These drugs are classified as Limited Use (offers limited benefit or benefits certain people or conditions).
Both oxybutynin (DITROPAN XL, GLENIQUE, OXYTROL, OXYTROL FOR WOMEN) and tolterodine (DETROL, DETROL LA) are approved by the Food and Drug Administration (FDA) to treat urge urinary incontinence (loss of bladder control due to sporadic contractions of the bladder muscle) and frequent urination. The drugs decrease the spasms in the bladder that produce these symptoms and increase the bladder’s ability to hold urine.
Although oxybutynin is used by some doctors to treat disorders of the stomach and intestines, it has not been proven effective for those purposes.
Oxybutynin was first approved in 1975. For years, it dominated the incontinence therapy market. It is now available as a less expensive generic. In 1998, tolterodine was approved by the FDA for the same indications. Reflecting the new competition in the market, Pharmacia & Upjohn, tolterodine’s manufacturer, was twice cited by the FDA for overstating the benefits of the drug.
These drugs are in the family known as anticholinergic agents. Such drugs block the effects of acetylcholine, a substance produced by the body and responsible for certain nervous system (parasympathetic) activities. Drugs with anticholinergic effects (including antidepressants, antihistamines, antipsychotics, drugs for intestinal problems and antiparkinsonians) all inhibit the secretion of acid in the stomach; slow the passage of food through the digestive system; inhibit the production of saliva, sweat and lung secretions; and increase heart rate and blood pressure.
Adverse effects of these drugs thus include dry mouth, constipation, difficulty urinating and decreased sweating. Angioedema and palpitations were observed with tolterodine in postmarketing surveillance. Angioedema is a potentially serious allergic reaction which can cause welts in the skin and swelling of the face, lips and tongue. In severe cases, patients may experience breathing difficulty, upper airway obstruction and blood pressure decreases. They should seek immediate medical attention if they suffer any of these symptoms, including weakness from decreased blood pressure.
Other side effects are described in the "Anticholinergic Effects" box on this page.
Because both the effectiveness and the side-effect profile of these drugs are related to their anticholinergic activity, more effective drugs in this class or stronger doses are likely to be more toxic. The drugs are contraindicated in patients with urinary retention (an inability to urinate), gastric retention or narrow-angle glaucoma.
In 2015, a study published in JAMA Internal Medicine showed that strong anticholinergic drugs were associated with an increased risk for dementia in older adults. The study also showed that higher doses and longer use of these drugs are associated with higher risk for dementia.
Refer to the August 2015 issue of Worst Pills, Best Pills News for examples of strong anticholinergic drugs.
In clinical trials, both drugs performed better than a placebo, although the extent of the drugs’ effectiveness is disappointing. For example, in one trial comparing short-acting versions of the drugs, after subtracting the effects of the placebo, tolterodine on average reduced the number of episodes of incontinence per day by 0.5, compared to a reduction of 0.8 for oxybutynin. A type of statistical summary of clinical trials known as a meta-analysis found tolterodine and oxybutynin to be clinically similar. Oxybutynin was more effective, in statistically significant results, but tolterodine was better tolerated.
Similarly, the editors of The Medical Letter on Drugs and Therapeutics (The Medical Letter) concluded their review of tolterodine by saying, “Tolterodine appears to be tolerated better than older drugs for treatment of overactive bladder, but it may be less effective.”
Extended-release formulations and the skin patch
Since the arrival of tolterodine, there has been marketing of extended-release versions of both oxybutynin and tolterodine, as well as a skin patch (OXYTROL) that delivers oxybutynin and is applied every three to four days. All seek to keep drug levels in the blood more stable and to improve patient compliance with the drugs by reducing the number of doses per day. This might reduce anticholinergic adverse effects by avoiding the ups and downs associated with intermittent drug dosing. Indeed, clinical trials show that dry mouth, in particular, is less common with the extended-release formulations. However, as The Medical Letter points out, “Both the tolerability and the effectiveness of these drugs are related to their [anticholinergic] activity. The less dry mouth, the less effective they are likely to be. None of them are as effective as advertisements to the public have suggested.”
When the oxybutynin patch was introduced, The Medical Letter had a similar reaction: “Oxybutynin delivered transdermally may cause less dry mouth than when it is taken orally, but it may be less effective for incontinence, and itching at the application site can be a problem.” Here is why the authors reached that conclusion: In the first of two clinical trials described in the drug’s product label, patch oxybutynin was compared to placebo in patients experiencing an average of about 5.1 episodes of incontinence per day. At the end of 12 weeks, there was an average reduction in incontinence episodes of 3.0 per day in patients using the patch, compared to 2.7 in patients on placebo. In the second study mentioned in the label, patients who had previously responded to an anticholinergic drug and had approximately 4.9 incontinence episodes per day were studied for 12 weeks. The average daily reduction in incontinence episodes was 2.9 in the patch-treated group, compared to 2.1 in the placebo group. These are not major differences.
Nondrug alternatives for treating urge urinary incontinence
There are also effective nondrug treatments available to manage urge urinary incontinence. In Public Citizen's view, a proper trial of these should precede drug treatment whenever possible.
The first randomized trial of behavioral treatment compared to a drug (oxybutynin) was conducted in older women and actually showed the behavioral intervention to be more effective. Behavioral treatment (four treatments including biofeedback on contraction of pelvic muscles) reduced the number of incontinence episodes by 81 percent compared with 69 percent for oxybutynin and 39 percent for placebo. The authors concluded, “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.”
A follow-up study in which patients were given the option of adding the other treatment (biofeedback for the oxybutynin group and oxybutynin for the biofeedback group) suggested that the combination is more effective than either treatment alone. The least invasive or dangerous treatment should be tried first, and for many forms of urinary incontinence, this is behavioral treatment rather than drugs.
Drug-induced urinary incontinence
Importantly, there are a number of drugs that can cause loss of bladder control. Click here to view the list.
Regulatory actions surrounding anticholinergic agents
2011: In August 2011, the drug product label for oxybutynin was updated to include information on possible side effects of angioedema of the face, lips, tongue and larynx.
In September 2011, the FDA updated the warning section of the tolterodine drug label to include information that anaphylaxis and angioedema have been reported in patients after the first or subsequent doses of the drug. In some cases, hospitalization and emergency medical treatment were required.
2013: On Jan. 25, 2013, the FDA approved over-the-counter (OTC) oxybutynin, over the objections of a slim majority of an advisory committee that had reviewed the drug. Prescription versions of oxybutynin for treatment of urinary incontinence and overactive bladder (OAB) in both women and men have been available since 1975. OTC oxybutynin, which is applied as a patch to the skin, is the first FDA-approved OTC drug for OAB in women. Because the drug is an anticholinergic, it generally should be avoided by elderly individuals, particularly those with cognitive impairment or dementia. No one should take OTC oxybutynin without first consulting a doctor.
2015: In February 2015 the FDA issued the following advisory for DITROPAN XL:
- DITROPAN XL may worsen the symptoms of Parkinson’s disease and should be used with caution in patients with Parkinson’s.
- DITROPAN XL may also worsen the symptoms of decreased gastrointestinal motility (slow movement of food through the digestive tract, which can cause constipation and nausea) and should be used with caution in patients with autonomic neuropathy (a type of nerve damage).