Darifenacin

Before taking darifenacin,

• tell your doctor and pharmacist if you are allergic to darifenacin or any other medications.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Adapin, Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil); antihistamines; clarithromycin (Biaxin); flecainide (Tambocor); ipratropium (Atrovent); itraconazole (Sporanox); ketoconazole (Nizoral); medications for irritable bowel disease, motion sickness, Parkinson's disease, ulcers, or urinary problems; nefazodone (Serzone); nelfinavir (Viracept); ritonavir (Norvir); and thioridazine (Mellaril). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had urinary obstruction (a blockage of urine flowing out of the bladder), any type of blockage in the digestive system, benign prostatic hypertrophy (enlargement of the prostate), severe constipation, ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum), myasthenia gravis (a disorder of the nervous system that causes muscle weakness), glaucoma, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking darifenacin, call your doctor.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking darifenacin.
• you should know that darifenacin may cause blurred vision or make you dizzy. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that darifenacin causes decreased sweating, which may cause heat prostration (collapse because of high body temperature) in hot weather.

Skip the missed dose and continue your regular dosing schedule. Do not take two doses in the same day or a double dose to make up for a missed one.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• vision problems

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using darifenacin and call your doctor at once if you have:

• severe stomach pain or constipation;
• confusion, hallucinations;
• little or no urinating;
• pain or burning when you urinate; or
• signs of dehydration--feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin.

Common side effects may include:

• nausea, indigestion;
• constipation;
• headache, dizziness;
• dry mouth; or
• blurred vision.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Before starting darifenacin, tell your doctor or healthcare professional about all of your medical conditions including if you:

• have any stomach or intestinal problems, or problems with constipation
• have trouble emptying your bladder or if you have a weak urine stream
• have an eye problem called narrow-angle glaucoma
• have liver problems
• are pregnant or are planning to become pregnant. It is not known if darifenacin can harm your unborn baby.
• are breastfeeding. It is not known if darifenacin passes into breast milk and if it can harm your baby.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Darifenacin and certain other medicines can interact with each other, causing side effects. Especially tell your doctor if you take:

• ketoconazole (Nizoral) or itraconazole (Sporanox), antifungal medicines
• clarithromycin (Biaxin), an antibiotic medicine
• ritonivir or nelfinavir (Viracept), antiviral medicines
• nefazadone (Serzone), a depression medicine
• flecainide (Tambocor), an abnormal heartbeat (antiarrhythmia) medicine
• thioridazine (Mellaril), a mental disorder (antipsychotic) medicine
• a medicine 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.

If you take too much darifenacin call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

You should not take darifenacin if you are allergic to it, or if you have:

• untreated or uncontrolled narrow-angle glaucoma;

• a stomach disorder causing delayed emptying; or

• if you have trouble emptying your bladder.

To make sure darifenacin is safe for you, tell your doctor if you have:

• glaucoma;

• liver disease;

• ulcerative colitis;

• a blockage in your stomach or intestines;

• a muscle disorder such as myasthenia gravis; or

• if you have very little urine or a weak stream of urine.

FDA pregnancy category C. It is not known whether darifenacin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether darifenacin passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

In the U.S.

• Enablex

Available Dosage Forms:

• Tablet, Extended Release

Therapeutic Class: Urinary Antispasmodic

Pharmacologic Class: Antimuscarinic

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take darifenacin at the same time of day.
• Take with or without food.
• Take with a full glass of water.
• Swallow whole. Do not chew, break, or crush.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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

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

• urinary retention
• gastric retention, or
• uncontrolled narrow-angle glaucoma

CYP3A4 Inhibitors

The systemic exposure of Darifenacin from Darifenacin extended-release tablets is increased in the presence of CYP3A4 inhibitors. The daily dose of Darifenacin 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)]. 

CYP2D6 Inhibitors

No dosing adjustments are recommended in the presence of CYP2D6 inhibitors (for example, paroxetine, fluoxetine, quinidine and duloxetine) [see Clinical Pharmacology (12.3)].

CYP2D6 Substrates

Caution should be taken when Darifenacin 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)]. 

CYP3A4 Substrates

Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [see Clinical Pharmacology (12.3)]. 

Combination oral contraceptives

Darifenacin (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)]. 

Warfarin

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

Digoxin

Darifenacin (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)]. 

Other Anticholinergic Agent

The concomitant use of Darifenacin 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. 

Mechanism of Action

Darifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion.
In vitro studies using human recombinant muscarinic receptor subtypes show that Darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9- and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. 

