Vesigard should not exceed 7.5 mg. Vesigard is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) [see Warnings & Precautions ( 5.6 ), Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )].

The recommended starting dose of Vesigard extended-release tablets is 7.5 mg once daily. Based upon individual response, the dose may be increased to 15 mg once daily, as early as two weeks after starting therapy (2)

The daily dose of Vesigard should not exceed 7.5 mg in the following patients:

• Patients with moderate hepatic impairment (Child-Pugh B) (2, 8.6)
  

• Patients taking potent CYP3A4 inhibitors (2, 7.1)

Vesigard is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) (2, 8.6)

Vesigard may be taken with or without food. The tablet should be swallowed whole with water and not chewed, divided or crushed (2)

3 DOSAGE FORMS AND STRENGTHS

Vesigard extended-release tablets 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse.

Vesigard extended-release tablets 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.

Extended-release tablets 7.5 mg and 15 mg (3)

4 CONTRAINDICATIONS

Vesigard is contraindicated in patients with, or at risk for, the following conditions:

• urinary retention
  

• gastric retention, or
  

• uncontrolled narrow-angle glaucoma.

Vesigard is contraindicated in patients with, or at risk for, the following conditions (4):

• urinary retention,
  

• gastric retention, or
  

• uncontrolled narrow-angle glaucoma.

5 WARNINGS AND PRECAUTIONS

• Vesigard should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention
  

• Vesigard should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (5.2)
  

• Vesigard should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks (5.3)
  

• Central Nervous System Effects: Somnolence has been reported with Vesigard. Advise patients not to drive or operate heavy machinery until they know how Vesigard affects them (5.5)

5.1 Risk of Urinary Retention

Vesigard should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.

5.2 Decreased Gastrointestinal Motility

Vesigard should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Vesigard, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as severe constipation, ulcerative colitis, and myasthenia gravis.

5.3 Controlled Narrow-Angle Glaucoma

Vesigard should be used with caution in patients being treated for narrow-angle glaucoma and only where the potential benefits outweigh the risks.

5.4 Angioedema

Angioedema of the face, lips, tongue, and/or larynx have been reported with Vesigard. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, Vesigard should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

5.5 Central Nervous System Effects

Vesigard is associated with anticholinergic central nervous system effects [see Adverse Reactions ( 6.2 )]. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Vesigard affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

5.6 Patients with Hepatic Impairment

The daily dose of Vesigard should not exceed 7.5 mg for patients with moderate hepatic impairment (Child-Pugh B). Vesigard has not been studied in patients with severe hepatic impairment (Child-Pugh C) and therefore is not recommended for use in this patient population [see Dosage and Administration ( 2 ) Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )].

6 ADVERSE REACTIONS

The most frequently reported adverse reactions for Vesigard are: constipation, dry mouth, headache, dyspepsia, nausea, urinary tract infection, accidental injury, and flu symptoms (6)

To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott at 1-800-521-8813 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 practice.

The safety of Vesigard was evaluated in controlled clinical trials in a total of 8,830 patients, 6,001 of whom were treated with Vesigard. Of this total, 1,069 patients participated in three, 12-week, randomized, placebo-controlled, fixed-dose efficacy and safety studies (Studies 1, 2 and 3). Of this total, 337 and 334 patients received Vesigard 7.5 mg daily and 15 mg daily, respectively. In all long-term trials combined, 1,216 and 672 patients received treatment with Vesigard for at least 24 and 52 weeks, respectively.

In Studies 1, 2 and 3 combined, the serious adverse reactions to Vesigard were urinary retention and constipation.

In Studies 1, 2 and 3 combined, dry mouth leading to study discontinuation occurred in 0%, 0.9%, and 0% of patients treated with Vesigard 7.5 mg daily, Vesigard 15 mg daily and placebo, respectively. Constipation leading to study discontinuation occurred in 0.6%, 1.2%, and 0.3% of patients treated with Vesigard 7.5 mg daily, Vesigard 15 mg daily and placebo, respectively.

Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events in 2% or more of patients treated with 7.5 mg or 15 mg Vesigard, and greater than placebo in Studies 1, 2 and 3. In these studies, the most frequently reported adverse reactions were dry mouth and constipation. The majority of the adverse reactions were mild or moderate in severity and most occurred during the first two weeks of treatment.

Other adverse reactions reported by 1% to 2% of Enablex-treated patients include: abnormal vision, accidental injury, back pain, dry skin, flu syndrome, hypertension, vomiting, peripheral edema, weight gain, arthralgia, bronchitis, pharyngitis, rhinitis, sinusitis, rash, pruritus, urinary tract disorder and vaginitis.

Study 4 was a randomized, 12-week, placebo-controlled, dose-titration regimen study in which Vesigard was administered in accordance with dosing recommendations [see Dosage and Administration ( 2 )]. All patients initially received placebo or Vesigard 7.5 mg daily, and after two weeks, patients and physicians were allowed to adjust upward to Vesigard 15 mg if needed. In this study, the most commonly reported adverse reactions were also constipation and dry mouth. Table 2 lists the identified adverse reactions, derived from all adverse events reported in greater than 3% of patients treated with Vesigard and greater than placebo.

6.2 Post Marketing Experience

The following adverse reactions have been reported during post-approval use of Vesigard extended-release tablets (darifenacin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

Dermatologic: erythema multiforme, interstitial granuloma annulare

General: hypersensitivity reactions, including angioedema with airway obstruction and anaphylactic reaction

Central Nervous: confusion, hallucinations and somnolence

Cardiovascular: palpitations and syncope

7 DRUG INTERACTIONS

• Caution should be taken when Vesigard is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window, such as flecainide, thioridazine and tricyclic antidepressants
  

• The concomitant use of Vesigard with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects of gastrointestinal motility (7.3)

7.1 CYP3A4 Inhibitors

The systemic exposure of Vesigard from Vesigard extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of Vesigard should not exceed 7.5 mg when co-administered with potent CYP3A4 inhibitors (for example, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin and nefazadone). No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )].

7.2 CYP2D6 Inhibitors

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors [see Clinical Pharmacology ( 12.3 )].

7.3 CYP2D6 Substrates

Caution should be taken when Vesigard is used concomitantly with medications that are predominantly metabolized by CYP2D6 and which have a narrow therapeutic window (for example, flecainide, thioridazine and tricyclic antidepressants) [see Clinical Pharmacology ( 12.3 )].

7.4 CYP3A4 Substrates

Vesigard did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology ( 12.3 )].

7.5 Combination oral contraceptives

Vesigard (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol [see Clinical Pharmacology ( 12.3 )].

7.6 Warfarin

Vesigard had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with Vesigard at steady-state. Standard therapeutic prothrombin time monitoring for warfarin should be continued.

7.7 Digoxin

Vesigard (30 mg daily) did not have a clinically relevant effect on the pharmacokinetics of digoxin (0.25 mg) at steady-state. Routine therapeutic drug monitoring for digoxin should be continued [see Clinical Pharmacology ( 12.3 )].

7.8 Other Anticholinergic Agents

The concomitant use of Vesigard with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Vesigard should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus
  

• Nursing Mothers: It is not known whether Vesigard is excreted into human milk and therefore caution should be exercised before Vesigard is administered to a nursing woman (8.3)
  

• Pediatric Use: The safety and effectiveness of Vesigard in pediatric patients have not been established (8.4)

8.1 Pregnancy

Pregnancy Category C

There are no studies of Vesigard in pregnant women.

Vesigard was not teratogenic in rats and rabbits at plasma exposures of free drug (via AUC) up to 59 times and 28 times, respectively (doses up to 50 and 30 mg/kg/day, respectively) the maximum recommended human dose [MRHD] of 15 mg. At approximately 59 times the MRHD in rats, there was a delay in the ossification of the sacral and caudal vertebrae which was not observed at approximately 13 times the AUC. Dystocia was observed in dams at approximately 17 times the AUC (10 mg/kg/day). Slight developmental delays were observed in pups at this dose. At five times the AUC (3 mg/kg/day), there were no effects on dams or pups. In rabbits, an exposure approximately 28 times (30 mg/kg/day) the MRHD of Vesigard was shown to increase post-implantation loss, with a no effect level at nine times (10 mg/kg/day) the AUC at the MRHD. Dilated ureter and/or kidney pelvis was also observed in offspring at this dose along with urinary bladder dilation consistent with the pharmacological action of Vesigard, with one case observed at nine times (10 mg/kg/day). No effect was observed at approximately 2.8 times (3 mg/kg/day) the AUC at the MRHD.

Because animal reproduction studies are not always predictive of human response, Vesigard should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

8.3 Nursing Mothers

Vesigard is excreted into the milk of rats. It is not known whether Vesigard is excreted into human milk and therefore caution should be exercised before Vesigard is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of Vesigard in pediatric patients have not been established.

8.5 Geriatric Use

In the fixed-dose, placebo-controlled, clinical studies, 30% of patients treated with Vesigard were over 65 years of age. No overall differences in safety or efficacy were observed between patients over 65 years and younger patients less than 65 years (n = 464). No dose adjustment is recommended for elderly patients [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )].

8.6 Hepatic Impairment

Subjects with severe hepatic impairment (Child-Pugh C) have not been studied, therefore Vesigard is not recommended for use in these patients [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.6 )]. The daily dose of Vesigard should not exceed 7.5 mg once daily for patients with moderate hepatic impairment (Child-Pugh B) [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.6 )]. After adjusting for plasma protein binding, unbound Vesigard exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

8.7 Renal Impairment

A study of subjects with varying degrees of renal impairment demonstrated no clear relationship between renal function and Vesigard clearance. No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology ( 12.3 )].

8.8 Gender

No dose adjustment is recommended based on gender [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )].

10 OVERDOSAGE

Overdosage with antimuscarinic agents, including Vesigard, can result in severe antimuscarinic effects. Treatment should be symptomatic and supportive. In the event of overdosage, ECG monitoring is recommended. Vesigard has been administered in clinical trials at doses up to 75 mg (five times the maximum therapeutic dose) and signs of overdose were limited to abnormal vision.

11 DESCRIPTION

Enablex is an extended-release tablet for oral administration which contains 7.5 mg or 15 mg Vesigard as its hydrobromide salt. The active moiety, Vesigard, is a potent muscarinic receptor antagonist.

Chemically, Vesigard hydrobromide is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide. The empirical formula of Vesigard hydrobromide is C₂₈H₃₀N₂O₂-HBr.

The structural formula is:

*Includes 95 EMs and 6 PMs for 7.5 mg; 104 EMs and 10 PMs for 15 mg.

A summary of mean (standard deviation, SD) steady-state pharmacokinetic parameters of Vesigard 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3.

The mean oral bioavailability of Vesigard in EMs at steady-state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively.

Effect of Food

Following single dose administration of Vesigard with food, the AUC of Vesigard was not affected, while the C_max was increased by 22% and T_max was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from Vesigard.

Distribution

Vesigard is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (V_ss) is estimated to be 163 L.

Metabolism

Vesigard is extensively metabolized by the liver following oral dosing.

Metabolism is mediated by cytochrome P450 enzymes CYP2D6 and CYP3A4. The three main metabolic routes are as follows:

(i)monohydroxylation in the dihydrobenzofuran ring;

(ii)dihydrobenzofuran ring opening;

(iii)N-dealkylation of the pyrrolidine nitrogen.

The initial products of the hydroxylation and N-dealkylation pathways are the major circulating metabolites but they are unlikely to contribute significantly to the overall clinical effect of Vesigard.

Variability in Metabolism

A subset of individuals (approximately 7% Caucasians and 2% African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. Individuals with normal CYP2D6 activity are referred to as extensive metabolizers (EMs). The metabolism of Vesigard in PMs will be principally mediated via CYP3A4. The Vesigard ratios (PM versus EM) for C_max and AUC following Vesigard 15 mg once daily at steady-state were 1.9 and 1.7, respectively.

Excretion

Following administration of an oral dose of ¹⁴C-darifenacin solution to healthy volunteers, approximately 60% of the radioactivity was recovered in the urine and 40% in the feces. Only a small percentage of the excreted dose was unchanged Vesigard (3%). Estimated Vesigard clearance is 40 L/h for EMs and 32 L/h for PMs. The elimination half-life of Vesigard following chronic dosing is approximately 13 to 19 hours.

Drug-Drug Interactions

Effects of Other Drugs on Vesigard

Vesigard metabolism is primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. Therefore, inducers of CYP3A4 or inhibitors of either of these enzymes may alter Vesigard pharmacokinetics [see Drug Interactions ( 7 )].

CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Vesigard was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean Vesigard C_max increased to 11.2 ng/mL for EMs (n = 10) and 55.4 ng/mL for one PM subject (n = 1). Mean AUC increased to 143 and 939 ng-h/mL for EMs and for one PM subject, respectively. When a 15 mg daily dose of Vesigard was given with ketoconazole, mean Vesigard C_max increased to 67.6 ng/mL and 58.9 ng/mL for EMs (n = 3) and one PM subject (n = 1), respectively. Mean AUC increased to 1110 and 931 ng-h/mL for EMs and for one PM subject, respectively [see Dosage and Administration ( 2 ) and Drug Interactions ( 7.1 )].

The mean C_max and AUC of Vesigard following 30 mg once daily dosing at steady-state were 128% and 95% higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and Vesigard 30 mg once daily at steady-state increased Vesigard C_max and AUC by 88% and 84%, respectively [see Drug Interactions ( 7.1 )].

The mean C_max and AUC of Vesigard following 30 mg once daily at steady-state were 42% and 34% higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor.

CYP2D6 Inhibitors: Vesigard exposure following 30 mg once daily at steady-state was 33% higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see Drug Interactions ( 7.2 )].

Effects of Vesigard on Other Drugs

In Vitro Studies: Based on in vitro human microsomal studies, Vesigard is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations.

In Vivo Studies: The potential for clinical doses of Vesigard to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies.

CYP2D6 Substrates: The mean C_max and AUC of imipramine, a CYP2D6 substrate, were increased by 57% and 70%, respectively, in the presence of steady-state Vesigard 30 mg once daily. The mean C_max and AUC of desipramine, the active metabolite of imipramine, were increased by 260% [see Drug Interactions ( 7.3 )].

CYP3A4 Substrates: Vesigard (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17% increase in midazolam exposure.

Combination Oral Contraceptives: Vesigard (10 mg three times daily) had no effect on the pharmacokinetics of a combination oral contraceptive containing levonorgestrel (0.15 mg) and ethinyl estradiol (0.03 mg).

Warfarin: Vesigard had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with Vesigard (30 mg daily) at steady-state [see Drug Interactions ( 7.6 )].

Digoxin: Vesigard (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16% increase in digoxin exposure [see Drug Interactions ( 7.7 )].

Pharmacokinetics in Special Populations

Age: A population pharmacokinetic analysis of patient data indicated a trend for clearance of Vesigard to decrease with age (6% per decade relative to a median age of 44). Following administration of Vesigard 15 mg once daily, Vesigard exposure at steady-state was approximately 12% to 19% higher in volunteers between 45 and 65 years of age compared to younger volunteers aged 18 to 44 years [see Use in Specific Populations ( 8.5 )].

Pediatric: The pharmacokinetics of Vesigard has not been studied in the pediatric population [see Use in Specific Populations ( 8.4 )].

Gender: PK parameters were calculated for 22 male and 25 female healthy volunteers. Vesigard C_max and AUC at steady-state were approximately 57% to 79% and 61% to 73% higher in females than in males, respectively [see Use in Specific Populations ( 8.8 )].

Renal Impairment: A study of subjects with varying degrees of renal impairment (creatinine clearance between 10 and 136 mL/min) given Vesigard 15 mg once daily to steady-state demonstrated no clear relationship between renal function and Vesigard clearance [see Use in Specific Populations ( 8.7 )].

Hepatic Impairment: Vesigard pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given Vesigard 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of Vesigard. However, protein binding of Vesigard was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound Vesigard exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function. Subjects with severe hepatic impairment (Child-Pugh C) have not been studied [see Dosage and Administration ( 2 ), Warning and Precautions ( 5.5 ) and Use in Specific Population ( 8.6 )].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with Vesigard were conducted in mice and rats. No evidence of drug-related carcinogenicity was revealed in a 24-month study in mice at dietary doses up to 100 mg/kg/day or approximately 32 times the estimated free plasma AUC reached at the maximum recommended human dose (the AUC at the MRHD) of 15 mg and in a 24-month study in rats at doses up to 15 mg/kg/day or up to approximately 12 times the AUC at the MRHD in female rats and approximately eight times the AUC at the MRHD in male rats.

