Do Not Use Over-the-Counter Oxybutynin Without First Checking With Your Doctor

Merck, the manufacturer of the newly approved over-the-counter (OTC) oxybutynin (OXYTROL FOR WOMEN), has announced that the product should be available in stores this fall for treatment of overactive bladder (OAB) symptoms in women over age 18.[1] Soon, consumers will undoubtedly see a wave of advertisements promoting the drug. But patients should be aware that the drug has well-known, potentially dangerous side effects.

On Jan. 25, 2013, the Food and Drug Administration (FDA) approved OTC oxybutynin,[2] over the objections of a slim majority of an advisory committee that had reviewed the drug.[3] Prescription versions of oxybutynin for treatment of urinary incontinence and OAB in both women and men have been available since 1975.[4] OTC oxybutynin, which is applied as a patch to the skin, is the first FDA-approved OTC drug for OAB in women.[5] It is part of a family of drugs known as anticholinergics, which generally should be avoided by elderly individuals, particularly those with cognitive impairment or dementia.[6] No one should take OTC oxybutynin without first consulting a doctor.

Overview of condition

OAB is a common chronic disorder of unknown cause that occurs in women and men. Its symptoms include urinary urgency (having a strong need or urge to urinate immediately), urinary frequency (needing to urinate more often than normal, typically more than eight to 10 times per day), nocturia (needing to go to the bathroom two or more times during the night) and urge incontinence (inability to control the urge to urinate, causing leakage of urine).[7] These symptoms, which can range from mild to severe, are caused by abnormal, frequent spasms or contractions in the muscles within the walls of the bladder, often when the bladder is only partially filled with urine. OAB should be diagnosed only when other causes of such urinary symptoms have been excluded.

Although OAB symptoms are not life-threatening, they can cause embarrassment and adversely affect quality of life. The management of these symptoms, including urge incontinence, should always begin with noninvasive, nondrug therapies. Behavioral interventions, including pelvic floor muscle training, bladder training and lifestyle modifications,[8] are considered the mainstays of nondrug treatment for this condition. Lifestyle modifications that may reduce OAB symptoms include smoking cessation, reduction of caffeine and alcohol intake, limitation of fluid intake, and weight loss.

The first randomized trial comparing behavioral treatment to a drug (oxybutynin), conducted in older women and published in 1998, showed the behavioral intervention to be more effective.[9] The behavioral intervention involved four sessions over an eight-week period, during which patients were taught skills and strategies for preventing incontinence. Biofeedback techniques were also used to improve contraction of pelvic muscles. This behavioral treatment reduced the number of incontinence episodes by an average of 81 percent, compared with 69 percent for oxybutynin-treated patients and 39 percent for placebo-treated patients. The authors of the study concluded that “behavioral treatment is a safe and effective conservative intervention that should be made more readily available to patients as a first-line treatment for urge and mixed incontinence.”[10]

For patients whose OAB symptoms are not adequately controlled with behavioral treatments, drug therapy may offer some limited benefit. Both oxybutynin and tolterodine (DETROL, DETROL LA)[11] — another anticholinergic drug — are FDA-approved for treating these symptoms. WorstPills.org designates these as Limited Use.[12] They work by blocking the effects of acetylcholine, a substance produced by nerves in the body that control a variety of bodily functions. In the bladder, acetylcholine causes the muscle of the bladder to contract. By blocking the action of acetylcholine, drugs such as oxybutynin cause the bladder muscles to relax and can prevent or lessen the abnormal contractions or spasms in these muscles.

