Safety analysis of long-term phenazopyridine use for radiation cystitis

Abstract

Background

Phenazopyridine is a urinary tract analgesic indicated for short-term treatment of irritation in the lower urinary tract. Despite the lack of evidence for extended use, it is often used in varying durations for supportive care for cancer patients with radiation-induced cystitis. The objective of this study was to compare the incidence of adverse drug reactions in patients with radiation cystitis receiving long-term phenazopyridine (>14-day supply) compared to a matched comparator group.

Methods

This retrospective cohort study compared adverse events among cancer patients with and without phenazopyridine exposure. Included patients received radiation and at least one chronic medication between 1 July 2008 and 30 June 2017. The phenazopyridine group also received >14-day supply of phenazopyridine during the study period. Patients were matched based on gender, age (±5 years), cancer diagnosis, and palliative or curative treatment intent. Data collection occurred at baseline, during the time of presumed exposure, and through the end of the study period for surveillance purposes.

Results

A total of 272 patients received phenazopyridine for >14-day supply during the study period. Of these, 90 patients were included and matched to an equal number of patients in the comparator group. The included patients were similar between groups and were largely male with a diagnosis of prostate cancer. Most patients received between a 30- and 60-day supply of phenazopyridine. There were a total of 13 adverse drug reactions in the phenazopyridine group and 18 in the comparator group (p = 0.32). No differences were identified between the phenazopyridine and comparator groups for the incidence of individual adverse drug reactions, emergency department visits, hospitalizations, or new diagnoses of hepatocellular or colorectal cancer.

Conclusion

There was no difference in adverse drug reactions among patients receiving phenazopyridine for >14 days compared to a matched comparator group. The overall incidence of adverse events in both groups was low.

Keywords

Dysuria uroanalgesic urinary tract analgesic supportive care urinary tract infection adverse drug reaction cancer

Introduction

Phenazopyridine is a urinary tract analgesic, or uroanalgesic, which has been in use for more than 100 years.¹ In the United States, it was marketed prior to the Food, Drug, and Cosmetic Act of 1938. As such, phenazopyridine is considered a “grandfathered” drug that lacks both the safety and efficacy data required for Food and Drug Administration approval. While it has not received formal approval, prescribing information for phenazopyridine supports its use for the symptomatic relief of irritation triggered by urinary tract infections (UTIs), trauma, surgery, or various procedures.²

Phenazopyridine is available both with a prescription and over-the-counter, with usual dosing of 200 mg three times daily after meals. It is rapidly excreted in the urine, where it exerts a topical analgesic effect via an unknown mechanism of action. Prescribing information states that phenazopyridine use should not exceed two days for patients receiving concurrent antibiotic treatment for a UTI, and that the underlying cause of urinary irritation should be addressed and phenazopyridine discontinued when symptoms are controlled.² For non-infectious clinical scenarios, there is a lack of evidence surrounding the optimal duration of therapy. The American Hospital Formulary Service states that therapy may be extended for up to 15 days in non-infectious scenarios, but no specific reference is cited with this recommendation.³

Phenazopyridine is also used in clinical practice to provide supportive care for cancer patients with radiation-induced cystitis, although this practice also lacks clinical data to support its use.^4,5 Normal bladder epithelium has a low proliferative rate, making it sensitive to radiation used in the treatment of cancers affecting pelvic organs, including bladder, gynecological, prostate, and rectal cancers.^4,5 The incidence of acute radiation cystitis is highly variable and dose-dependent. Among patients receiving pelvic radiation, the incidence of acute radiation-induced cystitis is estimated to be between 23% and 80%.⁵ During or within three to six months of radiation, patients may present with dysuria, frequency, and urgency.⁴ Treatment is limited to supportive care with agents such as phenazopyridine, flavoxate hydrochloride, and oxybutynin, the durations of which are not well-defined.^4,5 Late radiation cystitis may also occur six months or more after radiation, with a mean latent period of 35 months. Among patients receiving pelvic radiation, the incidence of late radiation cystitis is estimated to be 5–10%, most commonly among patients with bladder cancer. Hematuria is the hallmark symptom, but dysuria, frequency, and urgency are often present as well. Depending on the extent of hematuria, the severity of late radiation cystitis can range from mild to life-threatening hemorrhage. Initial management may include fluid resuscitation and blood transfusion, followed by catheterization and bladder irrigation.⁵ Phenazopyridine has a limited role in late radiation cystitis.^4,5

