Oxytrol - Scientific Information
|Condition:||Dysuria, Overactive Bladder, Urinary Incontinence|
|Form:||Skin patch (transdermal)|
|Chemical name:||d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate|
|Description:||Oxybutynin is a white powder. It is soluble in alcohol, but relatively insoluble in water. Oxybutynin is administered as a racemate of R- and S-enantiomers. The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride.|
OXYTROL 3.9 mg/day (oxybutynin transdermal system)
Each 39 cm2 system imprinted with “OXYTROL 3.9” contains 36 mg oxybutynin for nominal delivery of 3.9 mg oxybutynin per day when dosed in a twice weekly regimen.
Transdermal System Components
OXYTROL is a matrix-type transdermal system composed of 3 layers, illustrated in the figure below. Layer 1 (Backing Film) is a thin flexible polyester/ethylene-vinyl acetate film that provides the matrix system with occlusivity and physical integrity and protects the adhesive/drug layer. Layer 2 (Adhesive/Drug Layer) is a cast film of acrylic adhesive containing oxybutynin and triacetin USP. Layer 3 (Release Liner) is two overlapped siliconized polyester strips that are peeled off and discarded by the patient prior to applying the matrix system.
Store at room temperature at 15 - 30°C. Protect from moisture and humidity. Do not store outside the sealed pouch. Apply immediately after removal from protective pouch. Discard used OXYTROL in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.
Availability of dosage form
OXYTROL (oxybutynin transdermal system) is supplied in Patient Calendar Boxes of 8 systems.
Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. In patients with overactive bladder, characterized by detrusor muscle instability or hyperreflexia, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and the frequency of both incontinence episodes and voluntary urination.
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 systems 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 interval 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 1.
Figure 1: 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 N- desethyloxybutynin (Figure 2).
Figure 2: 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 1 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of OXYTROL.
(ng/mL x h)
|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|
1 Tmax given as median
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 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 3). The plasma concentration 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 the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite (see figure 3). 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 3: 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 N-desethyloxybutynin decline with an apparent half-life of approximately 7 to 8 hours.
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.
Analysis of pharmacokinetic data from Phase I studies indicates that females exhibit a slightly greater metabolism of oxybutynin than males. This is consistent with the known higher cytochrome CYP 3A4 activity in females (Beirle et a1 1999). However, gender differences were not detected in the analysis of steady-state levels of oxybutynin and N-desethyloxybutynin in patients with over-active bladder during clinical development.
Age was not found to have a significant effect on steady-state levels of oxybutynin and N-desethyloxybutynin in patients with over-active bladder, including patients up to the age of 88 years.
Race was not found to have a significant effect on steady-state levels of oxybutynin and N-desethyloxybutynin.
Pharmacokinetic and clinical studies were not conducted in pediatric patients for the indication of over-active bladder.
Hepatic and Renal Insufficiency:
Pharmacokinetic trials were not conducted in this patient population during the development program for OXYTROL.
The efficacy and safety of OXYTROL were evaluated in patients with urge, urinary incontinence in two Phase III controlled studies and one open-label extension. Study 1 was a Phase III, 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 Phase III 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 OXYTROL doses of 1.3, 2.6, and 3.9 mg/day with matching placebo. An open-label, dose titration treatment extension allowed continued treatment for 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 urinary diary during a treatment-free baseline period confirmed the diagnosis of urge incontinence. Approximately 80% of patients had no prior pharmacological treatment for incontinence. Reductions in weekly incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 2.
|Parameter||Placebo||OXYTROL 3.9 mg/mL|
|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|
|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, double-dummy, study of OXYTROL 3.9 mg/day versus an active comparator (tolterodine oral treatment 4 mg daily long- acting capsules) versus placebo, conducted in 361 patients. 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. Reductions in daily incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 3.
|Parameter||Placebo||OXYTROL 3.9 mg/mL|
|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
The adhesion of OXYTROL to the skin of patients was assessed during the conduct of the two phase III trials described above (see Clinical Studies). In Study 2, 361 active and placebo patients had 993 transdermal systems evaluated for adhesion. The patches were found to be at least 75% adhered in 99% of the cases, with detachment being noted at the edges only, and complete adherence being documented in 92% of the patients. There were no reports of the patch becoming completely detached in this study.
In assessing the adhesion characteristics of the OXYTROL Transdermal System during Study 1, 300 systems were evaluated in 97 patients. The adhesion assessment results were similar, but two OXYTROL systems did become completely detached.
The estimated minimal lethal dose of single subcutaneous administration of oxybutynin to rats was > 12,000 mg/kg. Survivors had decreased motor activity and unsteady gaits. Anticholinergic and smooth muscle relaxation effects, such as mydriasis, were seen at all doses tested. At the site of injection, induration was observed at 3000 mg/kg dose and above.
In dogs subcutaneous administration of oxybutynin at 2000 mg/kg, the highest dose tested, was not lethal. All other doses tested, including the lowest dose of 125 mg/kg, caused signs of pronounced anticholinergic activity. There was decrease or disappearance of pupil light reflex, nasal dryness, salivary decrease and constipation. Reactions at the administration site included tylosis, induration or ulcer and were likely due to irritant effects. The two high doses used (500 and 2000 mg/kg) generated peak plasma concentrations of oxybutynin in the range of 399 -719 ng/mL and AUC values above 20,000 ng.hr/mL.
Oxybutynin administration by the percutaneous route at approximately 1300 mg/m2, representing exposure to about 10% of body surface, did not cause lethality. Transient pharmacological effects, such as mydriasis and decrease of pupil light reflex were observed at all doses tested. No other specific effects were observed. The systemic exposure of 1300 mg/m2 percutaneous dose was about 10% of that for 125 mg/kg given subcutaneously.
Repeated doses of oxybutynin were subcutaneously administered for thirteen weeks to rats (0, 1.2, 9 or 72 mg/kg/every 3rd day). The dose was administered every third day for 90 days. The following reactions were observed: mydriasis at all dose levels; increased water intake and urine volume at 9 and 72 mg/kg. The only other effect at 1.2 mg/kg was an increase in blood cell count which was exacerbated at the highest dose level. Other observations included induration, ulcer, encrustation at administration sites and increased leucocytes. Non-specific effects such as inhibition of weight gain and decreased food intake suggested deterioration in general health. No other specific effects or gender differences were noted. No significant histopathology was recorded.
Toxicokinetic data indicate little accumulation of exposure for the two lower dose levels but greater plasma exposure to oxybutynin on Day 84 than on day 1 for the 72 mg/kg regimen.
For dogs, the dose levels administered every third day were 1.2, 6 and 30 mg/kg and there were 3 animals/sex/group. Mydriasis occurred at the lowest dose, as did some local administration site effects and changes in blood biochemistry. Higher doses produced anticipated toxicity.
A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg showed no evidence of carcinogenicity.
Genotoxicity and Reproductive Studies
The mutagenic potential of oxybutynin was tested by a bacterial reversion assay in Escherichia coli and Salmonella typhimurium test systems and was found to be negative. A chromosomal aberration test in mammalian cells in vitro and micronucleus assay in the bone marrow of mice were also negative. In summary, no evidence for genotoxic potential was observed.
In reproductive studies in rats, the no effect dose for female fertility was close to 5 mg/kg/day. 125 mg/kg/day did not affect primary blastogenesis. The rate of implantation and mortality in rats were not statistically significantly changed at 125 mg/kg, but live embryo count was reduced at 25 and 125 mg/kg, indicating a need for caution when considering the use of oxybutynin in pregnant humans.
In rabbits, maternal toxicity was observed at quite low doses (less than 1 mg/kg). Nevertheless, the incidence of abnormalities in surviving neonates did not increase with doses up to 25 mg/kg oxybutynin.
Reproductive toxicology studies in rat and rabbit indicated a slight increase in foetal malformations in rats, together with lengthened gestation and impaired post-natal thriving, at doses associated with maternal toxicity. Lower doses (20 mg/kg) were without adverse effect in rats and there were no effects in rabbits at 48 mg/kg on embryo-foetal development, despite maternal toxicity.
In summary, reproduction studies with oxybutynin chloride in the rat and rabbit showed no definite evidence of impaired fertility or harm to the animal fetus.
Local Tolerance Studies
No dermal phototoxicity was observed following oxybutynin application with ultraviolet irradiation to guinea pigs for 24 hours. Oxybutynin patches did not produce delayed contact sensitization.
The primary dermal irritation index was calculated to be 0.8 (barely perceptible irritant) for the placebo patch and 1.9 (slight irritant) for the oxybutynin patch.