Phenazopyridine

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Continuing Education Activity

Phenazopyridine is an azo dye first synthesized in 1914 and adopted by the U.S. Pharmacopoeia in 1928. Phenazopyridine is used as an adjuvant medicine to treat the discomfort, urgency, and frequency associated with lower urinary tract infections (UTIs). It is commonly used and available medication over the counter (OTC) and with a prescription. Phenazopyridine is compatible with concurrent antibiotic therapy, and its analgesic properties should improve the patient’s comfort until antibiotics can control the infection. This activity reviews the use, mechanism of action, adverse effects, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) of phenazopyridine pertinent for members of the healthcare team in the management of patients with UTI and related conditions. In this article, a UTI will refer to an infection of the lower urinary tract, the bladder (cystitis), and the urethra.

Objectives:

  • Identify the mechanism of action of phenazopyridine.
  • Review the indications for phenazopyridine use.
  • Describe the potential adverse effects of phenazopyridine.
  • Summarize the interprofessional team strategies for improving care coordination and outcomes when phenazopyridine is administered in UTIs and related conditions.

Indications

Phenazopyridine is an azo dye first synthesized in 1914 and adopted by the U.S. Pharmacopoeia in 1928.[1][2] There was no regulatory requirement for pre-clinical studies to prove that medications were safe and effective. Phenazopyridine was widely prescribed to treat lower urinary tract infections (UTIs) under the false assumption that it was bactericidal. Antibiotics, introduced in the late 1930s, provided a curative treatment for UTIs, and the use of phenazopyridine continued as an adjuvant.[1]

Over the decades, the drug was marketed alone and combined with an antibiotic or other agents.[3] Currently, the drug is sold as a single-agent product and is classified as a urinary analgesic. It is FDA-approved and used in the outpatient setting to relieve the burning, urgency, frequency, and pain associated with lower UTIs.

Phenazopyridine is compatible with concurrent antibiotic therapy, and its analgesic properties should improve the patient’s comfort until antibiotics can control the infection. Because of its analgesic properties, it should decrease the need for systemic analgesics and other medications. In clinical and inpatient environments, phenazopyridine alleviates these same symptoms following endoscopic procedures, the passage of catheters, trauma, and surgery. The drug has limited diagnostic uses.

Mechanism of Action

Although this mechanism has not been substantiated, phenazopyridine is believed to exert an analgesic action locally on the urinary tract mucosa.[1][4] There is some evidence that it inhibits afferent nerve fibers in the bladder that are mechanosensitive.[5] The drug is now known to inhibit kinases involved with cell growth, metabolism, and nociception.[6]

The pharmacokinetic characteristics of phenazopyridine are known but have not been evaluated in depth. The drug is absorbed in the gastrointestinal tract quickly following oral administration and achieves a Tmax in the plasma after 2 to 3 hours.[7][8]  The absorption location is unknown, and two distinct areas may be involved.[7] Studies investigating half-life report has varying results, and one investigation reported an average half-life of 9.4 hours.[8] The extent of protein binding is unknown.

Studies show that the kidneys excrete roughly one-half (41 to 65%) of phenazopyridine as an unchanged drug following an oral dose.[9][10] Information about the drug's metabolism is derived from animal studies.[10] Two metabolites, aniline and triaminopyridine, may be responsible for causing hematologic and renal adverse events, respectively.[9][11] A further metabolite of aniline is N-acetyl-4-aminophenol, commonly known as acetaminophen and paracetamol.  However, the clinical significance of this metabolite is believed to be nil.

Administration

Clinical Studies

Phenazopyridine was marketed before the regulations required pre-clinical studies to prove a drug's safety and effectiveness. As a result, large and robust studies are not available, and the drug’s role in treating UTIs is primarily based on clinical observations. A critical analysis of the available studies has been published. One study involved 118 patients, 64% of which had cystitis or pyelonephritis. All subjects received phenazopyridine 200 mg three times a day for two weeks, a longer duration than what is currently recommended. The study was open-label and had one treatment arm. The authors reported improved symptomatic response dysuria (95.3%), burning (93.6%), frequency (85.6%), and nocturia (83.7%).[1]

Another investigation involved 49 subjects with acute UTIs who received phenazopyridine 200 mg three times a day. Patients were assessed after 24 and 72 hours for nocturia, burning, and urgency. Mean symptom scores were reported as slight (3 or 4 symptoms) after 24 hours and none (1 or 2 symptoms) after 72 hours.[12]

Phenazopyridine was compared to flavoxate, an antispasmodic drug, in 392 subjects with UTI symptoms, incontinence, and/or suprapubic pain. The subjects received either phenazopyridine 200 mg three times a day or flavoxate 100 mg four times a day. The differences in clinical response were not statistically significant. In a separate analysis of men with prostatitis, the subjects were treated with phenazopyridine 200 mg three times a day. Satisfactory alleviation of symptoms was reported in only 31% of the subjects.[13] 

Use in Adults

Phenazopyridine is usually dosed with 100 to 200 mg three times a day in healthy adults. Over-the-counter (OTC) tablets are available in lower strengths, ranging from 50 mg to 99.5 mg. The OTC tablets are frequently taken two pills at a time and three times a day, effectively matching the prescription regimen. The OTC formulation is helpful for temporary symptom relief pending further medical care. Phenazopyridine is best taken with or after meals to avoid stomach upset.[13] 

The recommended treatment duration is two days, and this short period alleviates discomfort until antibiotics can control the infection and protects the patient from potentially severe adverse effects. Some clinicians advocate that patients with uncomplicated UTI symptoms take OTC phenazopyridine alone for five days hoping that the infection will resolve spontaneously. However, most patients prefer a more certain resolution, the practice is not yet validated, and five days of therapy is longer than currently recommended.

The drug is commonly used in outpatients with uncomplicated UTIs to improve their comfort. However, it is not routinely used in treating complicated UTIs or inpatient settings when treating acute pyelonephritis in patients with risk factors for developing a more severe infection. 

Diagnostic Uses

One study indicates that using oral phenazopyridine with dextrose instillation is effective in visualizing ureteral patency during intraoperative cystoscopy.[14] A single 200 mg dose the evening before an operation helps identify the urethral orifice.[15] Phenazopyridine is not a useful diagnostic tool for detecting incontinence or premature membrane rupture.[16][17]

Use in Cystoscopy

In a randomized controlled study, 97 cystoscopy patients received either phenazopyridine 200 mg twenty minutes before the procedure and then every eight hours for three total doses and lidocaine gel or only lidocaine gel. Subjects who received the phenazopyridine and lidocaine gel reported less discomfort and lower heart rates than the lidocaine gel control group. The authors concluded that phenazopyridine reduces pain intensity associated with both cystoscopy and during the first urination.[18]

Post Operative Use

In a randomized controlled study of 152 women undergoing prolapse surgery, administration of a single phenazopyridine 200 mg dose postoperatively did not improve postoperative voiding compared to the control group.[19] A retrospective cohort study involving 149 women who underwent a retropubic mid-urethral sling operation reported that phenazopyridine improved postoperative voiding.[20]

Supportive Care

Phenazopyridine has been used safely for up to two months as supportive care in radiation-induced cystitis.[21]

Pediatrics Considerations

Dosing for children ages 6 to 12 is 12 mg/kg/day in three equally divided doses. A pediatric formulation is not commercially available and requires compounding.[22] However, it should be noted that review articles and consensus publications discussing the treatment of pediatric UTIs do not mention phenazopyridine.[23][24]

Patients with Renal Insufficiency

In mild renal failure (glomerular filtration rate over 50 mL/min), the recommended dosing frequency is every 8 to 16 hours. Phenazopyridine should not use in patients with a glomerular filtration rate of less than 50 mL/min.[25]

Pregnancy/Lactation Considerations

Phenazopyridine is FDA class B and is known to cross the placenta.[17] It should be used in pregnancy only if it is clearly indicated. There is no information about the drug’s use during lactation.

Adverse Effects

Phenazopyridine has a good safety profile, and severe adverse events are uncommon. Severe and potentially life-threatening adverse effects are typically limited to cases of overdose, preexisting renal insufficiency, and exceeding the dosing and duration recommendations.[26][27]

The following adverse drug reactions have been reported:

  • CNS: Headache
  • Dermatological: Rash, discoloration, pruritus
  • Hypersensitivity: Anaphylactoid-like reaction and/or hypersensitivity hepatitis
  • Gastrointestinal: Nausea, vomiting, and/or diarrhea
  • Hematologic: Methemoglobinemia, sulfhemoglobinemia, and hemolytic anemia (potential hemolytic agent in G-6-PD deficiency)[28][29][30]
  • Other: Discoloration of body fluids, aseptic meningitis, visual disturbances, renal/hepatic toxicity associated with overdose, jaundice, and renal calculi[4]

The drug is known to cause methemoglobinemia and hemolytic anemia, likely through a metabolite, aniline. In cases of hemolytic anemia, microscopic examination of red blood cells will reveal the presence of Heinz bodies and degmacytes(bite cells).[31] 

Treatment of drug-induced hemolytic anemia is discontinuing the offending agent and considering the use of corticosteroids.[32] Interstitial nephritis may also occur after an overdose, although it has been reported with therapeutic doses and normal renal function.[33] In cases of phenazopyridine-induced nephrotoxicity, the use of roentgenographic contract media may result in additional renal damage.[34] 

Cases of hepatitis appear to be associated with dose-related hypersensitivity.[35][36] Other adverse effects such as thrombocytopenia and allergic-like skin reactions are rare.[37][38]

Contraindications

Contraindications

Patients with previously demonstrated hypersensitivity to phenazopyridine should not receive the drug. In addition, it is contraindicated in severe renal insufficiency (glomerular filtration rate less than 50 mL/min). It is now also contraindicated in patients with severe hepatitis.

Precautions

Patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency are at greater risk of hemolysis and should not receive phenazopyridine.[28] In addition, in cases of impaired hepatic function, the drug should be administered cautiously.

Carcinogenicity

Rats fed phenazopyridine developed liver and colorectal tumors, both malignant and benign. There has been no association between phenazopyridine use in humans and carcinogenicity.

Interactions

Phenazopyridine has no known drug-drug or drug-food interactions. The drug is also a dye, so it is expected to interfere with urinalysis tests that use a color reaction or spectrometry.  Theoretically, there is an increased risk of methemoglobinemia occurring when phenazopyridine is combined with a local anesthetic (benzocaine and others). Such a risk is not substantiated in the medical literature, and the drug has been used successfully with lidocaine gel.[18]

Monitoring

Patient Education

Because phenazopyridine is available as an OTC product, there is an opportunity for misuse and abuse. Effective patient education is important.[39] Patients should be instructed that phenazopyridine is not an antibiotic and only provides symptomatic relief.[40]

Although some uncomplicated lower UTIs spontaneously resolve and even have a bacteriological cure, the cure rate is comparatively low. It is well documented that appropriate antibiotic treatment results in faster symptom resolution and bacteriological cure than placebo.[41][42] If an antibiotic is prescribed, the phenazopyridine improves comfort until the antibiotic clears the offending bacteria.

In two surveys of OTC phenazopyridine purchasers in Los Angeles County, 71% of respondents were unaware their symptoms were from a bladder infection or UTI, and 38% reported buying the drug as a substitution for medical care.[43][44]

Because phenazopyridine is a dye, the drug will change the urine color to a reddish-orange color. The color change is from the drug and is not a symptom of bleeding. Any spilled urine may result in staining, especially on clothing. Inappropriately prolonged use may result in a yellowing of the skin and sclera. The drug is also reported to change the color of tears and ejaculate and stain contact lenses. Patients should also report any urinary tract symptoms that do not resolve or worsen.[22][39]

Toxicity

Phenazopyridine-induced methemoglobinemia is rare, and there have been fewer than 50 cases published since 1951. Methemoglobinemia is managed with standard treatment, methylene blue (1 to 2 mg/kg/dose administered IV as a 1% solution as needed) being the antidote of choice. Methylene blue should not be given to patients with known or suspected G6PD deficiency. It should also be avoided in patients taking antidepressants, as it increases the risk of serotonin syndrome.[45] 

In these cases, high-dose ascorbic acid is the recommended alternative antidote given intravenously. It is now known why phenazopyridine and other drugs, such as dapsone and chloroquine cause methemoglobinemia more frequently compared to other medications. Oxidative Heinz body hemolytic anemia also may precipitate, and "bite cells" (degmacytes) can be present in chronic overdosage incidents.

Renal toxicity, occasional renal failure, and/or hepatic impairment can occur in overdose patients.[46] The mechanism of renal toxicity is unclear, but a metabolite, triaminopyridine, may damage the distal renal tubules.[11] Life-threatening side effects, such as hemolytic anemia with renal failure, have been related to inappropriate OTC phenazopyridine use and intentional overdose.[47][48]

Enhancing Healthcare Team Outcomes

Because phenazopyridine is available as an OTC product, there is an opportunity for misuse and abuse. In conducting medication reviews, collecting OTC drug use and prescription use should be considered.[48] 

The health care team should provide effective patient education. Treatment with an appropriate antibiotic will result in much faster symptom relief and eradication of the infection. Clinicians should prescribe phenazopyridine to relieve the burning, urgency, frequency, and pain associated with lower UTIs, possibly for two days only until the antibiotic should have cleared the offending bacteria. Use after two days may delay diagnosis and appropriate treatment.

Nurses should verify the dose before administration and counsel patients that the longer duration of treatment increases the potential for severe adverse effects. [Level 4]

Pharmacists should educate patients that phenazopyridine only provides symptomatic relief and should not replace seeing a medical provider but should instead work collaboratively with the patient's medical provider, reporting their findings regarding the patient's medication regimen. Open communication and collaborative work of all interprofessional health care team members (MDs, DOs, NPs, PAs, nurses, and pharmacists) improves patient safety and betters treatment outcomes using phenazopyridine.



(Click Image to Enlarge)
Phenazopyridine chemical structure
Phenazopyridine chemical structure
Contributed by John H. Eastham, Pharm.D., M.A.

(Click Image to Enlarge)
Phenazopyridine metabolism
Phenazopyridine metabolism
Contributed by John H. Eastham, Pharm.D., M.A.

(Click Image to Enlarge)
OTC phenazopyridine U.S. FDA labeling
OTC phenazopyridine U.S. FDA labeling
Contributed by John H. Eastham, Pharm.D., M.A.

(Click Image to Enlarge)
Urine colored with Phenazopyridine
Urine colored with Phenazopyridine
Contributed by John H. Eastham, Pharm.D., M.A.
Article Details

Article Author

john H. eastham

Article Editor:

Preeti Patel

Updated:

5/24/2022 11:39:12 AM

PubMed Link:

Phenazopyridine

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