Oxybutynin-transdermal

If you are taking the over-the-counter product to self treat, read all directions on the product package before taking this medication. If your doctor has prescribed this medication, read the Patient Information Leaflet if available from your pharmacist before you start using oxybutynin and each time you get a refill. If your doctor has prescribed this medication, take it as directed. If you have any questions, consult your doctor or pharmacist.Apply one patch to your skin as directed by your doctor, usually every 3 to 4 days. If you are self-treating, apply one patch to your skin every 4 days. Follow the dosing schedule carefully.Remember to remove the old patch before applying a new patch.Apply the new patch to a different area of skin to prevent skin irritation. Do not apply a patch to the same area within 7 days.Before applying the patch, wash the area you will be using for the patch gently and thoroughly with soap and water. Rinse and dry with a clean dry towel.Do not open the sealed pouch container until you are ready to apply the patch. Open the pouch and remove the protective liner from the patch to expose the adhesive. Apply the patch to an area of clean, dry, smooth skin on the stomach (abdomen), hips, or buttocks. Press firmly to be sure the patch stays on. Apply to an area of skin that is under clothing and protected from sunlight. Avoid applying the patch on your waistline, since tight clothing may rub the patch off, or on areas where sitting may loosen it. Do not apply the patch to oily/red/cut/irritated/broken skin or skin covered with lotion or powder. Do not cut the patch into smaller sizes unless otherwise directed.Contact with water (such as swimming, bathing) will not change the way the patch works. Avoid rubbing the patch area during these activities.If the area around the patch becomes red, itchy, or irritated, try a new site. If irritation continues or becomes worse, tell your doctor promptly.If the patch falls off, reapply it or apply a new patch to a new area and continue on your same schedule.When it is time to apply a new patch, remove the old one and dispose of it properly in the trash. Fold the sticky sides of the patch together and throw it away where it cannot be accidentally worn or swallowed by others, especially a child or pet.The length of treatment is determined by your doctor, who may have you stop using the medication sometimes to see if you still need to use it.Use this medication regularly to get the most benefit from it. To help you remember, try to always change the patch on the same 2 days of the week. Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of side effects will increase.Tell your doctor if your condition persists or worsens. If you are self-treating, tell your doctor if your condition does not improve after 2 weeks. If you think you may have a serious medical problem, get medical help right away.

Skin redness/itching/irritation at the application site, dry mouth, drowsiness, dizziness, blurred vision, headache, weakness, nausea or constipation may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.To relieve dry mouth, suck (sugarless) hard candy or ice chips, chew (sugarless) gum, drink water or use a saliva substitute.To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. If you become constipated while using this drug, consult your pharmacist for help in selecting a laxative.If your doctor has directed you to use this medication, remember that he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: vision problems, difficulty urinating, signs of kidney infection (such as burning/painful/frequent urination, lower back pain), fast/irregular heartbeat, mental/mood changes (such as confusion), fever, flushed/hot/dry skin.Get medical help right away if you have any very serious side effects, including: eye pain, signs of stomach/intestinal blockage (such as severe stomach pain, persistent nausea/vomiting, severe constipation).A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Before using oxybutynin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: active internal bleeding, blockage/slowed movement of the stomach/intestines (such as gastric retention, paralytic ileus), certain bladder problems (urinary retention, bladder outflow obstruction, stress incontinence), glaucoma (narrow-angle), a certain muscle disease (myasthenia gravis), liver disease, high blood pressure, heart problems (such as coronary artery disease, congestive heart failure, arrhythmias), stomach/intestinal disease (such as acid reflux, hiatal hernia, ulcerative colitis, intestinal atony), kidney disease, loss of mental abilities (dementia), enlarged prostate, overactive thyroid (hyperthyroidism), a certain nervous system disorder (autonomic neuropathy).In addition, before you self treat with this medication, tell your doctor if you have any of these signs of a more serious condition: signs of a bladder/kidney infection (such as burning/pain when you urinate, fever, pink/bloody urine), signs of diabetes (such as increased thirst, dizziness/fainting, vision changes, change in the amount of urine, wounds that are slow to heal).This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).This medication may decrease your ability to sweat, making you more likely to get heat stroke. Avoid activities that may cause you to overheat (such as doing strenuous work/exercise in hot weather, using hot tubs). When the weather is hot, drink plenty of fluids and dress lightly. If you become overheated, promptly seek cooler shelter and stop exercising. Get medical help right away if you develop a fever, mental/mood changes, headache, or dizziness.If you are going to have an MRI test, tell testing personnel that you are using this patch. Some patches may contain metals that can cause serious burns during an MRI. Ask your doctor whether you will need to remove your patch before the test and apply a new patch afterward, and how to do so properly.Older adults may be more sensitive to the side effects of this drug, especially drowsiness, confusion, constipation, trouble urinating. Drowsiness and confusion can increase the risk of falling.Tell your doctor if you are pregnant before using this medication.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Mechanism Of Action

The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride. Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. In patients with conditions characterized by involuntary detrusor contractions, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction.

Oxybutynin is a racemic (50:50) mixture of R-and S-isomers. Antimuscarinic activity resides predominantly in the R-isomer. The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. The average daily dose of oxybutynin absorbed from the 39 cm² OXYTROL system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm² surface area, was obtained from analysis of residual oxybutynin content of systems worn over a continuous 4-day period during 303 separate occasions in 76 healthy volunteers. Following application of the first OXYTROL 3.9 mg/day system, oxybutynin plasma concentrations increase for approximately 24 to 48 hours, reaching average maximum concentrations of 3 to 4 ng/mL. Thereafter, steady concentrations are maintained for up to 96 hours. Absorption of oxybutynin is bioequivalent when OXYTROL is applied to the abdomen, buttocks, or hip. Average plasma concentrations measured during a randomized, crossover study of the three recommended application sites in 24 healthy men and women are shown in Figure 2.

Figure 2: Average plasma oxybutynin concentrations (Cp) in 24 healthy male and female volunteers during single-dose application of OXYTROL 3.9 mg/day to the abdomen, buttock, and hip (System removal at 96 hours).

Steady-state conditions are reached during the second OXYTROL application. Average steady-state plasma concentrations were 3.1 ng/mL for oxybutynin and 3.8 ng/mL for Ndesethyloxybutynin (Figure 3). Table 3 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of OXYTROL.

Figure 3: Average (SEM) steady-state oxybutynin and N-desethyloxybutynin plasma concentrations (Cp) measured in 13 healthy volunteers following the second transdermal system application in a multiple-dose, randomized, crossover study.

Table 3: Mean (SD) oxybutynin pharmacokinetic parameters from single and multiple dose studies in healthy men and women volunteers after application of OXYTROL on the abdomen.

Dosing	Oxybutynin
	Cmax (SD) (ng/mL)	Tmax1 (hr)	Cavg (SD) (ng/mL)	AUC (SD) (ng/mLxh)
Single	3.0 (0.8)	48	-	245 (59)2
	3.4 (1.1)	36	-	279 (99)2
Multiple	6.6 (2.4)	10	4.2 (1.1)	408 (108)3
	4.2 (1.0)	28	3.1 (0.7)	259 (57)4
1Tmax given as median 2AUCinf 3AUC0-96 4AUC0-84

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin chloride.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin, which is pharmacologically active.

After oral administration of oxybutynin, pre-systemic first-pass metabolism results in an oral bioavailability of approximately 6% and higher plasma concentration of the N-desethyl metabolite compared to oxybutynin (see Figure 4). The plasma concentration area under the time-concentration curve (AUC) ratio of N-desethyl metabolite to parent compound following a single 5 mg oral dose of oxybutynin chloride was 11.9:1.

Transdermal administration of oxybutynin bypasses first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite (see Figure 4). Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The resulting plasma concentration AUC ratio of N-desethyl metabolite to parent compound following multiple OXYTROL applications was 1.3:1.

Figure 4: Average plasma concentrations (Cp) measured after a single, 96-hour application of the OXYTROL 3.9 mg/day system (AUCinf /96) and a single, 5 mg, oral immediate-release dose of oxybutynin chloride (AUCinf /8) in 16 healthy male and female volunteers.

Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. Following removal of OXYTROL, plasma concentrations of oxybutynin and Ndesethyloxybutynin decline with an apparent half-life of approximately 7 to 8 hours.

Excretion

Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.

Specific Populations

Renal Impairment: The effects of renal impairment on the pharmacokinetics of oxybutynin and N-desethyloxybutynin are not known.

Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of oxybutynin and N-desethyloxybutynin are not known.

Geriatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were similar in older and younger patients .

Pediatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were not evaluated in individuals younger than 18 years of age.

Gender: There were no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following application of OXYTROL.

Race: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of OXYTROL. Japanese volunteers demonstrated a somewhat lower metabolism of oxybutynin to N-desethyloxybutynin compared to Caucasian volunteers.

Clinical Studies

The efficacy and safety of OXYTROL were evaluated in patients with urge urinary incontinence in two controlled studies and one open-label extension. Study 1 was a placebo controlled study, comparing the safety and efficacy of OXYTROL at dose levels of 1.3, 2.6, and 3.9 mg/day to placebo in 520 patients. Open-label treatment was available for patients completing the study. Study 2 was a study comparing the safety and efficacy of OXYTROL 3.9 mg/day versus active and placebo controls in 361 patients.

Study 1 was a randomized, double-blind, placebo-controlled, parallel group study of three dose levels of OXYTROL conducted in 520 patients. The 12-week double-blind treatment included an OXYTROL dose of 3.9 mg/day or matching placebo. An open-label, dose titration treatment extension allowed continued treatment for up to an additional 40 weeks for patients completing the double-blind period. The majority of patients were Caucasian (91%) and female (92%) with a mean age of 61 years (range, 20 to 88 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of ≥ 10 per week, and ≥ 8 micturitions per day. The patient's medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Approximately 80% of patients had no prior pharmacological treatment for incontinence. Changes in weekly incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 4.

Table 4: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with OXYTROL 3.9 mg/day or placebo for 12 weeks (Study 1).

Parameter	Placebo (N = 127)		OXYTROL 3.9 mg/day (N = 120)
	Mean (SD)	Median	Mean (SD)	Median
Weekly Incontinence Episodes
Baseline	37.7 (24.0)	30	34.3 (18.2)	31
Reduction	19.2 (21.4)	15	21.0 (17.1)	19
p value vs. placebo	-		* 0.0265
Daily Urinary Frequency
Baseline	12.3 (3.5)	11	11.8 (3.1)	11
Reduction	1.6 (3.0)	1	2.2 (2.5)	2
p value vs. placebo	-		* 0.0313
Urinary Void Volume (mL)
Baseline	175.9 (69.5)	166.5	171.6 (65.1)	168
Increase	10.5 (56.9)	5.5	31.6 (65.6)	26
p value vs. placebo	-	* * 0.0009
*Comparison significant if p < 0.05 **Comparison significant if p ≤ 0.0167

Study 2 was a randomized, double-blind, study of OXYTROL 3.9 mg/day versus active and placebo controls conducted in 361 patients. The 12-week double-blind treatment included an OXYTROL dose of 3.9 mg/day, an active comparator, and placebo. The majority of patients were Caucasian (95%) and female (93%) with a mean age of 64 years (range, 18 to 89 years). Entry criteria required that all patients have urge or mixed incontinence (with a predominance of urge) and had achieved a beneficial response from the anticholinergic treatment they were using at the time of study entry. The average duration of prior pharmacological treatment was greater than 2 years. The patient's medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Changes in daily incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 5.

Table 5: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with OXYTROL 3.9 mg/day or placebo for 12 weeks (Study 2).

Parameter	Placebo (N = 117)		OXYTROL 3.9 mg/day (N = 121)
	Mean (SD)	Median	Mean (SD)	Median
Daily Incontinence Episodes
Baseline	5.0 (3.2)	4	4.7 (2.9)	4
Reduction	2.1 (3.0)	2	2.9 (3.0)	3
p value vs. placebo	-		0.0137*
Daily Urinary Frequency
Baseline	12.3 (3.3)	12	12.4 (2.9)	12
Reduction	1.4 (2.7)	1	1.9 (2.7)	2
p value vs. placebo	-		* 0.1010
Urinary Void Volume (mL)
Baseline	175.0 (68.0)	171.0	164.8 (62.3)	160
Increase	9.3 (63.1)	5.5	32.0 (55.2)	24
p value vs. placebo	-	* 0.0010
*Comparison significant if p < 0.05

In a controlled clinical trial of skin sensitization, none of the 103 test subjects demonstrated skin hypersensitivity to OXYTROL.

Adhesion

Adhesion was periodically evaluated during the pivotal studies. Of the 4,746 OXYTROL evaluations in the trials, 20 (0.4%) were observed at clinic visits to have become completely detached and 35 (0.7%) became partially detached during routine clinic use. Similar to the pharmacokinetic studies, > 98% of the systems evaluated in the pivotal studies were assessed as being ≥ 75% attached and thus would be expected to perform as anticipated.

If you forget to change a patch on your scheduled day, remove and replace the patch as soon as you remember. Wear the patch until your next regular patch-changing day. Do not change your schedule, even if you wear the new patch for less that 3 days.

Do not apply two patches at the same time to make up the missed dose.

Oxybutynin can cause blurred vision, drowsiness, or dizziness. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Drinking alcohol can increase certain side effects of oxybutynin.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Drink plenty of fluids to keep yourself hydrated while you are using oxybutynin transdermal.

Do not expose the oxybutynin transdermal transdermal patch to sunlight. It should be worn under clothing.

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:

More common

• Bladder pain
• blistering, crusting, irritation, itching, or reddening of the skin
• bloody or cloudy urine
• burning, skin rash, swelling, or soreness at the application site
• cracked, dry, or scaly skin
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain
• redness, pain, itching, or irritation at the application site
• unusually warm skin

Less common

• Abdominal or stomach pain
• diarrhea
• loss of appetite
• nausea
• weakness

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:

More common

• Body aches or pain
• chills
• cough
• difficulty with breathing
• ear congestion
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat

Less common

• Back pain
• bloated
• changes in vision
• constipation
• excess air or gas in the stomach or intestines
• full feeling
• muscle aches
• passing gas
• sleepiness or unusual drowsiness

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.

This medication is used to treat an overactive bladder. Oxybutynin improves your ability to control your urination by relaxing the muscles in the bladder. It helps to reduce leaking of urine, feelings of needing to urinate right away, and frequent trips to the bathroom. This medication belongs to the class of drugs known as antispasmodics.

How to use Oxybutynin Gel In Metered-Dose Pump

Read the Patient Information Leaflet provided by your pharmacist before you start using oxybutynin and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Using mild soap and water, wash your hands and the area of skin where the gel will be applied. Allow the area to dry completely before applying.

Prime the pump before using for the first time as directed by the Patient Information Leaflet.

Apply the gel to an area of skin on the shoulders/upper arms, abdomen, or thigh as directed by your doctor, usually once daily. Do not apply to the breasts or groin. Do not apply the gel to open sores, scars, tattoos, areas with a rash, recently shaved, irritated, or oily skin. Gently rub into your skin until it dries. Do not continue rubbing after the gel has dried. This medication may be used before or after applying sunscreen.

Oxybutynin gel is for use on the skin only. Avoid getting the gel in the eyes, nose, or mouth. Wash your hands with soap and water after applying this medication. If the gel gets in your eyes, rinse your eyes right away with warm, clean water.

You may apply the gel to a different area of skin with each dose to reduce the chances of having skin reactions at the application site.

Allow this medication to dry completely on the skin before getting dressed. Cover the area to prevent spreading the medication through skin contact. If contact occurs, immediately wash the area with soap and water. After applying the gel, wait 1 hour before exercising, bathing, showering, swimming, or getting the application area wet, to make sure all the drug is absorbed. This medication contains alcohol. Avoid smoking and open flame until the gel has dried.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time each day.

Tell your doctor if your condition persists or worsens.

Skin redness/itching/swelling at the application site, dry mouth, constipation, dizziness, drowsiness, or blurred vision may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

To relieve dry mouth, suck (sugarless) hard candy or ice chips, chew (sugarless) gum, drink water or use a saliva substitute.

To prevent constipation, eat a diet adequate in fiber, drink plenty of water, and exercise. If you become constipated, consult your pharmacist for help in choosing a laxative (such as a stimulant-type with stool softener).

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: difficulty urinating, signs of kidney infection (such as burning/painful/frequent urination, lower back pain), mental/mood changes (such as confusion, hallucinations), signs of stomach/intestinal blockage (such as severe stomach pain, persistent nausea/vomiting, severe constipation).

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

List Oxybutynin Gel In Metered-Dose Pump side effects by likelihood and severity.

Before using oxybutynin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blockage/slowed movement of the stomach/intestines (such as severe constipation, gastric retention, paralytic ileus), stomach/intestinal disease (such as acid reflux, hiatal hernia, ulcerative colitis), problems emptying your bladder (such as urinary retention, obstruction, enlarged prostate), a certain eye problem (glaucoma), liver disease, kidney disease, a certain muscle disease (myasthenia gravis), Parkinson's disease, a certain nervous system disorder (autonomic neuropathy).

This drug may make you dizzy or drowsy or blur your vision. Alcohol or marijuana can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness or clear vision until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication may make you sweat less, making you more likely to get heat stroke. Avoid doing things that may cause you to overheat, such as hard work or exercise in hot weather, or using hot tubs. When the weather is hot, drink a lot of fluids and dress lightly. If you overheat, quickly look for a place to cool down and rest. Get medical help right away if you have a fever that does not go away, mental/mood changes, headache, or dizziness.

Older adults may be more sensitive to the side effects of this drug, especially drowsiness, confusion, constipation, trouble urinating. Drowsiness and confusion can increase the risk of falling.

Tell your doctor if you are pregnant before using this medication.

It is unknown if this drug passes into breast milk. Consult your doctor before breast-feeding.