Usage
Darifenacin is prescribed for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. It is pharmacologically classified as a competitive muscarinic receptor antagonist, specifically an M3 selective antagonist. Darifenacin works by blocking the action of acetylcholine at M3 muscarinic receptors in the bladder, reducing detrusor muscle contractions and thus decreasing OAB symptoms.
Alternate Names
The International Nonproprietary Name (INN) is darifenacin. A common brand name is Enablex. Emselex is another brand name used internationally.
How It Works
Pharmacodynamics: Darifenacin competitively binds to muscarinic M3 receptors located on the detrusor smooth muscle of the bladder. This inhibits acetylcholine-mediated bladder contractions, leading to increased bladder capacity and reduced OAB symptoms like urgency, frequency, and urge incontinence.
Pharmacokinetics:
- Absorption: Darifenacin is well-absorbed after oral administration, reaching peak plasma concentration in approximately 6 to 8 hours. Food does not significantly affect its absorption.
- Metabolism: Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 in the liver. This information is crucial for understanding potential drug interactions.
- Elimination: Excreted primarily in feces and to a smaller extent in urine. The elimination half-life is around 14-19 hours.
Mode of Action: Darifenacin’s mechanism of action involves competitive antagonism of the M3 muscarinic receptors on bladder detrusor muscle cells. By binding to these receptors, it blocks the binding of the neurotransmitter acetylcholine. This reduces the activation of the M3 receptors and the subsequent intracellular signaling pathways responsible for detrusor muscle contraction, thereby increasing bladder capacity and reducing OAB symptoms.
Dosage
Standard Dosage
Adults:
Initial dose: 7.5 mg orally once daily. The dose may be increased to 15 mg orally once daily after 2 weeks if there is insufficient response, as long as the 7.5 mg dose was well-tolerated.
Children:
Safety and efficacy in children have not been established. Darifenacin is not recommended for pediatric use.
Special Cases:
- Elderly Patients: The initial dose is 7.5 mg orally once a day. Increase to 15mg as needed and tolerated. Close monitoring is recommended.
- Patients with Renal Impairment: No dosage adjustment is necessary.
- Patients with Hepatic Dysfunction:
- Mild impairment (Child-Pugh A): No dose adjustment is required, but use with caution.
- Moderate impairment (Child-Pugh B): The maximum dose is 7.5 mg once daily.
- Severe impairment (Child-Pugh C): Darifenacin is not recommended.
- Patients with Comorbid Conditions: Exercise caution in patients with gastrointestinal obstructive disorders, such as pyloric stenosis, and severe constipation. Close monitoring is advised.
Clinical Use Cases
Darifenacin is specifically indicated for overactive bladder. It is not indicated for use in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
For patients taking potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin), the maximum daily dose is 7.5 mg.
Side Effects
Common Side Effects
- Dry mouth
- Constipation
- Blurred vision
- Headache
- Nausea
- Dyspepsia (indigestion)
- Urinary tract infection
Rare but Serious Side Effects
- Angioedema (swelling of the face, lips, tongue, or throat)
- Allergic reactions (hives, difficulty breathing)
- Urinary retention
- Worsening of gastrointestinal conditions
- Hallucinations
- Confusion
Long-Term Effects
Limited information is available on long-term effects of darifenacin. Monitor patients regularly for any new or worsening symptoms.
Adverse Drug Reactions (ADR)
Angioedema, severe allergic reactions, urinary retention, and significant gastrointestinal adverse events represent clinically significant ADRs. Immediate discontinuation of the drug and appropriate medical intervention are necessary.
Contraindications
- Urinary retention
- Gastric retention
- Uncontrolled narrow-angle glaucoma
- Hypersensitivity to darifenacin
Drug Interactions
- Potent CYP3A4 Inhibitors: (e.g., ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin) can increase darifenacin plasma concentrations.
- Moderate CYP3A4 Inhibitors: (e.g., erythromycin, fluconazole, grapefruit juice): Dosage adjustment may be needed.
- Potent CYP2D6 Inhibitors: (e.g., paroxetine, terbinafine, quinidine) Dosage adjustment may be needed.
- Digoxin: Darifenacin can increase digoxin exposure. Therapeutic drug monitoring of digoxin is recommended.
- Antimuscarinic Agents: Concurrent use may enhance anticholinergic effects.
Pregnancy and Breastfeeding
- Pregnancy: Darifenacin is Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Breastfeeding: It is unknown if darifenacin is excreted in human milk. Use caution when administering to breastfeeding women.
Drug Profile Summary
- Mechanism of Action: Competitive muscarinic M3 receptor antagonist, reducing detrusor muscle contractions.
- Side Effects: Dry mouth, constipation, blurred vision, headache, nausea, dyspepsia, urinary tract infection; rarely angioedema, allergic reactions, urinary retention.
- Contraindications: Urinary/gastric retention, uncontrolled narrow-angle glaucoma, hypersensitivity.
- Drug Interactions: Potent CYP3A4 and moderate CYP3A4 inhibitors, potent CYP2D6 inhibitors, digoxin, antimuscarinic agents.
- Pregnancy & Breastfeeding: Category C; unknown if excreted in human milk; caution advised.
- Dosage: Adults: 7.5 mg once daily, may increase to 15 mg; dosage adjustments needed in moderate hepatic impairment and with potent CYP3A4 inhibitors.
- Monitoring Parameters: Monitor for efficacy, side effects, and signs of urinary retention.
Popular Combinations
Darifenacin is typically used as monotherapy. Combining it with other antimuscarinics may increase side effects. No specific combinations are routinely recommended.
Precautions
- General Precautions: Assess for underlying medical conditions, including outflow obstruction and gastrointestinal disorders.
- Specific Populations: Caution in pregnancy and breastfeeding, not recommended for pediatric use. Caution in those with moderate hepatic impairment and elderly individuals.
- Lifestyle Considerations: Caution patients about potential for blurred vision and its impact on activities like driving. Advise patients about the importance of maintaining adequate hydration due to the risk of dry mouth.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Darifenacin?
A: Adults: Initial dose is 7.5 mg orally once a day. May increase to 15 mg daily after 2 weeks if needed. Dosage adjustments are necessary for patients with moderate hepatic impairment or those taking potent CYP3A4 inhibitors (maximum 7.5 mg daily). Not recommended for pediatric use.
Q2: What is the mechanism of action of Darifenacin?
A: Darifenacin is a competitive M3 muscarinic receptor antagonist. It blocks the action of acetylcholine at these receptors in the bladder, reducing detrusor muscle contractions and thus alleviating OAB symptoms.
Q3: What are the common side effects of Darifenacin?
A: Common side effects include dry mouth, constipation, blurred vision, headache, nausea, dyspepsia, and urinary tract infection.
Q4: What are the contraindications for using Darifenacin?
A: Darifenacin is contraindicated in patients with urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, and hypersensitivity to the drug.
Q5: How should Darifenacin be administered?
A: Darifenacin should be administered orally once daily, with or without food. The tablets should be swallowed whole and not crushed, chewed, or divided.
Q6: What are the potential drug interactions with Darifenacin?
A: Darifenacin can interact with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole), potent CYP2D6 inhibitors (e.g., paroxetine), moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole), digoxin and other antimuscarinic agents.
Q7: Can Darifenacin be used during pregnancy?
A: Darifenacin is Pregnancy Category C. It should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
Q8: Can Darifenacin be used during breastfeeding?
A: It is unknown if darifenacin passes into human breast milk. Caution should be exercised when administering to breastfeeding women.
Q9: What should I monitor in patients taking Darifenacin?
A: Monitor for treatment efficacy (reduction in OAB symptoms), adverse events (especially dry mouth, constipation, blurred vision), and signs of urinary retention. Periodically reassess the need for continued therapy.
Q10: Are there any specific precautions for elderly patients taking Darifenacin?
A: Start elderly patients on a lower dose (7.5 mg) and monitor closely for efficacy and tolerability. Titrate to 15 mg cautiously as needed and tolerated. Pay close attention to cognitive function and potential for anticholinergic side effects.
