英文药名: Gelnique 10% gel(Oxybutynin Chloride) 中文药名: 氯化奥昔布宁10% 凝胶 生产厂家: Watson Laboratories Inc. 药品简介 美国FDA批准沃森公司（Watson）的10%氯化奥昔布宁凝胶（oxybutynin chloride，Gelnique）上市，首个和唯一用于治疗以尿急、失禁和尿频为症状的膀胱过度活动症（OAB）。 本品为OAB患者提供了不同于口服的新有效治疗理念。由于本品中的药物经皮释药，不会像口服奥昔布宁制剂被肝脏代谢。因而，诸如口干和便秘等不良反应的发生率低。 临床研究显示，本品作用强、患者耐受性好和此独特的释药系统可作为OAB患者的一线治疗药。 本品是可快速干燥清澈无色无芳香剂的氯化奥昔布宁亲水凝胶制剂，一日1次涂于大腿、腹部、上臂或肩，1g凝胶（含氯化奥昔布宁100 mg）可持续释药24小时，提供了强效且耐受性好的外用制剂。 本品获准上市是基于对789例OAB患者双盲安慰剂对照的Ⅲ期临床评价的研究结果。12周以上的研究，一日1次本品用药组解除OAB症状（减少尿失禁的发生率和尿频的次数，增加尿排空量）优于安慰剂组。治疗组患者耐受性好，不良反应发生率低，无治疗引起的严重不良反应。最常见的不良反应为口干和用药部位局部反应。 另外的药理学研究证明，本品使用1小时或以后、用前或用后30分钟使用遮光剂均不显著影响药物的吸收。 HIGHLIGHTS OF PRESCRIBING INFORMATION GELNIQUE® (oxybutynin chloride) gel 10% Rx only These highlights do not include all the information needed to use GELNIQUE safely and effectively. See full prescribing information for GELNIQUE. GELNIQUE (oxybutynin chloride) 10% gel Initial U.S. Approval: 1975 RECENT MAJOR CHANGES WARNINGS AND PRECAUTIONS, Central Nervous System Effects (5.5) 07/2015 INDICATIONS AND USAGE GELNIQUE is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1) DOSAGE AND ADMINISTRATION Apply contents of one sachet of GELNIQUE once daily to dry, intact skin on the abdomen, upper arms/shoulders, or thighs. (2) Rotate application sites, avoiding use of the same site on consecutive days. (2) GELNIQUE is for topical application only and should not be ingested. (2) DOSAGE FORMS AND STRENGTHS Gel: 10% (3) CONTRAINDICATIONS Urinary retention (4) Gastric retention (4) Uncontrolled narrow-angle glaucoma (4) Known serious hypersensitivity reaction to GELNIQUE, oxybutynin, or to any of the components of GELNIQUE (4) WARNINGS AND PRECAUTIONS Urinary Retention: Use caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. (5.1) Gastrointestinal Disorders: Use caution in patients with gastrointestinal obstructive disorders or decreased intestinal motility because of the risk of gastric retention. Use caution in patients with gastroesophageal reflux and/or those taking drugs that can cause or exacerbate esophagitis. (5.2) Angioedema: Angioedema has been reported with oral oxybutynin use. If symptoms of angioedema occur, discontinue GELNIQUE and initiate appropriate therapy. (5.3) Skin Hypersensitivity: Discontinue GELNIQUE in patients with skin hypersensitivity. (5.4) Central Nervous System Effects: Somnolence has been reported with GELNIQUE. Advise patients not to drive or operate heavy machinery until they know how GELNIQUE affects them. (5.5) Skin Transference: Advise patients to cover the application site with clothing if skin-to-skin contact at the application site is anticipated. Wash hands immediately after product application. (5.6) Flammable Gel: Contains alcohol-based gel. Avoid open fire or smoking until the gel has dried. (5.7) ADVERSE REACTIONS The most common adverse reactions (incidence > 5% and > placebo) were dry mouth, urinary tract infection, and application site reactions. (6) To report SUSPECTED ADVERSE REACTIONS, contact Actavis, Inc. at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Other Anticholinergics (muscarinic antagonists): Concomitant use with other anticholinergic agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision and other anticholinergic pharmacological effects. (7.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 7/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE GELNIQUE is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency [see Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION The contents of one sachet of GELNIQUE should be applied once daily to dry, intact skin on the abdomen, upper arms/shoulders, or thighs. Application sites should be rotated. Application of GELNIQUE should not be made to the same site on consecutive days [see Clinical Pharmacology (12.3)]. GELNIQUE is for topical application only and should not be ingested. 3 DOSAGE FORMS AND STRENGTHS Gel: 10% 4 CONTRAINDICATIONS   The use of GELNIQUE is contraindicated in the following conditions: Urinary retention Gastric retention Uncontrolled narrow-angle glaucoma Known serious hypersensitivity reaction to GELNIQUE, oxybutynin, or to any of the components of GELNIQUE [see Warnings and Precautions (5.3, 5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Urinary Retention Administer GELNIQUE with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. 5.2 Use in Patients with Gastrointestinal Disorders Administer GELNIQUE with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention. GELNIQUE, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis or intestinal atony. GELNIQUE 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. 5.3 Angioedema Angioedema requiring hospitalization and emergency medical treatment has occurred with the first or subsequent doses of oral oxybutynin. In the event of angioedema, oxybutynin-containing product should be discontinued and appropriate therapy promptly provided. 5.4 Skin Hypersensitivity In a controlled clinical trial of skin sensitization, 1 of 200 patients (0.5%) demonstrated skin hypersensitivity to GELNIQUE. Patients who develop skin hypersensitivity to GELNIQUE should discontinue drug treatment. 5.5 Central Nervous System Effects GELNIQUE is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, somnolence, confusion and hallucinations. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment. Advise patients not to drive or operate heavy machinery until they know how GELNIQUE affects them. If a patient experiences anticholinergic CNS effects, drug discontinuation should be considered. 5.6 Skin Transference Transfer of oxybutynin to another person can occur when vigorous skin-to-skin contact is made with the application site. To minimize the potential transfer of oxybutynin from GELNIQUE-treated skin to another person, patients should cover the application site with clothing after the gel has dried if direct skin-to-skin contact at the application site is anticipated [see Clinical Pharmacology (12.3)]. Patients should wash their hands immediately after application of GELNIQUE. 5.7 Flammable Gel GELNIQUE is an alcohol-based gel and is therefore flammable. Avoid open fire or smoking until gel has dried. 5.8 Myasthenia Gravis Administer GELNIQUE with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. 6 ADVERSE REACTIONS 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. 6.1 Clinical Studies Experience The safety of GELNIQUE was evaluated in 789 patients (389 randomized to GELNIQUE 1 g and 400 randomized to placebo) during a randomized, placebo-controlled, double-blind, 12-week clinical efficacy and safety study. A subset of these 789 patients (N = 216) participated in the 14-week open-label safety extension that followed the placebo-controlled study. Of 216 patients in the safety extension, 107 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 496 patients were exposed to at least one dose of GELNIQUE. Four hundred thirty-one (431) patients received at least 12 weeks of GELNIQUE treatment and 85 patients received 26 weeks of GELNIQUE treatment. The study population primarily consisted of Caucasian women (approximately 90%) with an average age of 59 years who had overactive bladder with urge urinary incontinence. Table 1 lists adverse reactions that were reported in the randomized, double-blind, placebo-controlled 12-week study in greater than 2% of patients treated with GELNIQUE and at an incidence greater than placebo. Table 1: Common Adverse Reactions in the Randomized, Double-blind, Placebo-controlled 12-Week Study (> 2% and > placebo)  Adverse Reaction  GELNIQUE 1 gram N = 389 n (%)  Placebo N = 400 n (%)  Dry mouth  29 (7.5)  11 (2.8)  Urinary tract infection  27 (6.9)  17 (4.3)  Application site reactions*  21 (5.4)  4 (1.0)  Upper respiratory tract infection  21 (5.4)  20 (5.0)  Dizziness  11 (2.8)  4 (1.0)  Nasopharyngitis  11 (2.8)  9 (2.3)  Fatigue  8 (2.1)  4 (1.0)  Gastroenteritis viral  8 (2.1)  7 (1.8) Includes application site pruritus, dermatitis, papules, anesthesia, erythema, irritation, pain and papules Other common adverse reactions that were reported in ≥ 1% of GELNIQUE-treated patients were headache (1.5%), constipation (1.3%), and pruritus (1.3%). Application site pruritus (2.1%) and application site dermatitis (1.8%) were the most commonly reported application site reactions. A majority of adverse reactions were described as mild or moderate in intensity, except for two patients reporting severe headache. The most common adverse reaction leading to drug discontinuation was application site reaction (0.8% with GELNIQUE versus 0.3% with placebo). The most common adverse reactions reported during the 14-week open-label extension study were application site reactions (6.0%) and dry mouth (1.9%). The most common reason for premature discontinuation was application site reactions (9 patients or 4.2%). Two of these 9 patients experienced application site reactions of severe intensity (dermatitis, urticaria, and erythema). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of GELNIQUE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders: dizziness, somnolence, confusion Psychiatric Disorders: hallucinations 7 DRUG INTERACTIONS No specific drug-drug interaction studies have been performed with GELNIQUE. 7.1 Other Anticholinergics The concomitant use of GELNIQUE with other anticholinergic (antimuscarinic) agents may increase the frequency and/or severity of dry mouth, constipation, blurred vision, somnolence and other anticholinergic pharmacological effects. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of topical or oral oxybutynin use in pregnant women. Subcutaneous administration to rats at doses up to 25 mg/kg (approximately 50 times the human exposure based on surface area) and to rabbits at doses up to 0.4 mg/kg (approximately 1 times the human exposure) revealed no evidence of harm to the fetus due to oxybutynin chloride. The safety of GELNIQUE administration to women who are or who may become pregnant has not been established. Therefore, GELNIQUE should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards. 8.3 Nursing Mothers It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GELNIQUE is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of GELNIQUE 10% have not been established in pediatric patients. 8.5 Geriatric Use Of the 496 patients exposed to GELNIQUE in the randomized, double-blind, placebo-controlled 12-week study and the 14-week safety extension study, 188 patients (38%) were 65 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment  There is no experience with the use of GELNIQUE in patients with renal impairment. 8.7 Hepatic Impairment There is no experience with the use of GELNIQUE in patients with hepatic impairment. 10 OVERDOSAGE Overdosage with oxybutynin has been associated with anticholinergic effects including central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Oral ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in a 13-year-old boy who experienced memory loss, and in a 34-year-old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients recovered fully with symptomatic treatment. Plasma concentrations of oxybutynin begin to decline 24 hours after GELNIQUE application. If overexposure occurs, monitor patients until symptoms resolve. 11 DESCRIPTION Oxybutynin is an antispasmodic, antimuscarinic agent. GELNIQUE (oxybutynin chloride) is a clear and colorless hydroalcoholic gel containing 100 mg oxybutynin chloride per gram of gel. GELNIQUE is available in a 1 gram (1.14 mL) unit dose. Each dose contains 100 mg oxybutynin chloride. Oxybutynin is delivered as a racemate of R- and S- isomers. Chemically, oxybutynin chloride is d, l (racemic) 4-(Diethylamino)-2-butynyl (±)-α-phenylcyclohexaneglycolate hydrochloride. The empirical formula of oxybutynin is C22H31NO3•HCl. Its structural formula is: Oxybutynin chloride is a white powder with a molecular weight of 393.95. Inactive ingredients in GELNIQUE are alcohol, USP; glycerin, USP; hydroxypropyl cellulose, NF; sodium hydroxide, NF; and purified water, USP. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly with 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. 12.3 Pharmacokinetics Absorption Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Steady-state concentrations are achieved within 7 days of continuous dosing. Absorption of oxybutynin is similar when GELNIQUE is applied to the abdomen, upper arm/shoulders or thighs. Mean plasma concentrations during a randomized, crossover study of the three recommended application sites in 39 healthy men and women are shown in Figure 1. Average steady-state plasma oxybutynin concentrations were 4.7, 5.2, and 5.5 ng/mL for the abdomen, upper arm/shoulder and thigh application sites, respectively (Table 2). Table 2: Mean (SD) steady-state pharmacokinetic parameters for oxybutynin following GELNIQUE application to the abdomen, upper arm/shoulder and thigh (N = 39). Application Site  AUC0-24 (ng•hr/mL)  Cmax (ng/mL)  Cavg (ng/mL)  Abdomen  112.7 (58.00)  6.8 (3.93)  4.7 (2.39)  Upper Arm/Shoulder  133.8 (81.58)  8.3 (5.97)  5.5 (3.37)  Thigh  125.1 (84.67)  7.0 (4.95)  5.2 (3.50) 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 (DEO), which is pharmacologically active. 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 GELNIQUE. Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. After the final steady-state dose of GELNIQUE, oxybutynin and N-desethyloxybutynin demonstrated biphasic elimination with plasma concentrations beginning to decrease 24 hours after dosing. Elimination was more rapid between 24 and 48 hours after dosing, during which time plasma concentrations of oxybutynin and N-desethyloxybutynin declined by about one-half. This rapid elimination phase was followed by a more prolonged terminal elimination phase. The apparent elimination half-lives including the terminal elimination phase were 64 hours and 82 hours for oxybutynin and DEO, respectively. Excretion Oxybutynin is extensively metabolized by the liver, 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. Person-to-Person Transference 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 GELNIQUE engaged in vigorous contact with an untreated partner for 15 minutes, either with (N = 14 couples) or without (N = 12 couples) clothing covering the application area. The untreated partners not protected