In July 2012, the FDA approved another drug, mirabegron (MYRBETRIQ) for treatment of OAB. This drug is not an anticholinergic, but instead is a member of a new class of drugs known as beta-3 receptor agonists. Public Citizen’s Health Research Group strongly opposed FDA approval of this drug, and WorstPills.org has designated it as Do Not Use.[13]

Overview of oxybutynin

Oxybutynin comes in several prescription formulations, including a once-daily, controlled-release tablet (DITROPAN XL);[14] once-daily topical gels applied to the skin (ANTUROL, GELNIQUE);[15] and a transdermal patch (OXYTROL) applied twice a week to the skin.[16] The patch delivers a daily 3.9 milligram (mg) dose of oxybutynin. The OTC formulation of oxybutynin also is a transdermal patch, applied every four days, that delivers the same daily dose of oxybutynin as the prescription patch.[17]

Like all anticholinergic drugs, each formulation can cause numerous side effects, most of which are directly related to blocking the action of acetylcholine in other organs of the body beyond the bladder. Common anticholinergic side effects include:[18]

• dry mouth caused by decreased saliva production;
• constipation due to slowed passage of food through the digestive system;
• nausea and vomiting;
• difficulty swallowing;
• decreased sweating, which can lead to heat stroke and other heat-related injuries;
• difficulty urinating because of the effects on bladder muscles;
• increased heart rate and palpitations;
• daytime sleepiness;
• blurred vision; and
• impaired cognition.

An uncommon but potentially life-threatening adverse reaction associated with oxybutynin is angioedema, which causes swelling of the lips, tongue and lining of the throat. Angioedema may lead to obstruction of the airway (windpipe) leading to the lungs, resulting in difficulty breathing and, in severe cases, respiratory arrest.[19]

The introduction of the prescription oxybutynin transdermal patch in 2003[20] represented an attempt to keep levels of the drug more stable by avoiding the ups and downs associated with intermittent oral drug dosing. The advantage of the patch is that it may reduce the anticholinergic side effects and improve compliance. However, because both the desired effects on the bladder and the undesired side effects on other parts of the body are both directly related to the drug’s anticholinergic effects, a formulation of the drug that causes fewer side effects also may be less effective. Indeed, when the prescription oxybutynin patch was introduced, The Medical Letter, a medical journal that provides reviews of drugs, offered the following assessment: “Oxybutynin delivered transdermally may cause less dry mouth than when it is taken orally, but it may also be less effective for incontinence. ...”[21]

FDA approval

In March 2012, Merck submitted a new drug application to the FDA seeking approval for an OTC version of the oxybutynin transdermal patch for treatment of OAB in women only.[22] To support its application, the company submitted results from two randomized, placebo-controlled phase 3 trials.

The first trial involved approximately 500 subjects, most of whom were elderly women.[23] The subjects were randomly assigned to receive one of three different doses of the oxybutynin patch (1.3, 2.6 and 3.9 mg/day) or a placebo for a 12-week period. The 1.3 and 2.6 mg/day doses failed to show any evidence of benefit compared with placebo. The 3.9 mg/day dose showed a slightly greater reduction in the frequency of weekly episodes of incontinence compared with placebo. The number of incontinence episodes was reduced from an average of 34 to 13 per week (reduction of 21 per week) in the oxybutynin-treated subjects and from 38 to 19 per week (reduction of 19 per week) in placebo-treated subjects. Likewise, the number of times the subjects needed to go to the bathroom (frequency rate) was reduced from an average of 11.8 to 9.6 times per day (reduction of 2.2 per day) in the oxybutynin-treated subjects and from 12.3 to 10.7 times per day (reduction of 1.6 per day) in the placebo-treated subjects, demonstrating a very small benefit of oxybutynin over placebo.

The second trial involved approximately 360 patients. (Similar to the first trial, 93 percent of patients were women, with an average age of 64).[24] In this trial, the subjects were randomly assigned to receive either the oxybutynin patch (3.9 mg/day), the oral anticholinergic drug tolterodine or a placebo. Again, the oxybutynin patch was found to slightly (statistically significantly) lower the number of daily incontinence episodes compared with placebo. However, in this trial, the drug did not significantly reduce the daily urinary frequency rate compared with placebo.