Pharmacodynamics

In three cystometric studies performed in patients with involuntary detrusor contractions, increased bladder capacity was demonstrated by an increased volume threshold for unstable contractions and diminished frequency of unstable detrusor contractions after Darifenacin treatment. These findings are consistent with an antimuscarinic action on the urinary bladder. 
Electrophysiology
The effect of six-day treatment of 15 mg and 75 mg Darifenacin on QT/QTc interval was evaluated in a multiple-dose, double-blind, randomized, placebo-and active-controlled (moxifloxacin 400 mg) parallel-arm design study in 179 healthy adults (44 percent male, 56 percent female) aged 18 to 65. Subject included 18 percent poor metabolizer (PMs) and 82 percent extensive metabolizer (EMs). The QT interval was measured over a 24-hour period both predosing and at steady-state. The 75 mg Darifenacin dose was chosen because this achieves exposure similar to that observed in CYP2D6 poor metabolizers administered the highest recommended dose (15 mg) of Darifenacin in the presence of a potent CYP3A4 inhibitor. At the doses studied, Darifenacin did not result in QT/QTc interval prolongation at any time during the steady-state, while moxifloxacin treatment resulted in a mean increase from baseline QTcF of about 7.0 msec when compared to placebo. In this study, Darifenacin 15 mg and 75 mg doses demonstrated a mean heart rate change of 3.1 and 1.3 bpm, respectively, when compared to placebo. However, in the clinical efficacy and safety studies, the change in median HR following treatment with Darifenacin was no different from placebo.

Pharmacokinetics

Absorption
After oral administration of Darifenacin to healthy volunteers, peak plasma concentrations of Darifenacin are reached approximately seven hours after multiple dosing and steady-state plasma concentrations are achieved by the sixth day of dosing. The mean (SD) steady-state time course of Darifenacin 7.5 mg and 15 mg extended-release tablets is depicted in Figure 1.
Figure 1 Mean (SD) Steady-State Darifenacin Plasma Concentration-Time Profiles for Darifenacin 7.5 mg and 15 mg in Healthy Volunteers Including Both CYP2D6 EMs and PMs* 

*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 from Darifenacin 7.5 mg and 15 mg extended-release tablets in EMs and PMs of CYP2D6 is provided in Table 3.
Table 3: Mean (SD) Steady-State Pharmacokinetic Parameters from Darifenacin 7.5 mg and 15 mg Extended-Release Tablets Based on Pooled Data by Predicted CYP2D6 Phenotype

aN = 25; bN = 8; cN = 2; dN = 1; AUC24 = Area under the plasma concentration versus time curve for 24h;

Cmax = Maximum observed plasma concentration; Cavg = Average plasma concentration at steady-state;

  Tmax = Time of occurrence of Cmax; t1/2 = Terminal elimination half-life. Regarding EM and PM [see CLINICAL PHARMACOLOGY, Pharmacokinetics, Variability in Metabolism (12.3)]. 
The mean oral bioavailability of Darifenacin in EMs at steady-state is estimated to be 15 percent and 19 percent for 7.5 mg and 15 mg tablets, respectively.

Effect of food

Following single dose administration of Darifenacin with food, the AUC of Darifenacin was not affected, while the Cmax was increased by 22 percent and Tmax was shortened by 3.3 hours. There is no effect of food on multiple-dose pharmacokinetics from Darifenacin.

Distribution
Darifenacin is approximately 98 percent bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). The steady-state volume of distribution (Vss) is estimated to be 163 L. 
Metabolism

Darifenacin 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 Darifenacin.
Variability in Metabolism
A subset of individuals (approximately 7 percent Caucasians and 2 percent 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 Darifenacin in PMs will be principally mediated via CYP3A4. The Darifenacin ratios (PM versus EM) for Cmax and AUC following Darifenacin 15 mg once daily at steady-state were 1.9 and 1.7, respectively.
CYP3A4 Inhibitors: In a drug interaction study, when a 7.5 mg once daily dose of Darifenacin was given to steady-state and co-administered with the potent CYP3A4 inhibitor ketoconazole 400 mg, mean Darifenacin Cmax 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 Darifenacin was given  with ketoconazole mean Darifenacin Cmax 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 Cmax and AUC of Darifenacin following 30 mg once daily dosing at steady-state were 128 percent and 95 percent higher, respectively, in the presence of a moderate CYP3A4 inhibitor, erythromycin. Co-administration of fluconazole, a moderate CYP3A4 inhibitor and Darifenacin 30 mg once daily at steady-state increased Darifenacin Cmax and AUC by 88 percent and 84 percent, respectively [see Drug Interactions (7.1)]. 
The mean Cmax and AUC of Darifenacin following 30 mg once daily at steady-state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine, a mixed CYP P450 enzyme inhibitor.
Excreation
Following administration of an oral dose of 14C-Darifenacin  solution to healthy volunteers, approximately 60 percent of the radioactivity was recovered in the urine and 49 percent in the feces. Only a small percentage of the excreted dose was unchanged Darifenacin (3 percent). Estimated Darifenacin clearance is 40 L/h for EMs and 32 L/h for PMs.  The elimination half-life of Darifenacin following chronic dosing is approximately 13 to 19 hours. 