by clothing demonstrated detectable plasma concentrations of oxybutynin (mean Cmax = 0.94 ng/mL). Two of the 14 untreated subjects participating in the clothing-to-skin contact regimen had measurable oxybutynin plasma concentrations (Cmax ≤ 0.1 ng/mL) during the 48 hours following contact with treated subjects; oxybutynin was not detectable with the remaining 12 untreated subjects. Use of Sunscreen The effect of sunscreen on the absorption of oxybutynin when applied 30 minutes before or 30 minutes after GELNIQUE application was evaluated in a single-dose randomized crossover study (N = 16). Concomitant application of sunscreen, either before or after GELNIQUE application, had no effect on the systemic exposure of oxybutynin. Showering 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 GELNIQUE application (N = 20). The results of the study indicate that showering after one hour does not affect the overall systemic exposure to oxybutynin. Race The effect of race on the pharmacokinetics of GELNIQUE has not been studied. Specific Populations: Geriatric: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on geriatric status in patients following administration of GELNIQUE [see Use in Specific Populations (8.5)]. Pediatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin have not been evaluated in individuals younger than 18 years of age [see Use in Specific Populations (8.4)]. Gender: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on gender in healthy volunteers following administration of GELNIQUE. Renal Impairment: The effect of renal impairment on the pharmacokinetics of GELNIQUE has not been studied. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of GELNIQUE has not been studied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg showed no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the maximum exposure in humans taking an oral dose, based on 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 definite evidence of impaired fertility. 14 CLINICAL STUDIES The efficacy and safety of GELNIQUE were evaluated in a single randomized, double-blind, placebo-controlled, parallel group 12-week study for the treatment of overactive bladder with symptoms of urge incontinence, urgency and frequency. Key entry criteria included adults with symptomatic overactive bladder with an average of ≥ 4 incontinence episodes in a 3-day period and at least 8 micturitions per day. Patients were randomized to daily applications of GELNIQUE 1 gram or matching placebo gel. A total of 389 patients received GELNIQUE and 400 patients received placebo gel. The majority of patients were Caucasian (86.3%) and female (89.2%), with a mean age of 59.4 years (range: 18 to 88 years). The average duration of urinary incontinence was approximately 8.5 years and approximately 75% of patients had no prior pharmacological treatment for urinary incontinence. Patients treated with GELNIQUE experienced a statistically significant decrease in the number of urinary incontinence episodes per day from baseline to endpoint compared with placebo (p < 0.0001) as well as a decrease in the average daily urinary frequency (p = 0.0017) and an increase in the average urine volume per void (p = 0.0018). Mean and median change from baseline in daily incontinence episodes (primary endpoint), urinary frequency, and urinary void volume (secondary endpoints) between placebo and GELNIQUE are summarized in Table 3. Table 3: Mean and median change from baseline for incontinence episodes, urinary frequency, and urinary void volume at Week 12 (LOCF*).  GELNIQUE 1 gram (N = 389)  Placebo (N = 400) Parameter  Mean (SD)  Median  Mean (SD)  Median  Daily Incontinence Episodes               Baseline  5.4 (3.26)  4.7  5.4 (3.28)  4.7       Change from baseline  -3.0 (2.73)  -2.7  -2.5 (3.06)  -2.0       Mean difference [GELNIQUE – placebo]           (95% CI)  -0.5 (-0.14, -0.87)       P-value vs. placebo  < 0.0001  Daily Urinary Frequency               Baseline  12.4 (3.34)  11.7  12.2 (3.32)  11.3       Change from baseline  -2.7 (3.21)  -2.7  -2.0 (2.82)  -1.7       P-value vs. placebo  0.0017  Urinary Void Volume (mL)               Baseline  163.4 (65.85)  160.1  167.9 (68.40)  160.6       Change from Baseline  21.0 (65.33)  11.5  3.8 (53.79)  0.0       P-value vs. placebo  0.0018 Last-Observation-Carried-Forward statistical imputation for missing data 16 HOW SUPPLIED/STORAGE AND HANDLING Unit Dose: Heat-sealed sachet containing 1 gram (1.14 mL) of GELNIQUE gel for topical use. Carton of 30 Sachets (NDC 52544-084-30) Storage Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Protect from moisture and humidity. Apply immediately after the sachets are opened and contents expelled. Discard used sachets in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.