Urinary Tract Infections and the Role of Nonprescription Products

For years, patients with urinary tract infections (UTIs)
have asked pharmacists what they can take without seeing a physician.
Several products promise relief of UTI symptoms and/or claim to have an
antibacterial effect that inhibits progression of the infection, but
they are not proven safe and effective for any nonprescription use at
present.
Patients and UTIs
UTIs are much more common among women than men.1,2
Patients may ask the pharmacist about such symptoms as frequent and
intense urge to urinate, urethral or bladder burning, and pain during
urination.3-5 In older patients and males, UTIs also cause
fatigue, shakiness, weakness, muscle aches, and pain in the abdomen.
Patients may notice cloudy, dark, or bloody urine that has an
objectionable odor. If infection reaches the kidneys or prostate, fever
is also common. Patients may complain of pain in the back or side (below
the ribs), as well as nausea and vomiting.
Untreated UTIs
If a bacterial UTI is untreated and the causative organisms ascend the ureter without being washed out, pyelonephritis (kidney infection) is possible.5 At least 20% to 40% of women with asymptomatic bacteriuria will develop pyelonephritis.6
With appropriate treatment, the risk is reduced by 90%. This
underscores the importance of pharmacists recommending physician visits
in all cases.
Nonprescription UTI Products
Several widely available nonprescription products promise
relief of UTI symptoms. They include single-entity phenazopyridine
products (e.g., Azo Standard) and a combination product containing
methenamine and sodium salicylate (e.g., Cystex).7
Pharmacists may justifiably ask whether these products are safe and
effective when used by a patient with a UTI who does not plan to see a
physician for a prescription antibiotic or antibacterial.
The Status of Phenazopyridine
In 1983, the FDA published a Drug Efficacy Study
Implementation (DESI) notice with conditions for approval and marketing
of all phenazopyridine products.7 These included
sulfameth-oxazole/phenazopyridine combinations (e.g., Azo Gantanol),
similar combination products, and single-entity phenazopyridine
products. (Phenazopyridine had traditionally been included in
sulfonamide combinations to provide relief of pain, burning, or urgency
caused by a sulfonamide-susceptible organism.) The FDA presented newly
required statements for all phenazopyridine products intended to relieve
symptoms associated with a UTI. One of the statements was critical in
determining the length of dosing: “Treatment of a urinary tract
infection with phenazopyridine HCl or a combination drug product
containing phenazopyridine HCl should not exceed 2 days because there is
a lack of evidence that the combined administration of phenazopyridine
HCl and an antibacterial provides greater benefit than administration of
the anti-bacterial alone after 2 days.”7
The FDA also required the following carcinogenicity
statement on all phenazopyridine labels: “Long-term administration of
phenazopyridine hydrochloride has induced neoplasia in rats (large
intestine) and mice (liver). Although no association between
phenazopyridine hydrochloride and human neoplasia has been reported,
adequate epidemiological studies along these lines have not been
conducted.”7
The 1983 document did not refer specifically to safety and efficacy of OTC single-entity phenazopyridine products.7 However, in 2003 the FDA did request data on safety and efficacy of all nonprescription urinary antiseptics/analgesics.8
This document discussed phenazopyridine in depth. The first issue the
agency reviewed was the strange dual marketing of the ingredient, a
situation that has long puzzled pharmacists. For decades,
phenazopyridine has been available as prescription single-entity 100 and
200 mg tablets (e.g., Pyridium), as well as in combinations, many of
which are no longer available (e.g., Azo Gantanol, Azo Gantrisin). The
core issue is why tablets containing 95 and 97.5 mg of phenazopyridine
are available without prescription, when tablets containing 100 mg are
prescription-only. In other words, how can the addition of a relatively
minor 2.5 mg cause a product to require a prescription? The FDA
attempted to explain this seemingly incongruous situation, pointing out
that the ingredient’s extensive U.S. marketing history as a
nonprescription ingredient predated the 1951 Durham-Humphrey Amendment
to the Food, Drug, and Cosmetic Act that delineated which conditions
would require prescription status. On the basis of this marketing
history alone, phenazopyridine was allowed to retain nonprescription
status, a situation that continues to this day.
The best known phenazopyridine nonprescription product is Azo Standard.9
Azo Standard contains 95 mg of phenazopyridine per tablet and Azo
Standard Maximum Strength contains 97.5 mg of phenazopyridine.10 The dosage of both is 2 tablets 3 times daily with or after meals as needed.
The FDA conducted an examination of nonprescription
phenazopyridine products prior to publication of the 2003 call for data,
reporting that one manufacturer did not place the required 1983
carcinogenesis warning on the outer package, but placed it on an insert
included in the package.8 In that case, a purchaser could not
be warned until after the product was bought and the tamper-proof
packaging destroyed. Should the purchaser subsequently decide against
using the product, his or her ability to return it for a refund would be
impaired.
The FDA addressed several questions to manufacturers
regarding the safety and efficacy of phenazopyridine in its 2003 call
for data8:
1. Is this condition (i.e., a UTI) appropriate for self-medication?
2. If the answer to the first question is yes, should the
product labeling mention the possible need for treatment with an
antibacterial drug also?
3. Is there a valid basis for having single-ingredient
prescription products with a 200 mg dosage and OTC products with a 190-
to 195-mg dosage? What data support these dosages? (Note that this
statement refers to the manufacturer-recommended dosages of 2 tablets of
Azo Standard, containing 95 mg per tablet, and 2 tablets of Azo
Standard Maximum Strength, containing 97.5 mg per tablet).
4-7. These items dealt with potential carcinogenicity. The
FDA asked whether any epidemiological studies since 1978 had addressed
the issue, whether the neoplasia findings were of sufficient concern to
restrict phenazopyridine to prescription status, and whether the
carcinogenicity label should be required to appear on the outer
packaging.
8. Provide updated safety data both from the literature and from adverse event reports for the last 20 years.8
Manufacturers Respond to the FDA
The FDA received at least three responses to its list of
phenazopyridine questions within a 6-month period. The Consumer
Healthcare Products Association (CHPA) asked the FDA to review
phenazopyridine, but completely sidestepped the issue of
carcinogenicity.11 A submission from Polymedica
Pharmaceuticals (distributor of Azo Standard) asserted that urinary
discomfort should be self-treatable, and further argued against warning
patients on product labels that they may need a concomitant
antibacterial.12 Polymedica also claimed that phenazopyridine
dosages of 190 to 195 mg are safe and effective, but did not submit
clinical dosage studies to support its assertions. Polymedica argued
against including any carcinogenesis statement. In short, the submission
was entirely laudatory about phenazopyridine, although it did not
report newly conducted clinical studies, as would have been required by
the FDA to establish safety and efficacy.
A brief submission from Johnson & Johnson (marketers
of the now-discontinued Uristat, a nonprescription phenazopyridine
product) made essentially the same arguments as Polymedica, denying the
need for carcinogenicity labeling.13 This submission also failed to include new clinical studies providing evidence of safety and efficacy.
The Status of Methenamine Combination Products
The FDA’s 2003 request for data and information also
targeted a combination product containing methenamine, sodium
salicylate, salicylamide, and benzoic acid.8 The FDA
mentioned that the manufacturer would be required to make a new
submission, as the old one from the 1970s was badly outdated. The
product most closely resembling this combination at present is Cystex.9
Each tablet contains 162 mg of methenamine and 162.5 mg of sodium
salicylate, with benzoic acid listed as an inactive ingredient. The
dosage is 2 tablets with a full glass of water 4 times daily.14
None of these ingredients as dosed in the nonprescription product is
proven to be safe and effective at preventing or treating UTIs at the
present time.
Potential Misuse of Nonprescription UTI Products
The danger of carcinogenicity with phenazopyridine
apparently remains open. However, the FDA and the manufacturers
overlooked a far more likely scenario that could cause patient harm. If a
woman has a UTI, she should make an appointment with a physician to
receive the appropriate antibacterial/antimicrobial prescription. If she
unwisely chooses to take an OTC product as her sole treatment, she may
experience relief of discomfort and assume that she does not need to see
a doctor. By doing so, she avoids the trouble of providing a urine
specimen and saves the associated costs of a physician office visit
(e.g., income loss from taking time off from work). Should she fail to
obtain a prescription, her UTI may continue, worsening as the days pass
without effective treatment.
Manufacturers responsibly urge purchasers on product
labels to obtain a diagnosis and use the product only for relief while
they are waiting to see their physicians or for the prescription to
begin to work. The labels also warn against use for more than 2 days.
Despite the presence of these warnings, research conducted by the
National Council on Patient Information and Education confirmed that
purchasers often disregard package labels.9 In this case, disregarding the label could lead to permanent kidney damage.6 Thus, the advice and assistance of the pharmacist is crucial when consumers request these products.
PATIENT INFORMATION
Types of UTIs
Many people refer to a urinary tract infection (UTI) as a
bladder or kidney infection, but it is more complicated than that. If
the infection occurs in the urine passage (urethra), it is known as urethritis. If it reaches the bladder, it is called cystitis. If the UTI moves to the kidney, it is known as pyelonephritis.
Are UTIs Serious?
Most UTIs are not serious if they are treated rapidly and
appropriately. But some can lead to dangerous problems, such as kidney
infections. You may lessen the risk of this by promptly seeing a
physician, getting your antibiotic/antimicrobial prescription filled,
and taking the medication exactly as directed to kill the organisms. If
you fail to do so, a kidney infection can occur and become chronic.
Chronic kidney infections can lead to permanent damage, such as scarring
of the kidneys, reduced kidney function, hypertension, and other
issues.
Nonprescription Products for UTIs
When you have a UTI, it is vital to make a doctor’s
appointment. You should never try to treat it on your own with home
remedies or nonprescription products. Some women purchase OTC products
without medical advice, such as those containing phenazopyridine (e.g.,
Azo Standard). Purchasers may believe that this ingredient alone can
cure the UTI. This is a common misconception, as the product may provide
only temporary relief of symptoms (e.g., burning, pain, urgency,
frequency).
After obtaining this relief, a woman may decide that the
UTI is gone and that she does not need to see her physician after all.
This is a mistake. Phenazopyridine does not act to kill bacteria, so any
relief obtained is probably short-lived. The label warns against using
the product for more than 2 days, and advises seeing a physician if
symptoms last more than 2 days. Of course, the safest course of action
is to see a physician first, and ask whether this product should be used
along with the antibiotic/antibacterial prescription product. Further,
no herbal product or dietary supplement is proven safe or effective for
preventing or treating a UTI.
Home Remedies
Some women attempt to prevent UTIs by drinking cranberry
juice. Cranberry juice is not proven medically to prevent UTIs. Neither
are cranberry tablets
(e.g., Azo Cranberry). A more dangerous practice is to rely on
cranberry juice to treat a UTI. Cranberry juice has no proven
antibiotic/antibacterial activity that would eradicate an existing UTI.
As described above, a physician visit is mandatory.
Preventing UTIs
There are some commonsense steps you can take to prevent
UTIs. Drink plenty of water every day. Urinate whenever you feel the
slightest urge and never try to hold it in. Urinate right after sexual
intercourse, as organisms can move from the bowel or vagina to the
urethral opening. If you have recurrent UTIs, switch to a different
method of birth control. Condoms, spermicides, and diaphragms may be
more conducive to the development of UTIs.