Anturol

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Oxybutynin is an antispasmodic, antimuscarinic agent. ANTUROL (oxybutynin) gel 3% is a topical, homogeneous, very lightly to moderately opalescent, translucent colorless to slightly colored gel, without particles hydroalcoholic gel containing 30 mg oxybutynin per gram of gel. ANTUROL is available in a 0.92 gram (1 mL) unit dose that contains 28 mg oxybutynin. Oxybutynin is delivered as a racemate of R- and S-isomers. Chemically, oxybutynin base is d, 1 (racemic) 4-(Diethylamino)-2-butynyl (±)-α- phenylcyclohexaneglycolate.

The empirical formula of oxybutynin base is C22H31NO3. Its structural formula is:

Oxybutynin is a white powder with a molecular weight of 357. Inactive ingredients in ANTUROL are diethylene glycol monoethyl ether, NF; alcohol, USP; hydroxypropyl cellulose, NF; propylene glycol, NF; butylated hydroxytoluene, NF; HC1 0.1 M, NF; and purified water, USP.

Dosage Forms and Strengths

ANTUROL is a homogeneous, colorless to slightly colored gel 3%.

ANTUROL (oxybutynin) gel 3% is supplied in a metered-dose pump dispenser composed of an inner aluminum laminated foil liner encased in a rigid plastic bottle with a plastic cap. The nozzle of the pump dispenser is sealed by a removable cap attached to the actuator by a plastic string.

55948-301-01 2 x 45 mL (2 x 42g) metered pump dispensers each containing 30 metered 0.92 g (1.0 mL) pumps delivering 28 mg oxybutynin per pump actuation.

55948-301-02 100 mL (92g) metered pump dispenser containing 90 metered 0.92 g (1 mL) pumps delivering 28 mg oxybutynin per pump actuation.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). See USP controlled room temperature. Protect from moisture and humidity.

Antares Pharma, Inc. Ewing, NJ 08618 USA. Issued: December 2011

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The safety of ANTUROL was evaluated in 626 patients (210 randomized to ANTUROL 56 mg/day, 214 randomized to ANTUROL 84 mg/day and 202 randomized to placebo) during a randomized, placebo-controlled, double-blind, 12-week clinical efficacy and safety study. A subset of these 626 patients (N = 77) participated in the 24-week open-label safety extension that followed the placebo-controlled study. Of the 77 patients in the safety extension, 24 were randomized to placebo gel during the double-blind, placebo-controlled 12-week study. In the combined double-blind, placebo-controlled study and the open-label safety extension, a total of 441 patients were exposed to at least one dose of ANTUROL. 364 patients received at least 12 weeks of ANTUROL treatment and 66 patients received an additional 24 weeks of ANTUROL treatment during the open-label safety extension. The study population primarily consisted of women (87%) of Caucasian descent (87%) with an average age of 59 years who had overactive bladder with urge urinary incontinence.

Table 1 lists adverse reactions (ARs), regardless of causality, that were reported in the randomized, double-blind, placebo-controlled 12-week study at an incidence greater than placebo and in greater than 3% of patients treated with ANTUROL.

Overall, 672 ARs were experienced by 51.9% of patients. Majority of the ARs were mild to moderate in intensity. The AR most commonly reported was dry mouth which was experienced by a greater proportion of patients in the oxybutynin group than the placebo group (26 patients [12.1%] in the oxybutynin 84 mg group, 10 patients [5.0%] in the placebo group). Application site erythema was the next most commonly reported AR (8 patients [3.7%] in the oxybutynin 84 mg group and 2 patients [1.0%] in the placebo group). Other commonly reported ARs experienced by more patients in the oxybutynin groups compared with placebo were application site rash (7 patients [3.3%] in the oxybutynin 84 mg group and 1 patient [0.5%] in the placebo group); application site pruritus (6 patients [2.8%] in the oxybutynin 84 mg group and 1 patient [0.5%] in the placebo group). The overall rate of application site adverse reactions of any kind was 14.2% in patients receiving ANTUROL as compared to 3.7% in patients receiving placebo. Other cholinergic AEs < 2% in occurrence include dry eyes and blurred vision.

There were no deaths during the study. There were no clinically meaningful changes in vital signs, laboratory values, or ECG examinations over the course of the study.

Table 1: Commonly Reported Adverse Reactions that were reported In greater than 3% of patients treated with ANTUROL and at an incidence greater than placebo.

During the 24-week open-label safety extension, the most commonly reported ARs were urinary tract infection and nasopharyngitis reported in 4 patients each (5.2%), followed by conjunctivitis and application site erythema (both occurred in 3 patients [3.9%]). One patient prematurely discontinued due to the application site erythema and pruritus (both considered to be of mild severity).

Mechanism of Action

Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly with the R-isomer. Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies. 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.

Pharmacokinetics

Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Steady-state concentrations are achieved within 3 days of continuous dosing.

Absorption of oxybutynin is similar when ANTUROL is applied to the abdomen, upper arm/shoulders or thighs. The pharmacokinetic parameters and mean plasma concentrations during a randomized, crossover study of the three recommended application sites in 25 healthy men and women are shown in Table 2 and Figure 1, respectively.

Table 2: Pharmacokinetic Parameters (mean values) for Oxybutynin (84 mg/day) 3% gel.

Figure 1: Mean (including SD) plasma oxybutynin concentrations versus time after application of ANTUROL to the abdomen (Site A), thigh (Site B), and upper arm/shoulder (Site C) (N=25).

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.

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

Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyloxybutynin metabolite. Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The AUC ratio of N-desethyloxybutynin metabolite to parent compound following multiple transdermal applications is approximately 1:1 for ANTUROL. The apparent half-life was approximately 30 hours.

Oxybutynin undergoes extensive hepatic metabolism, with less than 0.1% of the administered dose excreted unchanged in the urine. Less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.

The potential for dermal transfer of oxybutynin from a treated person to an untreated person was evaluated in a single-dose study where subjects dosed with ANTUROL engaged in vigorous contact with an untreated partner for 15 minutes, either with (N=14 couples) or without (N=14 couples) clothing covering the application area. The untreated partners not protected by clothing demonstrated low detectable plasma concentrations of oxybutynin (mean Cmax = 0.65 ng/mL). Only one of the 14 untreated subjects participating in the clothing-to-skin contact regimen had very low measurable oxybutynin plasma concentrations (Cmax = 0.06 ng/mL) during the 24 hours following contact with treated subjects; oxybutynin was not detectable with the remaining 13 untreated subjects. Regardless of the low exposure observed in this study, patients should avoid skin-to-skin contact with partners after applying the gel.

The effect of sunscreen on the absorption of oxybutynin when applied 30 minutes before or 30 minutes after ANTUROL application was evaluated in a single-dose randomized crossover study (N=20). Concomitant application of sunscreen, either before or after ANTUROL application, had no effect on the systemic exposure of oxybutynin.

The effect of showering on the absorption of oxybutynin was evaluated in a randomized, steady-state crossover study under conditions of no shower, or showering 1, 2 or 6 hours after ANTUROL application (N=22). The results of the study indicate that showering one hour after administration does not affect the overall systemic exposure to oxybutynin.

The effect of race on the pharmacokinetics of ANTUROL has not been studied.

Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on geriatric status in patients following administration of ANTUROL [see Use In Specific Populations].

The pharmacokinetics of oxybutynin and N-desethyloxybutynin following application of ANTUROL has not been evaluated in individuals younger than 18 years of age [see Use In Specific Populations].

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

There is limited experience with the use of ANTUROL in patients with renal insufficiency [see Use In Specific Populations].

There is limited experience with the use of ANTUROL in patients with hepatic insufficiency [see Use In Specific Populations].

Clinical Studies

The efficacy and safety of ANTUROL was evaluated in a single randomized, double-blind, placebo-controlled, multicenter 12-week study in patients with urinary frequency and urge and mixed urinary incontinence with a predominance of urge incontinence episodes. This was followed by an open-label safety extension. Key entry criteria included adults with overactive bladder (OAB) symptoms for at least 3 months who were either treatment-naive or had demonstrated a beneficial response to anticholinergic treatment for OAB. Subjects were randomly assigned to receive 84mg/day oxybutynin, 56mg/day oxybutynin, or placebo. A total of 214 patients received 84mg/day oxybutynin, 210 patients received 56 mg/day oxybutynin, and 202 patients received placebo gel. The majority of patients were Caucasian (87%) and female (87%), with a mean age of 59 years (range: 19 to 89 years). The primary efficacy endpoint was the change from baseline to week 12 in the number of urinary incontinence episodes (UIE) per week, as determined from a 3-day patient daily diary.

