Daritor-7.5/Daritor-15

Darifenacin hydrobromide.

Each extended-release tablet contains: Darifenacin 7.5 mg (Equivalent to Darifenacin hydrobromide 8.930 mg).
Each extended-release tablet contains: Darifenacin 15 mg (Equivalent to Darifenacin hydrobromide 17.860 mg).
Darifenacin (Daritor-7.5) 7.5 mg Extended-Release Tablet is a white to off-white colored, round, biconvex, bevel edged, film-coated tablets, debossed "202" on one side and plain on other side.
Darifenacin (Daritor-15) 15 mg Extended-Release Tablet is a light peach colored, round, biconvex, bevel edged, film-coated tablets, debossed "203" on one side and plain on other side.

Pharmacology: Mechanism of action: Darifenacin is a selective muscarinic M3 receptor antagonist (M3 SRA) in vitro. The M3 receptor is the major subtype that controls urinary bladder muscle contraction. It is not known whether this selectivity for the M3 receptor translates into any clinical advantage when treating symptoms of overactive bladder syndrome.
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. These findings are consistent with an antimuscarinic action on the urinary bladder.
Pharmacokinetics: Absorption: Due to extensive first-pass metabolism darifenacin has a bioavailability of approximately 15% and 19% after 7.5 mg and 15 mg daily doses at steady state. Maximum plasma level reached approximately 7 hours after administration of the prolonged-release tablets and steady state plasma levels are achieved by the sixth day of administration. Food had no effect on darifenacin pharmacokinetics during multiple-dose administration of prolonged-release tablets while C_max is increase by 22% and T_max was shortened by 3.3 hours.
Distribution: Distribution Darifenacin is a lipophilic base and is 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: Darifenacin is extensively metabolized by the liver following oral administration. Darifenacin undergoes significant metabolism by cytochrome CYP3A4 and CYP2D6 in the liver and by CYP3A4 in the gut wall. The three main metabolic routes are as follows: monohydroxylation in the dihydrobenzofuran ring, dihydrobenzofuran ring opening and N-dealkylation of the pyrrolidine nitrogen. The initial products of the hydroxylation and N-dealkylation pathways are major circulating metabolites but none contribute significantly to the overall clinical effect of darifenacin.
Variability in Metabolism: Darifenacin is metabolized by CYP3A4 and CYP2D6. Due to genetic differences, about 7% of the Caucasians lack the CYP2D6 enzyme and are said to be poor metabolizers. A few percent of the population have increased CYP2D6 enzyme levels (ultrafast metabolizers). The information previously mentioned applies to subjects who have normal CYP2D6 activity (extensive metabolizers) unless otherwise stated.
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 darifenacin (3%). Estimated darifenacin clearance is 40 L/hour. The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours.
Special Populations: Age: Darifenacin exposure at steady state was approximately 12-19% higher in volume in patients between 45 and 65 years of age compared to younger patients aged 18 to 44 years. Analysis data indicated a trend for clearance of Darifenacin to decrease with age (6% per decade relative to median age of 44).
Gender: A population pharmacokinetic analysis of patient data indicated that darifenacin exposure was 23% lower in males than females.
Race: The effect of race on the pharmacokinetics of Darifenacin has not been established.
Pediatric patients: The pharmacokinetics of darifenacin have not been established in the pediatric population.
Renal Impairment: A small study of subjects (n=24) with varying degrees of renal impairment (creatinine clearance between 10 mL/min and 136 mL/min) given darifenacin 15 mg once daily to steady state demonstrated no relationship between renal function and darifenacin clearance.
Hepatic Insufficiency: 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. Unbound darifenacin exposure was estimated to be 4.7-fold higher in subjects with moderate hepatic impairment than subjects with normal hepatic function.

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

The recommended starting dose is 7.5 mg daily. The dose may be increased to 15 mg daily, based on individual response, 2 weeks after therapy is initiated. It is taken with or without regards to food. The tablet must be swallowed whole, and not chewed, divided or crushed.
Pediatric Population: The safety and effectiveness of Darifenacin in pediatric patients have not been established.
Geriatric Use: No overall differences in safety and efficacy were observed between patients over 65 years and younger patients <65 years. No dose adjustment is recommended for elderly patients.
Renal impairment: No dose adjustment is required in patients with impaired renal function. However, caution should be exercised when treating this population.
Hepatic impairment: For patients with moderate hepatic impairment (Child-Pugh B) or when co-administered with potent CYP3A4 inhibitors, the daily dose should not exceed 7.5 mg daily. Darifenacin is not recommended for use in patients with severe hepatic impairment (Child-Pugh C).