There are risks that should be considered when utilizing phenazopyridine. The most common adverse drug reactions (ADRs) associated with phenazopyridine include headache, rash, pruritus, skin discoloration, and gastrointestinal disturbance.² Severe adverse effects include methylglobinemia, hemolytic anemia, thrombocytopenia, neutropenia, nephrotoxicity, and hepatotoxicity.^1,2,6 In addition, phenazopyridine is classified by the U.S. Department of Health and Human Services as “reasonably anticipated to be a human carcinogen.”⁷ In two rodent species, phenazopyridine exposure was associated with colorectal and hepatocellular malignancy.⁷ Consideration of these risks may be particularly important when utilizing phenazopyridine in extended durations given increased drug exposure.

Given its far-reaching use in various facets of the medical community, particularly supportive care for radiation cystitis, it is clinically relevant to explore the safety of long-term phenazopyridine use. The objective of this study was to compare the incidence of composite ADRs for patients receiving long-term treatment (defined as > 14 days) with phenazopyridine to a matched comparator group. The secondary objectives were to evaluate the incidence of individual ADRs, emergency department (ED) visits, hospitalizations, and new diagnoses of hepatocellular and colorectal cancer.

Methods

This was a retrospective cohort study using a matched comparator group. It was conducted at a Veterans Affairs (VA) medical center and approved by the health care system's Institutional Review Board. To be included, patients must have received radiation therapy between 1 July 2008 and 30 June 2017 under the care of the Radiation Oncology service and have received at least one chronic medication from the health care system during the study period. The requirement of one chronic medication was utilized to increase the likelihood that each included patient had an established relationship with the medical center and that the patient was not being treated only for a singular acute event. For inclusion in the phenazopyridine group, patients were required to have received greater than a 14-day supply of phenazopyridine. Patients were excluded if they did not have established primary care at a VA medical center or had a history of hepatocellular or colorectal cancer prior to the study time frame.

After screening for eligibility, patients in the phenazopyridine group were matched to patients from the comparator group based on gender, age (±5 years), cancer diagnosis, and whether the treatment intent was curative or palliative. All data was collected through a review of the electronic medical record. For the phenazopyridine group, data was collected at baseline and during the time of presumed drug exposure plus two weeks to account for delayed ADRs. Presumed drug exposure was defined as the duration of the initial prescription, including any refills with less than six months elapsing between fills.

For the comparator group, data collection began when radiation was initiated, and spanned the same length of time that the matched patient was exposed to phenazopyridine plus two weeks. Baseline data collection included demographic information, cancer diagnosis, treatment intent, radiation regimen, serum creatinine (SCr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin (Hb), and platelet (Plt) count. For patients in the phenazopyridine group, phenazopyridine dose, frequency, and refill history were also collected. For both groups, the previously stated laboratory values were collected during the exposure period. The medical record was reviewed for new rash or skin discoloration during the exposure period. Lastly, both groups were surveilled through the end of the study period to capture any new diagnoses of hepatocellular or colorectal cancer.

The primary endpoint was the incidence of composite ADRs which were defined a priori based on National Cancer Institute criteria for adverse events.⁸ Secondary endpoints included evaluating the incidence and changes from baseline of individual ADRs, including nephrotoxicity (i.e. increase in SCr by 0.3 mg/dL or 1.5 times above baseline), hepatotoxicity (i.e. AST > 56 IU/L or ALT > 60 IU/L), anemia (i.e. Hb < 10 mg/dL), thrombocytopenia (i.e. Plt < 150,000 µ/L), skin discoloration, and rash. Phenazopyridine dosing strategies and length of use were characterized. Additional secondary endpoints included evaluating the incidence of ED visits and hospitalizations, as well as the incidence of new hepatocellular or colorectal cancer diagnoses. Descriptive statistics were used to assess baseline characteristics, with student's t test and chi-square used for comparative analysis.

