US Pharm. 2012;37(6):12-15.
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.
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.
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.
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.
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.
Remember, if you have questions, Consult Your Pharmacist.
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2. Drekonja DM, Johnson JR. Urinary tract infections. Prim Care Clin Office Pract. 2008;35:345-367.
3. Urinary tract infections in adults. National Kidney and Urologic Diseases Information Clearinghouse. http://kidney.niddk.nih.gov/kudiseases/pubs/utiadult. Accessed April 29, 2012.
4. Urinary tract infections. MedlinePlus. www.nlm.nih.gov/medlineplus/urinarytractinfections.html. Accessed April 29, 2012.
5. Dielubanza EJ, Schaeffer AJ. Urinary tract infections in women. Med Clin North Am. 2011;95:27-41.
6. Thomas AA, Thomas AZ, Campbell SC, Palmer JS. Urologic emergencies in pregnancy. Urology. 2010;76:453-460.
7. Human drugs: combination drug containing sulfamethoxazole and phenazopyridine hydrochloride and related combination drugs; drug efficacy study implementation; conditions for approval and marketing phenazopyridine-containing drug products; labeling requirements. Fed Regist. 1983;48:34516-34519.
8. Over-the-counter drug products; safety and efficacy review. Fed Regist. 2003;68:75585-75591.
9. Submission of the National Council on Patient Information and Education (NCPIE) to the Food and Drug Administration’s Nonprescription Drug Advisory Committee (risks of acetaminophen). September 19-20, 2002. www.fda.gov/ohrms/dockets/ac/02/briefing/3882OPH1_03_NCPIE-Bullman.pdf. Accessed April 29, 2012.
10. Azo Standard. i-Health, Inc. www.azoproducts.com/products/azo_standard_facts. Accessed April 29, 2012.
11. Totman LC. Consumer Healthcare Products Association letter to FDA. Re: Docket No. 2003N-0539: over-the-counter drug products; safety and efficacy review. June 28, 2004. www.fda.gov/ohrms/dockets/dailys/04/july04/070704/03N-0539_emc-000003-01.pdf. Accessed April 29, 2012.
12. Collins PL. Polymedica Pharmaceuticals letter to FDA. Comments of Polymedica Pharmaceuticals on the request for data and information on the over-the-counter use of phenazopyridine hydrochloride as a urinary tract analgesic. Docket No. 2003N-0539. June 25, 2004. www.fda.gov/ohrms/dockets/dailys/04/july04/070704/03N-0539_emc-000001-01.pdf. Accessed April 29, 2012.
13. Latyszonek G. Johnson & Johnson letter to FDA. Re: Docket No. 2003N-0539: over-the-counter drug products; safety and efficacy; request for information on the OTC use of phenazopyridine HCl as a urinary tract analgesic. June 24, 2004. www.fda.gov/ohrms/dockets/dailys/04/June04/062804/03n-0539-c000005-01-vol4.pdf. Accessed April 29, 2012.
14. Cystex. DSE Healthcare Solutions. www.cystex.com/Pages/About%20Cystex_v3. Accessed April 29, 2012.
15. Azo Test Strips. i-Health, Inc. www.azoproducts.com/products/azo_test_strips. Accessed May 1, 2012.
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