Not surprisingly, across all trials used to assess the safety of the oxybutynin transdermal patch, including 17 early phase trials and the two phase 3 trials, adverse events were more common in oxybutynin-treated subjects (73 percent) than in placebo-treated subjects (57 percent).[25] Predictably, the most commonly occurring adverse events were anticholinergic side effects, with dry mouth being the most frequently reported. Also of note, the most common side effect considered to be related to treatment was localized skin reaction at the site of the patch, primarily itchy skin, which occurred in 23 percent of oxybutynin-treated subjects.[26] This also was the most common side effect leading to patients stopping the drug.

On Nov. 9, 2012, the FDA convened the Nonprescription Drugs Advisory Committee to consider whether an oxybutynin transdermal patch should be made available OTC for self-treatment by some patients instead of continuing to require a prescription in all cases. The key question considered by the committee was whether data presented by the drug’s manufacturer indicated that consumers who would purchase and use the OTC drug would be those for whom the drug is intended, based on the information provided in the proposed label for the product.[27] This process is referred to as “appropriate self-selection.”

On this key question, a majority of the advisory committee members (6 of 11) concluded that consumers cannot appropriately self-select to use this drug in the OTC setting and thus voted “no.”[28] Implicit in their “no” vote was the assessment that the FDA should not approve the drug for OTC sale. Committee members who voted “no” expressed particular concern about use of the product by elderly patients because of the significant risk of anticholinergic side effects in such patients. These members felt that consultation with a physician or pharmacist is warranted before using this drug.[29]

Committee members opposing approval also raised concern about incorrect use of the OTC product, noting that patients may not be able to accurately distinguish between OAB and other conditions with similar symptoms (for example, a bladder infection).[30] Several members voiced concern that use of OTC oxybutynin without evaluation by a health care provider could lead to a delay in diagnosis of conditions that initially cause OAB-like symptoms, including early cancer of the bladder, certain neurologic conditions and diabetes. Members who were urologists stated that they would not prescribe oxybutynin to a patient without first doing a urinalysis to look for blood or other abnormalities in the urine that might indicate a disease other than OAB.[31] Committee members also felt strongly that patients need to understand that behavioral therapy is the first-line treatment for OAB and should always be used in combination with drugs such as oxybutynin.

A further concern raised by one committee member included the public perception that an OTC drug is likely safer than a prescription drug because its OTC status means that there is no need to see a doctor to obtain the drug.[32]

Another important consideration for the advisory committee was whether patients would appropriately stop using the drug, as instructed on the label,[33] if their condition worsened or new symptoms appeared, or if the condition did not improve after two weeks of use.

Data presented by Merck from a study testing OTC use of the oxybutynin patch showed that some patients whose symptoms did not improve or worsened continued to use the drug beyond two weeks, despite the label instructing otherwise.[34] Such data suggest that some patients do not read or follow the directions on the label, which are intended to ensure safe use.

Despite the above concerns being raised by the majority of the advisory committee members, the FDA decided to approve OTC oxybutynin on Jan. 25, 2013.

What You Can Do

If you experience symptoms of OAB, such as urinary urgency, frequency, nocturia or urge incontinence, you should contact your primary health care provider for further evaluation. Your doctor can confirm the diagnosis of OAB and rule out other disorders. You should not use OTC oxybutynin unless directed to do so by your health care provider. Discuss with your doctor behavioral interventions, including lifestyle modifications, before starting any drug therapy for OAB.

If behavioral interventions do not result in adequate improvement of your symptoms, it may be reasonable to try therapy with a drug such as oxybutynin. The benefits of the drug may be minimal. You should not take OTC or prescription oxybutynin if you are pregnant; have had allergic reactions to the drug; or have urinary retention (you are unable to empty your bladder), gastric retention (your stomach empties abnormally slowly after a meal) or the eye disease narrow-angle glaucoma.[35]

If you start OTC oxybutynin, read the drug label and be alert for anticholinergic and other side effects. If you experience any swelling of the lips, tongue or throat, you should immediately discontinue the drug and seek urgent medical attention. If you experience other bothersome effects, contact your health care provider. You also should be aware that the current label for the prescription version of oxybutynin states, “Advise patients not to drive or operate heavy machinery until they know how OXYTROL affects them.”