Vesigard was not genotoxic in the bacterial mutation assay (Ames test), the Chinese hamster ovary assay, the human lymphocyte assay, or the in vivo mouse bone marrow cytogenetics assay.

There was no evidence for effects on fertility in male or female rats treated at oral doses up to approximately 78 times (50 mg/kg/day) the AUC at the MRHD.

14 CLINICAL STUDIES

Vesigard extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urgency, urge urinary incontinence, and increased urinary frequency in three randomized, fixed-dose, placebo-controlled, multicenter, double-blind, 12-week studies (Studies 1, 2 and 3) and one randomized, double-blind, placebo-controlled, multicenter, dose-titration study (Study 4). For study eligibility in all four studies, patients with symptoms of overactive bladder for at least six months were required to demonstrate at least eight micturitions and at least one episode of urinary urgency per day, and at least five episodes of urge urinary incontinence per week. The majority of patients were white (94%) and female (84%), with a mean age of 58 years, range 19 to 93 years. Thirty-three percent of patients were greater than or equal to 65 years of age. These characteristics were well balanced across treatment groups. The study population was inclusive of both naïve patients who had not received prior pharmacotherapy for overactive bladder (60%) and those who had (40%).

Table 4 shows the efficacy data collected from 7- or 14-day voiding diaries in the three fixed-dose placebo-controlled studies of 1,059 patients treated with placebo, 7.5 mg or 15 mg once daily Vesigard for 12 weeks. A significant decrease in the primary endpoint, change from baseline in average weekly urge urinary incontinence episodes was observed in all three studies. Data is also shown for two secondary endpoints, change from baseline in the average number of micturitions per day (urinary frequency) and change from baseline in the average volume voided per micturition.

Table 5 shows the efficacy data from the dose-titration study in 395 patients who initially received 7.5 mg Vesigard or placebo daily with the option to increase to 15 mg Vesigard or placebo daily after two weeks.

As seen in Figures 2 a, 2b and 2c, reductions in the number of urge incontinence episodes per week were observed within the first two weeks in patients treated with Vesigard 7.5 mg and 15 mg once daily compared to placebo. Further, these effects were sustained throughout the 12-week treatment period.

Figures 2a, 2b, 2c. Median Change from Baseline at Weeks 2, 6, 12 for Number of Urge Incontinence Episodes per Week (Studies 1, 2 and 3)

Figure 2a Figure 2b Figure 2c

16 HOW SUPPLIED/STORAGE AND HANDLING

Vesigard^®, 7.5 mg are round, shallow, bi-convex, white-colored tablets, and are identified with “DF” on one side and “7.5” on the reverse.

Bottle of 30... NDC 0430-0170-15

Bottle of 90... NDC 0430-0170-23

Vesigard^®, 15 mg are round, shallow, bi-convex, light peach-colored tablets, and are identified with “DF” on one side and “15” on the reverse.

Bottle of 30... NDC 0430-0171-15

Bottle of 90... NDC 0430-0171-23

Storage

Store at 25° C (77° F); excursions permitted to 15 to 30° C (59 to 86° F). Protect from light.

Keep this and all drugs out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information ).

Patients should be informed that anticholinergic agents, such as Vesigard, may produce clinically significant adverse effects related to anticholinergic pharmacological activity including constipation, urinary retention and blurred vision. Heat prostration (due to decreased sweating) can occur when anticholinergics such as Vesigard are used in a hot environment. Because anticholinergics, such as Vesigard, may produce dizziness or blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effects have been determined. Patients should read the patient information leaflet before starting therapy with Vesigard.

Patients should be informed that Vesigard may produce clinically significant angioedema that may result in airway obstruction. Patients should be advised to promptly discontinue Vesigard therapy and seek immediate medical attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.

Vesigard extended-release tablets should be taken once daily with water. They may be taken with or without food, and should be swallowed whole and not chewed, divided or crushed.

FDA-Approved Patient Labeling

Vesigard ^® (ěn-ā-blěx)

(darifenacin)

extended-release tablets

Read this Patient Information leaflet about Vesigard ^® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment.

What is Vesigard?

Vesigard is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:

• Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents
  

• Urgency: a strong need to urinate right away
  

• Frequency: urinating often

It is unknown if Vesigard is safe and effective in children.

Who should not take Vesigard?

Do not take Vesigard if you:

• are not able to empty your bladder (“urinary retention”)
  

• have delayed or slow emptying of your stomach (“gastric retention”)
  

• have an eye problem called “uncontrolled narrow-angle glaucoma”

What should I tell my healthcare provider before starting Vesigard?

Before starting Vesigard, tell your doctor if you:

• have trouble emptying your bladder or if you have a weak urine stream
  

• have any stomach or intestinal problems, or problems with constipation
  

• have liver problems
  

• have any other medical conditions
  

• are pregnant or are planning to become pregnant. It is not known if Vesigard can harm your unborn baby.
  

• are breastfeeding or plan to breastfeed. It is not known if Vesigard passes into breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you take Vesigard.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Vesigard and certain other medicines may affect each other, causing side effects.

Especially tell your healthcare provider if you take a:

• antifungal medicine ketoconazole (Nizoral^®) or itraconazole (Sporanox^®)
  

• antibiotic medicine clarithromycin (Biaxin^®)
  

• anti-HIV medicine ritonavir (Norvir^®) or nelfinavir (Viracept^®)
  

• medicine to treat depression nefazadone (Serzone^®)
  

• medicine to treat an abnormal heartbeat flecainide (Tambocor )
  

• antipsychotic medicine thioridazine (Mellaril^®)
  

• medicine to treat depression called a tricyclic antidepressant

Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Vesigard?

• Take Vesigard exactly as prescribed. Your doctor will prescribe the dose that is right for you. Take Vesigard 1 time daily with water.
  

• Vesigard should be swallowed whole. Do not chew, cut or crush Vesigard tablet.
  

• Vesigard may be taken with or without food.
  

• If you take too much Vesigard call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking Vesigard?

Vesigard can cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how Vesigard affects you.

What are the possible side effects of Vesigard?

Vesigard may cause serious side effects including:

• Serious allergic reaction. Stop taking Vesigard and get medical help right away if you have:
  • hives, skin rash or swelling
    

  • severe itching
    

  • swelling of your face, mouth or tongue
    

  • trouble breathing

The most common side effects with Vesigard are:

• constipation
  

• dry mouth
  

• headache
  

• heartburn
  

• nausea
  

• urinary tract infection
  

• blurred vision
  

• heat exhaustion or heat-stroke. This can happen when Vesigard is used in hot environments. Symptoms of heat exhaustion may include:
  • decreased sweating
    

  • dizziness
    

  • tiredness
    

  • nausea
    

  • increase body temperature

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Vesigard. 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 do I store Vesigard?

• Store Vesigard at room temperature, between 59° F to 86° F (15° C to 30° C).
  

• Keep Vesigard out of the light.

Keep Vesigard and all medicines out of the reach of children.

General information about Vesigard.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Vesigard for a condition for which it was not prescribed. Do not give Vesigard to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Vesigard. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Vesigard that is written for health professionals.

What are the ingredients in Vesigard?

Active ingredient: Vesigard

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose, magnesium stearate, polyethylene glycol, talc, titanium dioxide.

The 15 mg tablet also contains ferric oxide red and ferric oxide yellow.

The brands listed are the trademarks of their respective owners and are not trademarks of Warner Chilcott.

Manufactured by:

Warner Chilcott Deutschland GmbH

D-64331 Weiterstadt

Germany

Marketed by:

Warner Chilcott (US), LLC

Rockaway, NJ 07866

1-800-521-8813

0170G0115

Vesigard pharmaceutical active ingredients containing related brand and generic drugs:

• Darifenacin

Vesigard available forms, composition, doses:

• Tablets, Extended Release; Oral; Darifenacin 7.5 mg

Vesigard destination | category:

• Human:
• Drugs acting on the genito-urinary system
• Drugs for bladder and prostate disorders
• Genitourinary smooth muscle relaxants

Vesigard Anatomical Therapeutic Chemical codes:

• G04BD10 - Darifenacin

Vesigard pharmaceutical companies:

• Cipla

References

1. Dailymed."ENABLEX (DARIFENACIN) TABLET, EXTENDED RELEASE [WARNER CHILCOTT (US), LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "Darifenacin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "Darifenacin". http://www.drugbank.ca/drugs/DB0049... (accessed August 28, 2018).

Frequently asked Questions

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

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