Drug-Drug Interactions

Effects of Other Drugs on Darifenacin
Darifenacin 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 Darifenacin pharmacokinetics [see Drug Interactions (7)].
 CYP2D6 Inhibitors: Darifenacin exposure following 30 mg once daily at steady-state was 33 percent higher in the presence of the potent CYP2D6 inhibitor paroxetine 20 mg [see Drug Interactions (7.2)]. Effects of Darifenacin on Other Drugs
In Vitro Studies: Based on in vitro human microsomal studies, Darifenacin is not expected to inhibit CYP1A2 or CYP2C9 at clinically relevant concentrations. 
In Vivo Studies: The potential for clinical doses of Darifenacin to act as inhibitors of CYP2D6 or CYP3A4 substrates was investigated in specific drug interaction studies. 
CYP2D6 Substrates: The mean Cmax and AUC of imipramine, a CYP2D6 substrate, were increased by 57 percent and 70 percent, respectively, in the presence of steady-state Darifenacin 30 mg once daily. The mean Cmax and AUC of desipramine, the active metabolite of imipramine, were increased by 260 percent [see Drug Interactions (7.3)]. 
CYP3A4 Substrates: Darifenacin (30 mg daily) co-administered with a single oral dose of midazolam 7.5 mg resulted in a 17 percent increase in midazolam exposure. 
Combination Oral Contraceptives: Darifenacin (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: Darifenacin had no significant effect on prothrombin time when a single dose of warfarin 30 mg was co-administered with Darifenacin (30 mg daily) at steady-state [see Drug Interactions (7.6)].
Digoxin: Darifenacin (30 mg daily) co-administered with digoxin (0.25 mg) at steady-state resulted in a 16 percent 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 Darifenacin to decrease with age (6 percent per decade relative to a median age of 44). Following administration of Darifenacin 15 mg once daily, Darifenacin exposure at steady-state was approximately 12 percent to 19 percent 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 Darifenacin 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. Darifenacin Cmax and AUC at steady-state were approximately 57 percent to 79 percent and 61 percent to 73 percent 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 Darifenacin 15 mg once daily to steady-state demonstrated no clear relationship between renal function and Darifenacin clearance [see Use in Specific Populations (8.7)].
Hepatic Impairment: Darifenacin pharmacokinetics were investigated in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) impairment of hepatic function given Darifenacin 15 mg once daily to steady-state. Mild hepatic impairment had no effect on the pharmacokinetics of Darifenacin. However, protein binding of Darifenacin was affected by moderate hepatic impairment. After adjusting for plasma protein binding, unbound Darifenacin 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)].

Darifenacin extended-release tablets, 7.5 mg are white colored, round, bi-convex, film coated and are debossed with “L48” on one side and plain on the other side.
Bottle of 30 ............................NDC 33342-276-07

Bottle of 90 ............................NDC 33342-276-10

Carton of 100 tablets (10 x 10 unit-dose)…NDC 33342-276-12 

Darifenacin extended-release tablets, 15 mg are light peach colored, round, bi-convex, film coated and are debossed with “L49” on one side and plain on the other side.
Bottle of 30 ............................NDC 33342-277-07

Bottle of 90 ............................NDC 33342-277-10

Carton of 100 tablets (10 x 10 unit-dose)…NDC 33342-277-12
Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light.
Keep this and all drugs out of the reach of children. 

Clearance decreases 6% per decade relative to a median age of 44 years. Exposure at steady state was ~12% to 19% higher in subjects 45 to 65 years of age.

Cmax and AUC were ~57% to 79% and 61%to 73% higher, respectively, in women than in men.

Mild impairment (Child-Pugh class A): No dosage adjustment necessary; use with caution.

Moderate impairment (Child-Pugh class B): Maximum dose: 7.5 mg/day

Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Administer with water without regard to food. Swallow tablet whole; do not chew, crush, or divide.

Adverse events have been observed in animal reproduction studies.

Mild hepatic impairment (Child Pugh A): No adjustment recommended.
Moderate hepatic impairment (Child Pugh B): Do exceed 7.5 mg daily.
Severe hepatic impairment (Child Pugh C): Not recommended.

No adjustment recommended.

Data not available

Administration advice:
-This drug may be taken with or without food.
-The tablet should be swallowed whole with water and not chewed, divided, or crushed.