Due to the retrospective nature of the study, laboratory values were not consistently available during the pre-defined data collection period of the study. For patients without laboratory values during this time, the first available laboratory values following the data collection period were used. A post-hoc sensitivity analysis was conducted to compare the incidence of ADRs among the subset of patients with laboratory values available during the pre-defined data collection period.

Results

A total of 272 patients were identified with phenazopyridine prescriptions for greater than a 14-day supply. Among these patients, 90 were included and able to be matched to 90 patients in the comparator group (Figure 1). Baseline demographics are summarized in Table 1. The mean age was 66.4 years in the phenazopyridine group and 62.8 years in the comparator group. All patients in each group were male with the overwhelming majority having prostate cancer with curative treatment intent. The two groups appeared to be similar in terms of radiation method and dose.

Figure 1.

Patient selection and matching.

Table 1.

Patient demographics.

Characteristic	Phenazopyridine group (n = 90)	Comparator group (n = 90)
Male, n (%)	90 (100)	90 (100)
Mean age, years (SD)	66.4 (6.2)	62.8 (5.1)
Race, n (%)
African American	59 (65.6)	55 (61.1)
Caucasian	31 (34.4)	33 (36.7)
Other	0 (0)	2 (2.2)
Cancer diagnosis, n (%)
Prostate	88 (97.8)	88 (97.8)
Other	2 (2.2)	2 (2.2)
Cancer treatment intent, n (%)
Curative	87 (96.7)	87 (96.7)
Palliative	3 (3.3)	3 (3.3)
Radiation method, n (%)
Brachytherapy	7 (7.8)	6 (6.7)
External beam	83 (92.2)	84 (93.3)
Mean radiation dose, cGy (SD)	68 (6.0)	67.5 (8.7)

There was no significant difference in composite ADRs between the phenazopyridine and comparator groups (Table 2). Similarly, there was no difference in the distribution of individual ADRs among the two groups. For the post-hoc sensitivity analysis, 31 patients from the phenazopyridine group and 29 patients from the comparator group were included based on the availability of laboratory values during the pre-defined data collection period (Table 3). In this subset of patients, there was no significant difference in the incidence of composite or individual ADRs. The mean difference, compared to baseline, for each laboratory value in each group is summarized in Table 4. No significant differences were identified between groups.

Table 2.

Incidence of individual and composite adverse drug reactions.

Adverse drug reaction	Phenazopyridine group (n = 90)	Comparator group (n = 90)	p value
↑ SCr	3	4	0.69
↑ AST	1	2	0.56
↑ ALT	2	5	0.25
↓ Hb	3	0	0.08
↓ Plt	4	6	0.52
(+) Rash	0	1	0.31
(+) Skin discoloration	0	0	N/A
Composite	13	18	0.32

ALT: alanine aminotransferase; AST: aspartate aminotransferase; Hb: hemoglobin; Plt: platelets; SCr: serum creatinine.

Table 3.

Post-hoc sensitivity analysis of individual and composite adverse drug reactions.

ADR	Phenazopyridine group (n = 31)	Comparator group (n = 29)	p value
↑ SCr	2	2	0.92
↑ AST	1	1	0.98
↑ ALT	0	3	0.07
↓Hb	1	0	0.33
↓ Plt	1	1	0.98
(+) Rash	0	1	0.29
(+) Skin discoloration	0	0	N/A
Composite	5	8	0.22

ALT: alanine aminotransferase; AST: aspartate aminotransferase; Hb: hemoglobin; Plt: platelets; SCr: serum creatinine.

Table 4.

Mean difference in laboratory values compared to baseline.

Laboratory value	Phenazopyridine group (n = 90)	Comparator group (n = 90)	p value
SCr (mg/dL)	0.03	0	0.46
AST (IU/L)	0.16	2.56	0.34
ALT (IU/L)	0.84	5.37	0.06
Hb (mg/dL)	−0.26	−0.11	0.46
Plt (K/mm³)	−3.76	−5.23	0.84

ALT: alanine aminotransferase; AST: aspartate aminotransferase; Hb: hemoglobin; Plt: platelets; SCr: serum creatinine.

