DARITOR-15

Indications

• Overactive bladder
• Urinary incontinence
• Urgency urinary incontinence

Dosage

Children: The safety and efficacy of darifenacin in children have not been established; refer to the BNF for Children for appropriate management of paediatric conditions.

Adults: The typical adult starting dose is 7.5 mg once daily, which may be increased to 15 mg once daily based on individual response and tolerability.

Mechanism of action

Darifenacin selectively antagonizes the muscarinic M3 receptor, which is involved in the contraction of human bladder smooth muscle, saliva production, and iris sphincter function. By blocking these receptors, darifenacin reduces the activity of the bladder, leading to decreased urgency and frequency of urination.

Pharmacodynamics

Darifenacin is a competitive muscarinic receptor antagonist with a markedly greater affinity for the M3 receptor compared to other muscarinic receptors. It has 9 and 12-fold greater affinity for M3 than for M1 and M5 respectively, and 59-fold greater for M3 compared to M2 and M4. This specificity allows for targeted action in reducing bladder contractions and associated symptoms of overactive bladder, while minimizing effects on other cholinergically mediated functions.

Pharmacokinetics

Darifenacin is well absorbed after oral administration, with peak plasma concentrations occurring approximately 7 hours post-dose. It undergoes extensive hepatic metabolism, primarily via CYP3A4, resulting in several active metabolites. The elimination half-life is approximately 13 to 19 hours, allowing for once-daily dosing. Excretion is primarily via the feces, with a smaller fraction eliminated renally.

Contra-indications

• Acute myocardial infarction
• Narrow-angle glaucoma
• Severe urinary retention
• Severe gastrointestinal obstruction
• Hypersensitivity to darifenacin or any excipients

Adverse effects

• Dry mouth
• Constipation
• Abnormal vision
• Dizziness
• Fatigue
• Nausea
• Headache
• Urinary retention
• Tachycardia

Interactions

• Ciclosporin (severe - increases exposure)
• Cenobamate (moderate - decreases exposure)
• Tucatinib (moderate - increases exposure)
• Dronedarone (unknown - increases exposure)
• Flecainide (unknown - increases concentration)
• Fluconazole (unknown - increases exposure)
• Clozapine (unknown - additive effect)
• Bupropion (unknown - increases exposure)
• Diltiazem (unknown - increases exposure)
• Verapamil (unknown - increases exposure)

Precautions

• Use with caution in elderly patients
• Use cautiously in patients with cognitive impairment
• Monitor for signs of urinary retention in patients with prostatic hyperplasia
• Consider risk of antimuscarinic toxicity when used with other antimuscarinic drugs

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if clearly needed.

Breast-feeding

It is not known whether darifenacin is excreted in human milk. Caution is advised.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Darifenacin extended-release tablets

Indications

• Respiratory conditions (e.g., asthma, chronic obstructive pulmonary disease)
• Cough (e.g., as an antitussive)
• Anxiety and sleep disorders (when associated with specific formulations)

Dosage

Children: Refer to the BNF for Children for appropriate dosing information, as it is determined based on weight and age for the specific formulation.

Adults: Refer to the specific product monograph for dosing information, as it varies based on the drug formulation and indication.

Mechanism of action

Hydrobromides often act as competitive antagonists or agonists at specific receptor sites, depending on the drug involved. The exact mechanism can vary widely, but many hydrobromide-containing drugs modulate neurotransmitter activity, impacting various pathways in the body such as those involved in the central nervous system or respiratory function. The metabolic pathways include Phase I reactions primarily mediated by cytochrome P450 enzymes, which facilitate the functionalization and clearance of these compounds.

Pharmacodynamics

The pharmacodynamics of hydrobromide salts are largely determined by the specific drug they are associated with. Generally, hydrobromides may exhibit effects such as sedation, bronchodilation, or antitussive actions. The efficacy and adverse effects are influenced by the drug's receptor selectivity, affinity, and the pharmacological properties inherent to the parent compound.

Pharmacokinetics

Hydrobromides typically exhibit variable pharmacokinetic profiles depending on the specific drug formulation. They are generally absorbed rapidly following oral administration, with peak plasma concentrations occurring within a few hours. Metabolism primarily occurs in the liver through cytochrome P450 enzymes, particularly CYP2E1, among others. The elimination half-life varies but is often in the range of several hours, allowing for once or twice-daily dosing in many formulations. Excretion is usually via the kidneys, with metabolites being eliminated in urine.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if clearly needed and the potential benefits justify the potential risks to the fetus.

Breast-feeding

Caution is advised; consider the importance of the drug to the mother against potential risks to the breastfeeding infant.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Mechanism of action

Darifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function.

Pharmacodynamics

Darifenacin is a competitive muscarinic receptor antagonist. <i>In vitro</i> 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). 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. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs.