Extended-release oxybutynin relieves vasomotor symptoms in healthy postmenopausal women

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OBJECTIVE: To evaluate the effect of once-daily, extended-release oxybutynin chloride
15mg (Ditropan XL [DXL]) on the frequency and severity of hot flashes (HF) in
healthy, postmenopausal women with vasomotor symptoms.
METHODS: Women (N = 148), 40 to 65 years of age, with at least 7 moderate-to-
severe hot flashes (MSHF) daily participated in a randomized, double-blind, placebo-
controlled clinical trial with a 2-week pre-randomization and 12-week treatment
period. The primary endpoint was change from baseline in the frequency and severity
of HF to week 12. MSHF data were collected using daily diaries. Treatment effects
were assessed using a modified intent-to-treat analysis. Adverse events (AEs) were
collected at each clinic visit. Subject Global Assessment (SGA) was collected at the
final visit.
RESULTS: Women who received DXL had significantly fewer HF at weeks 4 and 12
than those who received placebo (DXL vs placebo): 11.9 vs 10.8 (baseline, P=ns);
3.0 vs 6.8 (week 4, P<0.001); 2.4 vs 6.2 (week 12, P<0.001). Daily HF severity also
decreased significantly at weeks 4 and 12. Average composite score for MSHF (DXL
vs placebo) was 31.1 vs 28 (baseline, P=ns); 7.6 vs 17.1 (week 4, P<0.001); 6.2 vs
15.8 (week 12, P<0.001). SGAs showed greater symptom improvement with DXL vs
placebo (93.6% vs 59.4%, P<0.001). AEs were more frequent with DXL, with dry
mouth (52.1%), dyspepsia (12.3%), and diarrhea (9.6%) reported. No serious AEs
were reported.
CONCLUSION: DXL 15 mg is a safe and effective non-hormonal therapy for MSHF
.
•Vasomotor symptoms, commonly referred to as hot flashes, are experienced by two thirds
or more of postmenopausal women1
–Ahot flash is a sudden onset of reddening of the skin over the head, neck, and
chest, accompanied by a feeling of intense body heat and concluded by sometimes
profuse perspiration
–The duration of hot flashes varies from a few seconds to several minutes; rarely, a hot
flash may last for an hour
•These symptoms may interfere with work, sleep, and activities of daily living, decreasing
overall quality of life2
•Traditionally, hormone replacement therapy (HRT) was used as an effective treatment for
hot flashes. However,data collected for more than 5 years in the Women’s Health
Initiative (WHI) suggested that the risks of HRT outweighed the benefits, and the estrogen
+progestogen portion of the study was halted prematurely3
–Use of HRT was associated with a small but significant risk of breast cancer, coronary
heart disease, stroke, and blood clots
– Many symptomatic menopausal women, fearful of the aforementioned findings, are
reluctant to use HRT
– These issues, taken together, suggest that alternative, non-hormonal therapies for hot
flashes should be considered
• Other agents that have been evaluated for use in this setting include the following:
selective serotonin reuptake inhibitor (SSRI) antidepressants (paroxetine, fluoxetine,
citalopram), venlafaxine, clonidine, gabapentin, and methyldopa2,4-6
•Oxybutynin chloride is an antimuscarinic agent with antispasmodic activity and is known
for its action of relaxing bladder smooth muscle
–Aonce-daily controlled-release formulation of oxybutynin chloride (extended release
[ER]) is approved by the US Food and Drug Administration (FDA) for the treatment of
overactive bladder with symptoms of urge urinaryincontinence, urgency, and
frequency (Ditropan XL®;Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ)7
–Anecdotal evidence of reduced frequency and severity of hot flashes in
postmenopausal women receiving oxybutynin chloride ER for overactive bladder
prompted further study of the effects of this treatment on hot flashes in a randomized,
controlled clinical trial
•To evaluate the effect of once-daily oxybutynin chloride ER 15 mg on the frequency and
severity of hot flashes in healthy, symptomatic postmenopausal women
Patients
•Key inclusion criteria
– Healthy, naturally postmenopausal women
• No menses for atleast 6 months prior to the start of the study
– 40 to 65 years of age
– Serum follicle-stimulating hormone (FSH) levels >40 mIU/mL
– At least 7 moderate-to-severe hot flashes daily during the pre-randomization period
•Key exclusion criteria
– Presence of a genitourinary condition that requires the use of an anticholinergic agent
– History of bilateral oophorectomy with or without hysterectomy
– Incomplete washout of hormone-containing drugs, including vaginal creams and gels,
hormonal rings, transdermal hormonal formulations, selective estrogen receptor
modulators, oral estrogens and/or progestins, intrauterine progestins, progestin
implants or injections, estrogen pellets or injections
– Presence of significant depression or psychiatric disease
Study Design
•This was a randomized, multicenter, double-blind, placebo-controlled, phase II clinical trial.