Additionally, there was a total of 14 ED visits (15.5%) in the phenazopyridine group and 15 ED visits (16.7%) in the comparator group (p = 0.84). There were six hospitalizations (6.7%) in the phenazopyridine group and three (3.3%) in the comparator group (p = 0.30). During the surveillance period, there was one new diagnosis (1.1%) of hepatocellular cancer identified in the phenazopyridine group and two new diagnoses (2.2%) in the comparator group (p = 0.56). Similarly, there was one new diagnosis (1.1%) of colorectal cancer in the phenazopyridine group and two new diagnoses (2.2%) in the comparator group (p = 0.56).

The most commonly prescribed phenazopyridine regimen was 200 mg three times daily (42%), followed by 100 mg three times daily (34%). Scheduled use of phenazopyridine was identified in 62% of patients compared to as needed use in 38%. The most common duration for phenazopyridine prescribing was 30–59 days for 67.8% of patients, followed by 60–90 days (14.4%) and greater than 90 days (13.3%). Only 4.4% of patients received less than a 30-day supply of phenazopyridine.

Discussion

Despite its widespread use for nearly a century, the safety of long-term phenazopyridine for radiation cystitis has not been well-defined. This is the first study to explore the safety of long-term phenazopyridine use, adding additional clinical evidence to better evaluate the risks of therapy.

Due to the often unpredictable and infrequent nature of ADRs, risks associated with long-term phenazopyridine use cannot be entirely excluded. However, this study suggests a relatively low incidence of examined renal, hepatic, hematologic, and dermatologic ADRs in both the phenazopyridine and comparator groups. No individual ADR emerged as more prominent in either group. A post-hoc sensitivity analysis including only patients with laboratory values during the exposure period produced similar results.

Phenazopyridine was largely prescribed 100–200 mg three times daily. While this dosing strategy is consistent with prescribing information, the dosing frequency was not assessed for appropriateness based on renal function.² The duration of phenazopyridine use for radiation cystitis has not been previously defined, but urinary symptoms such as dysuria and burning are typically presumed to be self-limiting.^5,6 In this study, patients most commonly received a 30–59-day supply of phenazopyridine. Thus, the safety findings of this study are most applicable to patients receiving similar durations of therapy. Similarly, this study predominantly included men with prostate cancer, although it is expected that these findings could presumably be applied to patients with other types of pelvic cancer who experience radiation-induced cystitis.

This study focused on the identification of hematologic, renal, hepatic, and dermatologic ADRs based on previous case reports of severe ADRs.^1,6 The relative incidence of these ADRs is unknown, both for short-term and long-term use of phenazopyridine.¹ Gould previously described a series of nine randomized clinical trials evaluating the safety and efficacy of phenazopyridine compared to flavoxate in patients with acute cystitis, prostatitis, urethritis, or trigonitis. Patients were randomized to a five-day supply of either flavoxate 200 mg four times daily or phenazopyridine 200 mg three times daily. A total of 392 patients were included, of whom 193 received phenazopyridine. In the phenazopyridine group, a total of 33 ADRs were reported. Nausea was reported in 8.3% of patients and diarrhea was reported in 3.6% of patients. Additional ADRs with less than 2% incidence included backache, headache, rash, vomiting, abdominal pain, and dizziness. ADRs led to phenazopyridine discontinuation in eight patients.⁹

In this trial, Gould also compared efficacy between flavoxate and phenazopyridine among patients with acute cystitis. After five days of treatment, patients rated efficacy as poor, fair, good, or excellent, of which an adequate response was defined as a good or excellent rating. Among 161 patients who received flavoxate, 128 patients (80%) had an adequate response. Among 156 patients in the phenazopyridine group, 88 patients (56%) had an adequate response, which was significantly lower (p < 0.01). This study was limited by its short duration of phenazopyridine, as well as its poorly defined efficacy rating system. Additionally, Gould focused on subjective reports of ADRs, whereas the current study primarily focused on severe ADRs identified via objective lab data.

Kirwin et al. presented a series of 118 cases in which patients received phenazopyridine 200 mg three times daily for 14 days. