Ditropan XL

Mechanism of Action

Exerts antispasmodic and antimuscarinic effects on smooth muscle; delays desire to void, increases bladder capacity, and decreases uninhibited contraction; decreases frequency and urgency

Absorption

Bioavailability: 6% (~1.5-2 times higher for extended-release)

Onset: 30-60 min

Peak effect: 3-6 hr

Duration: 6-10 hr

Peak plasma time: <1 hr (immediate-release); 12 hr (extended release)

Peak plasma concentration: Immediate-release, 3.6 ng/mL (R-) and 7.8 ng/mL (S-); extended-release, 1 ng/mL (R-) and 1.8 ng/mL (S-)

Distribution

Vd: 193 L

Metabolism

Metabolized in liver and gut by CYP3A4; converted to active metabolite N-desethyloxybutynin (DEO) by GI metabolic pathways, which are bypassed in transdermal delivery, resulting in lower DEO ratio

Metabolites: DEO (active)

Elimination

Half-life: 2-3 hr (immediate-release); 12-13 hr (extended-release)

Excretion: Urine

In the U.S.

• Ditropan
• Ditropan XL

Available Dosage Forms:

• Tablet, Extended Release
• Tablet
• Syrup

Therapeutic Class: Urinary Antispasmodic

Pharmacologic Class: Oxybutynin

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Eye pain
• skin rash or hives

Get emergency help immediately if any of the following symptoms of overdose occur:

• Clumsiness or unsteadiness
• confusion
• convulsions
• dizziness
• drowsiness (severe)
• fainting
• fast, slow, or irregular heartbeat
• fever
• flushing or redness of the face
• hallucinations (seeing, hearing, or feeling things that are not there)
• troubled breathing
• unusual excitement, nervousness, restlessness, or irritability

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• decreased sweating
• diarrhea
• difficulty having a bowel movement (stool)
• drowsiness
• dryness of the eyes, mouth, nose, or throat
• heartburn
• indigestion
• runny nose
• stomach discomfort, upset, or pain

• Blurred vision
• decreased flow of breast milk
• decreased sexual ability
• difficulty in swallowing
• feeling of warmth or heat
• headache
• increased sensitivity of the eyes to light
• nausea or vomiting
• trouble with sleeping
• unusual tiredness or weakness

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• decreased interest in sexual intercourse
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• rapid weight gain
• tingling of the hands or feet
• unusual weight gain or loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat an overactive bladder.
• It may be given to you for other reasons. Talk with the doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a urinary tract infection (UTI) like blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
• Very bad dizziness or passing out.
• Feeling confused.
• Hallucinations (seeing or hearing things that are not there).
• Feeling agitated.
• Feeling very sleepy.
• Mood changes.
• Fever.
• Not sweating during activities or in warm temperatures.
• Very bad headache.
• Seizures.
• Trouble passing urine.
• A fast heartbeat.
• A heartbeat that does not feel normal.
• Fast breathing.
• Very hard stools (constipation).
• Very bad belly pain.

Ditropan XL® extended-release tablets are available as 5, 10 and 15 mg tablets for oral use:

5 mg: Pale yellow, round, tablet with "5 XL" printed on one side with black ink.

10 mg: Pink, round, tablet with "10 XL" printed on one side with black ink.

15 mg: Gray, round, tablet with "15 XL" printed on one side with black ink.

Angioedema

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6)]. A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Ditropan XL® affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Ditropan XL® should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

Ditropan XL® should be used with caution in patients with Parkinson's disease due to the risk of aggravation of symptoms.

Worsening of Symptoms of Myasthenia Gravis

Ditropan XL® should be used with caution in patients with myasthenia gravis due to the risk of aggravation of symptoms.

Worsening of Symptoms of Decreased Gastrointestinal Motility in Patients with Autonomic Neuropathy

Ditropan XL® should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility.

Urinary Retention

Ditropan XL® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].

Gastrointestinal Adverse Reactions

Ditropan XL® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)].

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.

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.

As with any other nondeformable material, caution should be used when administering Ditropan XL® to patients with preexisting 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.

Ditropan XL® (oxybutynin chloride) is an antispasmodic, muscarinic antagonist. Each Ditropan XL® extended-release tablet contains 5 mg, 10 mg, or 15 mg of oxybutynin chloride USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin chloride is administered as a racemate of R- and S-enantiomers.

Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is C22H31NO3•HCl.

Its structural formula is:

Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily soluble in water and acids, but relatively insoluble in alkalis.

Ditropan XL® also contains the following inert ingredients: butylated hydroxytoluene, cellulose acetate, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate 80, propylene glycol, sodium chloride, synthetic iron oxides and titanium dioxide.

System Components and Performance

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the maximum human exposure, based on a human equivalent dose taking into account normalization of body surface area.

Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella typhimurium test systems.

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility.