Ditropan XL

Interactions with herbal products have not been established.

Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.

Mean oxybutynin plasma concentrations were approximately two-fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor.

Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., C_max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered.

Concurrent ingestion of an antacid (20 mL of an antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) with DITROPAN XL did not significantly affect the exposure of oxybutynin or desethyloxybutynin.

Concurrent ingestion of a proton pump inhibitor (20 mg omeprazole) with DITROPAN XL did not significantly affect the exposure of oxybutynin or desethyloxybutynin.

The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects.

Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index.

Patients already taking immediate-release oxybutynin chloride tablets may be switched to the nearest equivalent total daily dose of DITROPAN XL. Patients who are not fully continent on immediate-release oxybutynin may tolerate higher doses of DITROPAN XL, administered in 5 mg increments, and may achieve a greater improvement in their incontinence symptoms. Subsequent adjustment to higher or lower doses should be initiated as clinically warranted.

DITROPAN XL (oxybutynin chloride) must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

DITROPAN XL may be administered with or without food.

DITROPAN XL should be taken at a consistent time each day.

In adults, the usual starting dose of DITROPAN XL is 5 or 10 mg once daily at a consistent time each day. Dosage may be adjusted in 5 mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.

The missed dose should be taken as soon as possible. If it is almost time for the next dose, the missed dose should not be taken. Instead, the next scheduled dose should be taken. Doses should not be doubled.

fall.

Additional rare adverse drug reactions reported from worldwide post-marketing experience with DITROPAN XL include:

flushing.

arrhythmia, tachycardia.

The most common adverse events reported were the expected side effects of anticholinergic agents which include, but are not limited to, dry mouth, constipation and blurred vision. The incidence of dry mouth was dose related.

convulsions.

impotence.

Other adverse events have been reported with other oxybutynin chloride formulations: cycloplegia, mydriasis, suppression of lactation and QT interval prolongation.

rash.

hallucinations; psychotic disorder, agitation and memory impairment (very rare).

The safety and efficacy of DITROPAN XL in children have not been established.

The efficacy of DITROPAN XL is similar in patients younger or older than 65 years.

Each round, pink, extended-release tablet, imprinted with “10 XL”, contains: oxybutynin chloride USP 10 mg. Nonmedicinal ingredients: butylated hydroxytoluene, cellulose acetate, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate 80, sodium chloride, synthetic iron oxides and titanium dioxide. Bottles of 100 and 500.

Each round, pale yellow, extended-release tablet, imprinted with “5 XL”, contains: oxybutynin chloride USP 5 mg. Nonmedicinal ingredients: butylated hydroxytoluene, cellulose acetate, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate 80, sodium chloride, synthetic iron oxides and titanium dioxide. Bottles of 100 and 500.

DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice in the semipermeable membrane on the drug-layer side of the tablet. In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to go into suspension and the push layer to expand. This expansion pushes the suspended drug out through the orifice. The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility. The function of DITROPAN XL depends on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

DITROPAN XL should be used with caution in patients with renal disease.

The pharmacokinetics of DITROPAN XL are similar in patients younger or older than 65 years.

DITROPAN XL should be administered with caution to patients with clinically significant bladder obstruction because of the risk of urinary retention (see Contraindications).

DITROPAN XL should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see Contraindications).

Administration of DITROPAN XL to patients with severe ulcerative colitis may precipitate toxic megacolon.

DITROPAN XL, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis, and intestinal atony (see Contraindications).

DITROPAN XL should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

DITROPAN XL is associated with anticholinergic central nervous system (CNS) effects (see Adverse Reactions, Post-Market Adverse Drug Reactions). Patients should be monitored for signs of anticholinergic CNS effects (e.g. confusion, sedation, anxiety, nervousness, hallucinations, psychotic disorder, agitation and memory impairment), particularly in the first few months after beginning treatment or increasing the dose. If a patient experiences anticholinergic CNS effects, drug discontinuation or dose reduction should be considered.

DITROPAN XL, like other anticholinergic drugs, should be administered with caution to patients with pre-existing dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

DITROPAN XL should be used with caution in patients with myasthenia gravis.

As with any other nondeformable material, caution should be used when administering DITROPAN XL (oxybutynin chloride) to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations.

Patients should be informed that DITROPAN XL should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Patients should be informed that, when administered in the presence of high environmental temperature, anticholinergics such as DITROPAN XL can cause heat prostration (fever and heat stroke due to decreased sweating).

Because anticholinergic agents such as DITROPAN XL may produce drowsiness (somnolence) or blurred vision, patients should be advised to exercise caution.

Alcohol or other sedative drugs may enhance the drowsiness caused by anticholinergic agents such as DITROPAN XL.

The safety and efficacy of DITROPAN XL in children have not been established.

The safety of DITROPAN XL administration to women who are or who may become pregnant has not been established. Therefore, DITROPAN XL should not be given to pregnant women, unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DITROPAN XL is administered to a nursing woman.

Although there are no clinical trial or post-marketing data to confirm the potential for DITROPAN XL to aggravate certain pre-existing cardiac conditions, this product is in the class of anticholinergic medications which are known to have cardiac effects. Prescribers should therefore use caution when prescribing DITROPAN XL to patients with coronary heart disease, congestive heart failure, cardiac arrhythmias, tachycardia or hypertension.

Although no formal QT studies have been conducted for oxybutynin formulations, there have been very rare reports of QT interval prolongation with oxybutynin use. Newer antimuscarinic agents used in the treatment of urinary incontinence have been reported to prolong the QT/QTc interval of the electrocardiogram. Some drugs that cause QT/QTc prolongation may increase the risk of the rare, but serious ventricular arrhythmia—torsades de pointes. Patients at risk for QT/QTc prolongation, such as those with clinically relevant heart failure, long QT syndrome, recent significant hypokalemia, or receiving other drugs known to prolong QT/QTc, should be appropriately monitored when receiving oxybutynin. Patients who develop prolonged QT/QTc or symptoms of possible arrhythmia such as dizziness, palpitations, or fainting should be evaluated electrocardiographically and for electrolyte disturbances.

DITROPAN XL should be used with caution in patients with hepatic disease.

Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral administration. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride.

Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine.

There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of DITROPAN XL.

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following DITROPAN XL administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with immediate-release oxybutynin chloride tablets.

Several studies have assessed oxybutynin's urodynamic effect (increase in bladder capacity) as measured by cystometry. The onset of action was rapid (within 1 h) following 5 mg oral oxybutynin chloride. The effect was seen up to 10 hours post-drug administration. Intravesical administration of oxybutynin chloride has also shown increase in bladder capacity within 1-1.5 h after drug instillation.

The pharmacokinetics of DITROPAN XL were not evaluated in individuals younger than 18 years of age. The pharmacokinetics of immediate-release oxybutynin chloride in children (5-13 years) are similar to those in adults.

Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (C_max and AUC) following administration of DITROPAN XL are dose proportional.

The pharmacokinetics of DITROPAN XL are similar in patients younger or older than 65 years. In frail elderly patients treated with immediate-release oxybutynin chloride, C_max and AUC values were approximately twice those in elderly patients or young adult volunteers.

There is no experience with the use of DITROPAN XL in patients with hepatic insufficiency.

DITROPAN XL (oxybutynin chloride) is a tertiary amine anticholinergic agent which exerts antimuscarinic as well as direct antispasmodic action on smooth muscle. In addition to its smooth muscle relaxing effects, oxybutynin chloride exerts an analgesic and a local anesthetic effect.

Oxybutynin chloride relaxes bladder smooth muscle. In patients with uninhibited neurogenic and reflex neurogenic bladder, cystometric studies have demonstrated that oxybutynin chloride increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. DITROPAN XL thus decreases urgency and frequency of both incontinent episodes and voluntary urination.

Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of DITROPAN XL.

There is no experience with the use of DITROPAN XL in patients with renal insufficiency.

Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPAN XL dosing, with no drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters. The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.