References

[1] Merck. News release: Merck announces full-year and fourth-quarter 2012 financial results. Page 5. http://www.merck.com/investors/financials/4Q12SERelease-01-02-2013.pdf. Accessed June 14, 2012.

[2] U.S. Food and Drug Administration. FDA news release: FDA approves over-the-counter Oxytrol for Women to treat overactive bladder. January 25, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336815.htm. Accessed June 14, 2013.

[3] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Summary minutes of the November 9, 2012, meeting of the Nonprescription Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM334801.pdf. Accessed June 14, 2013.

[4] U.S. Food and Drug Administration. Drugs@FDA: FDA approved products: Ditropan. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed June 14, 2013.

[5] U.S. Food and Drug Administration. FDA news release: FDA approves over-the-counter Oxytrol for Women to treat overactive bladder. January 25, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336815.htm. Accessed June 14, 2013.

[6] The American Geriatric Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society update Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012.

[7] FDA Advisory Committee Briefing Document. Page 13-14. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM327160.pdf.

[8] Tran K, Levin RM, Mousa SA. Behavioral intervention versus pharmacotherapy or their combination in the management of overactive bladder dysfunction. Adv Urol. 2009:345324. doi: 10.1155/2009/345324. Epub Dec 15, 2009.

[9] Burgio KL, Locher JL, Goode PS, et al. Behavioral vs drug treatment for urge urinary incontinence in older women: A randomized controlled trial. JAMA. 1998;280:1995-2000.

[10] Ibid.

[11] Detrol label. August 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020771s028lbl.pdf.

[12] WorstPills.org. Oxybutynin and Detrol monographs. /monographs/view/111.

[13] WorstPills.org. Troubling New Drug Approvals of 2012. /newsletters/view/839.

[14] Janssen Pharmaceuticals. Drug label for Ditropan XL. Revised November 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020897s031lbl.pdf. Accessed June 14, 2013.

[15] Watson Pharm. Drug label for Gelnique. Revised October 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022204s006lbl.pdf. Accessed June 14, 2013.

[16] Watson Pharma. Drug label for Oxytrol. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021351s008s009lbl.pdf. Accessed June 14, 2013.

[17] U.S. Food and Drug Administration. FDA news release: FDA approves over-the-counter Oxytrol for Women to overactive bladder. January 25, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336815.htm. Accessed June 14, 2013.

[18] Janssen Pharmaceuticals. Drug label for Ditropan XL. Revised November 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020897s031lbl.pdf. Accessed June 14, 2013.

[19] Detrol Label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020897s031lbl.pdf.

[20] Oxytrol approval letter, dated 2003: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2003/21351ltr.pdf.

[21] Oxybutynin transdermal (Oxytrol) for overactive bladder. The Medical Letter on Drugs and Therapeutics. 2003(May 12):45:38-39.

[22] U.S. Food and Drug Administration. Letter to Merck Consumer Care for NDA 202211. January 25, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/202211Orig1s000ltr.pdf. Accessed June 14, 2013.

[23] U.S. Food and Drug Administration. FDA briefing document from nonprescription drugs advisory committee: Oxybutynin Transdermal System NDA 202211. Meeting date November 9, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM327160.pdf. Accessed June 14, 2013.

[24] Ibid.

[25] Ibid.

[26] Ibid.

[27] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Summary minutes of the November 9, 2012, meeting of the Nonprescription Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM334801.pdf. Accessed June 14, 2013.

[28] Ibid.

[29] Ibid.

[30] Ibid.

[31] Ibid.

[32] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Transcript of the November 9, 2012, meeting of the Nonprescription Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM336189.pdf. See page 229. Accessed July 1, 2013.

[33] U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Summary minutes of the November 9, 2012, meeting of the Nonprescription Drugs Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM334801.pdf. Accessed June 14, 2013.

[34] Ibid.

[35] Watson Pharma. Drug label for Oxytrol. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021351s008s009lbl.pdf. Accessed June 14, 2013.