Figure 1 provides an overview of the study design
•The trial contained a 2-week pre-randomization period and a 12-week treatment period
•The pre-randomization period involved a physical examination, medical history, hot flash
history, vital signs, and laboratory tests; subjects received daily diaries to record their hot
flashes starting on day –15
– Hot flash severity was defined based on the definitions found in the FDA Guidance for
Industry for estrogen and estrogen/progestin products to treat vasomotor symptoms
and vulvar and vaginal atrophy symptoms8
•Mild – sensation of heat without sweating (score of 1)
•Moderate – sensation of heat with sweating, able to continue activity (score of 2)
• Severe – sensation of heat with sweating, causing cessation of activity (score of 3)
–Episodes that awakened a subject from sleep were recorded separately and were
considered to be severe (score of 3)
–Diaries were collected and reviewed at each visit, starting at the randomization visit
(day –1)
•Women were randomized 1:1 to receive one of the following treatments (one tablet orally,
inthe morning) during the 12-week treatment period:
–Oxybutynin chloride ER 15 mg
–Placebo
•Women returned for follow-up visits between days 8 and 14, 22 and 28, and 50 and 56,
and the final study visit occurred between days 78 and 84
Study Endpoints
•The primary endpoint was change from baseline in the frequency and severity of
moderate-to-severe hot flashes to week 12, based on data from diarycards
–The composite score of moderate-to-severe hot flashes was defined as the sum of all
moderate hot flashes times 2 and all severe hot flashes times 3 in a time period
divided by the number of days in the corresponding period
•The Subject Global Assessment (SGA) was collected atthe final visit
– Subjects responded to the question, “Considering the entire studyperiod, how would
you rate your hot flashes compared to before you started taking study medication?”