Darifenacin tablets has been administered in clinical trials at doses up to 75 mg (five times maximum therapeutic dose). The most common adverse reactions seen were dry mouth, constipation, headache, dyspepsia and nasal dryness. However, overdose with darifenacin can potentially lead to severe anticholinergic effects and should be treated accordingly. Therapy should be aimed at reversing the anticholinergic symptoms under careful medical supervision. ECG monitoring is recommended.

Darifenacin tablets are contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, Urinary retention, Gastric retention and Uncontrolled narrow-angle glaucoma.

Risk of Urinary Retention: Darifenacin should be used with caution to patients with clinically significant bladder outflow obstruction due to the risk of urinary retention.
Decreased Gastrointestinal Motility: Like other anticholinergic drugs, Darifenacin may decrease gastrointestinal motility. Darifenacin should be used with caution in patients with gastrointestinal obstructive disorders due to the risk of gastric retention and with other conditions such as severe constipation, ulcerative colitis, and myasthenia gravis.
Controlled Narrow-Angle Glaucoma: Patients with narrow-angle glaucoma should use Darifenacin with caution and if only the benefits outweigh the risks.
Angioedema: In some cases, angioedema occurs after the first dose in the face, lips, tongue and/or larynx as reported with darifenacin use. Angioedema associated with upper airway swelling (tongue, hypopharynx, and larynx) may be life-threatening and discontinuation of therapy is advised. Appropriate measures necessary to ensure patient airway should be promptly provided.
Patients with Hepatic Impairment: The daily dose for patients with moderate hepatic impairment (Child-Pugh B) should not exceed 7.5 mg. Darifenacin has not been studied in patients with severe haptic impairment (Child-Pugh C) and therefore is not recommended for use.
Effects on ability to drive and use machines: As with other antimuscarinic agents, Darifenacin tablets may produce effects such as dizziness, blurred vision, insomnia and somnolence. Patients experiencing these side effects should not drive or use machines. For Darifenacin tablets, these side effects have been reported to be uncommon.

Pregnancy: Pregnancy Category C. Darifenacin should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.
Lactation: Darifenacin is excreted in the milk of rats. It is not known whether darifenacin is excreted in human milk. A risk to the nursing child cannot be excluded.

Very common (may affect more than 1 in 10 people): Dry mouth, constipation.
Common (may affect up to 1 in 10 people): Headache, abdominal pain, indigestion, feeling sick, dry eyes, nasal dryness.
Uncommon (may affect up to 1 in 100 people): Fatigue, accidental injury, facial swelling, high blood pressure, diarrhea, flatulence, inflammation of the mucous membrane of the mouth, increased liver enzymes, swelling, dizziness, sleeplessness, drowsiness, abnormal thinking, runny nose (rhinitis), cough, shortness of breath, dry skin, itching, rash, sweating, visual disturbance including blurred vision, taste disturbance, urinary tract disorder or infection, impotence, discharge and itching in the vagina, bladder pain, inability to empty the bladder.
Potentially Fatal: Angioedema of the face, lips, tongue, or larynx.

CYP3A4 Inhibitors: The systemic exposure of Darifenacin is increased with concomitant use of CYP3A4 Inhibitors. The dose should not exceed 7.5 mg daily when co-administered with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, and nefazadone). No dosage adjustment is required if co-administered with moderate CYP3A4 inhibitors (erythromycin, fluconazole, diltiazem, and verapamil).
CYP2D6 Inhibitors: No dosing adjustment needed in the presence of CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine, and duloxetine).
CYP2D6 Substrates: Caution should be taken when used concomitantly with drugs that are predominantly metabolized by CYP2D6 as they have a narrow therapeutic index (flecainide, thioridazine, and TCAs).
CYP3A4 Substrates: Darifenacin (30 mg daily) has no significant impact on the pharmacokinetics of Midazolam (7.5 mg).
Oral Contraceptives: Darifenacin (10 mg three times daily) had no effect on the pharmacokinetics of the combination oral contraceptives containing levonorgestrel and ethinyl estradiol.
Warfarin: Standard therapeutic prothrombin time monitoring for warfarin should be continued. The effect of warfarin on prothrombin time was not altered when co-administered with darifenacin.
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.
Other Anticholinergic Agents: Anticholinergic Agents may potentially alter the absorption of some concomitantly administered drugs due to effects on gastrointestinal motility. 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.

Store at temperatures not exceeding 30°C. Protect from light.

Drugs for Bladder & Prostate Disorders

G04BD10 - darifenacin ; Belongs to the class of urinary antispasmodics.

Rx