Patients treated with ANTUROL (84 mg) experienced a statistically significant decrease in the number of urinary incontinence episodes per week from baseline to endpoint (the primary efficacy endpoint) compared with placebo (p=0.0445) and patients treated with the 56 mg dose did not show statistically significant efficacy. Statistically significant improvements in daily urinary frequency (p=0.0010) and urinary void volume (p < 0.0001) were also seen with ANTUROL (84 mg) relative to placebo. The mean difference from placebo for ANTUROL (84 mg) was -2.3 for urinary incontinence episodes per week in a group of patients with a mean of greater than 40 incontinence episodes per week at baseline. Mean and median change from baseline in weekly incontinence episodes (primary endpoint), daily urinary frequency, and urinary void volume (secondary endpoints) between placebo and ANTUROL are summarized in Table 3.

Table 3: Mean (SD) and median change from baseline to Week 12 in incontinence episodes, urinary frequency, and urinary void volume: Intent-To-Treat population (LOCF*)

Oxybutynin is used to treat symptoms of an overactive bladder, such as incontinence (loss of bladder control) or a frequent need to urinate.

The gel form is available only with a doctor's prescription. The Oxytrol® for Men skin patch is available only with a doctor's prescription, but the Oxytrol® for Women skin patch is available without a prescription or over-the counter (OTC).

This section provides information on the proper use of a number of products that contain oxybutynin. It may not be specific to Anturol. Please read with care.

It is very important that you use this medicine only as directed. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Talk to your doctor if you have any questions.

This medicine is for use on the skin only. Do not get it in your eyes, nose, mouth, breasts, or genital area. Do not use it on skin areas that have cuts or scrapes. If it does get on these areas, rinse it off right away.

To use the gel:

• Wash your hands with soap and water before and after using this medicine.
• Before applying this medicine, wash the application site (eg, stomach, upper arms, shoulders, or thighs) with mild soap and water. Rinse well and pat dry.
• Tear and squeeze the entire contents of the packet into the palm of your hand or directly on the application site. Gently rub it until the gel dries.
• Do not apply this medicine on the same application site you applied the last one.
• Do not bathe, swim, shower, or exercise for 1 hour after applying oxybutynin.
• Cover the application site with a dry cloth after the medicine has dried to avoid direct contact or transfer of oxybutynin to another person.

To use the skin patch:

• Use this medicine exactly as directed by your doctor. It will work only if applied correctly.
• Wash your hands with soap and water before and after applying a patch. Do not touch your eyes until after you have washed your hands.
• Apply the patch right away after removing it from the protective pouch. Do not cut it into smaller pieces and do not touch the sticky surface of the patch.
• Apply the patch to a clean, dry, and intact skin area on your stomach, hips, or buttocks. Choose an area with little or no hair and free of scars, cuts, or irritation. Avoid putting the patch on areas where it could be rubbed off by tight clothing.
• Press the patch firmly in place with your fingertips to make sure that the edges of the patch stick well.
• When putting on each new patch, choose a different place within these areas. Do not put the new patch on the same place you wore the last one. Be sure to remove the old patch before applying a new one.

The gel form contains alcohol which is flammable. Do not use this medicine near heat, an open flame, or while smoking.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For bladder problems:
  • For transdermal dosage form (gel):
    • Adults—
      • Anturol™: 84 milligrams (mg) or 3 pumps of gel applied on dry, intact skin once a day.
      • Gelnique®: Apply the gel on dry, intact skin once a day.
    • Children—Use and dose must be determined by your doctor.
  • For transdermal dosage form (skin patch):
    • Adults—Apply one patch two times per week, which is one patch every 3 to 4 days.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

After removing a used patch, fold the patch in half with the sticky sides together. Make sure to dispose of it out of the reach of children and pets.

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

This medicine may cause a serious type of allergic reaction called angioedema. Angioedema may be life-threatening and requires immediate medical attention. Stop using this medicine and seek medical attention right away if you have a rash, itching, a large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs, trouble with breathing, or chest tightness while you are using this medicine.

If you develop a skin rash, hives, or any allergic reaction to this medicine, stop using the medicine and check with your doctor as soon as possible.

This medicine may make you sweat less, causing your body temperature to increase. Use extra care not to become overheated during exercise or hot weather while you are using this medicine, since overheating may result in heat stroke.

This medicine may cause some people to become dizzy, drowsy, or have blurred vision. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy, not alert, or not able to see well.

This medicine may cause dryness of the mouth, nose, and throat. For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Avoid drinking alcohol while you are using this medicine.

Do not use cosmetics or other skin care products on the treated skin areas. However, you may use this medicine with a sunscreen.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Protect from heat.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.