using a rating scale of much better, better, slightly better, no meaningful difference,
slightly worse, worse, or much worse
•Safety was assessed by pre- and post-studyphysical examinations, laboratory analysis,
vital signs, and adverse events (AEs)
– AEs were collected at each clinic visit
Statistical Analyses
•Treatment effects were assessed using a modified intent-to-treat (ITT) analysis
– An analysis of covariance (ANCOVA) was applied for treatment comparison with
baseline daily frequencyor severity score of moderate-to-severe hot flashes as a
covariate and treatment and center as qualitative design factors
•The SGA was analyzed using a Cochran-Mantel-Haenszel test, stratified by center
•The incidence of AEs was compared between treatment groups using Fisher exact test
•All statistical tests were conducted at the 2-sided, 5% significance level
Patients
•Atotal of 148 women were randomized to receive either oxybutynin chloride ER (n = 73)
or placebo (n = 75)
–All 12 weeks of treatment were completed by 121 women (56 in the oxybutynin
chloride ER group and 75 in the placebo group)
– Women (n = 27) discontinued the trial for the following reasons:
• Lack of efficacy (placebo, n = 3)
•AE (oxybutynin chloride ER, n = 10; placebo, n = 3)
•Subject choice (oxybutynin chloride ER, n = 2; placebo, n = 1)
• Lost to follow-up (oxybutynin chloride ER, n = 3; placebo, n = 3)
• Other (oxybutynin chloride ER, n = 2)
–One subject in the oxybutynin chloride ER group and 2 subjects in the placebo group
were excluded from the ITT analysis due to lack of a post-randomization efficacy
evaluation
•Demographics and baseline characteristics of the ITT population are summarized in
Table 1. No significant differences were observed between groups
Efficacy
•Women who received oxybutynin chloride ER had significantly fewer moderate-to-severe
hot flashes after treatment than those who received placebo
– At baseline, the incidence was similar between groups (P=ns)
•Oxybutynin chloride ER = 11.9
• Placebo = 10.8
– At week 4, the incidence was significantly lower in the oxybutynin chloride ER group
versus the placebo group (P<0.001)
•Oxybutynin chloride ER = 3.0
•Placebo = 6.8
–At week 12, the incidence was significantly lower in the oxybutynin chloride ER group
versus the placebo group (P<0.001)
•Oxybutynin chloride ER = 2.4
• Placebo = 6.2
–Figure 2 demonstrates the changes in moderate-to-severe hot flash frequency for
both treatment groups over the course of the study
•The severity of daily hot flashes decreased significantly at weeks 4 and 12 (Figure 3)
•The average composite score for moderate-to-severe hot flashes was significantly lower
after treatment with oxybutynin chloride ER versus placebo
– At baseline, scores were similar between groups (P=ns)
•Oxybutynin chloride ER = 31.1
• Placebo = 28
– At week 4, the score was significantly lower in the oxybutynin chloride ER group
versus the placebo group (P<0.001)
•Oxybutynin chloride ER = 7.6
• Placebo = 17.1
– At week 12, the score was significantly lower in the oxybutynin chloride ER group
versus the placebo group (P<0.001)
•Oxybutynin chloride ER = 6.2
• Placebo = 15.8
–Figure 4 demonstrates the changes in average composite score of moderate-to-
severe hot flashes for both treatment groups over the course of the study
•The SGA showed greater symptom improvement with oxybutynin chloride ER versus
placebo (P<0.001)
–Ratings of “slightly better, better, or much better” were reported by 93.6% of women in
the oxybutynin chloride ER group versus 59.4% of women in the placebo group
–Arating of “much better” was given by 73% of women in the oxybutynin chloride ER
group versus 26.1% in the placebo group
Safety
•AEs were more frequent with oxybutynin chloride ER than with placebo (Table 2);
however, they were consistent with those expected for oxybutynin chloride ER
according to the product labeling7
•No serious AEs were reported
•Daily administration of oxybutynin chloride ER to healthy postmenopausal
women who had experienced a mean of at least 7 moderate-to-severe hot
flashes per day prior to treatment decreased both the frequencyand severity of
hot flashes
•Oxybutynin chloride ER 15 mg is a safe and effective non-hormonal therapy for
moderate-to-severe hot flashes
References
1. Xu J, et al. JAm Board Fam Pract. 2005;18:374-382.
2. Bachmann GA. JReprod Med. 2005;50:155-165.
3. Writing Group for the Women’s Health Initiative Investigators. JAMA.2002;288:321-333.
4. Evans ML, et al. Obstet Gynecol. 2005;105:161-166.
5. Neff MJ. Am Fam Physician. 2004;70:393-399.
6. Stearns V, et al. JAMA.2003;289:2827-2834.
7. Ditropan XL®(oxybutynin chloride) extended release tablets [package insert]. Raritan, NJ: Ortho-McNeil
Pharmaceutical, Inc.; 2004.
8. FDA. Guidance for Industry. January 2003. Available at: www.fda.gov/cder/guidance/5412dft.pdf.
Accessed May 1, 2007.
Extended-Release Oxybutynin Relieves Vasomotor Symptoms in Healthy Postmenopausal Women
James A. Simon, MD, CCD1*; Katherine D. LaGuardia, MD, MPH2
1George Washington University, School of Medicine, Washington, DC, USA; 2Ortho Women’s Health and Urology, Raritan, NJ, USA.
*Presenting author.
ABSTRACT
Pre-randomization
phase
(2 weeks)
Treatment phase (12 weeks)
Oxybutynin chloride ER 15 mg
or
Placebo
Visit 1
Day –15
Diaries
distributed
Visit 4
Days 22-28
Diary
review
Visit 3
Days 8-14
Diary
review
Visit 2
Day –1
Randomization
Diary review
Visit 5
Days 50-56
Diary
review
Visit 6
Final visit
Days 78-84
Diary review
SGA
Figure 1. Study design.
INTRODUCTION
OBJECTIVE
METHODS
RESULTS
Table 2. Most Commonly Reported Adverse Events (≥5% Incidence)
Oxybutynin chloride ER Placebo
(n = 72) (n = 73) Pvalue
Any AE 58 (79.5) 40 (53.3) <0.001*
Diarrhea 7 (9.6) 0 (0) 0.006*
Dry mouth 38 (52.1) 4 (5.3) <0.001*
Dyspepsia 9 (12.3) 1 (1.3) 0.009*
Dysphagia 4 (5.5) 0 (0) 0.057
Nausea 4 (5.5) 1 (1.3) 0.206
URTI 4 (5.5) 3 (4.0) 0.717
UTI 5 (6.8) 0 (0) 0.027*
Dizziness 2 (2.7) 4 (5.3) 0.681
Headache 3 (4.1) 8 (10.7) 0.209
Insomnia 3 (4.1) 4 (5.3) 1.000
ER, extended release; AE, adverse event; URTI, upper respiratory tract infection; UTI, urinary tract infection.
*Statistically significant difference.
Table 1. Demographics and Baseline Characteristics
Oxybutynin chloride ER Placebo Total
(n = 72) (n = 73) (N = 145)
Age, y
Mean (SD) 54.2 (4.57) 54.2 (4.51) 54.2 (4.52)
Race, n (%)
Caucasian 60 (83.3) 58 (79.5) 118 (81.4)
African American 6 (8.3) 7 (9.6) 13 (9.0)
Asian 0 (0) 0 (0) 0 (0)
Other 6 (8.3) 8 (11.0) 14 (9.7)
Height, cm
Mean (SD) 162.4 (6.43) 162.7 (7.62) 162.5 (7.03)
Weight, kg
Mean (SD) 69.8 (13.15) 71.1 (13.41) 70.7 (13.27)
FSH, mIU/mL
Mean (SD) 87.0 (28.14) 87.7 (26.28) 87.3 (27.13)
TSH, µIU/mL
Mean (SD) 1.72 (0.971) 2.18 (1.987) 1.95 (1.579)
ER, extended release; SD, standard deviation; FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone.
12110
5
15
10
Average frequency of hot flashes
Week
9110
0Placebo
Oxybutynin chloride ER
8765432
*
*
Figure 2. Mean daily frequency of moderate-to-severe hot flashes.
12110
1
3
2
Average severity of hot flashes
Week
9110
0Placebo
Oxybutynin chloride ER
8765432
*
*
Figure 3. Mean daily severity of all hot flashes.
12110
25
40
35
Average composite score of hot flashes
Week
9110
0Placebo
Oxybutynin chloride ER
8765432
*
*
30
20
15
10
5
Figure 4. Average daily composite score of moderate-to-severe hot flashes.
CONCLUSIONS
ER, extended release.
*P<0.001.
ER, extended release.
*P<0.001.
ER, extended release.
*P<0.001.
SGA, Subject Global Assessment.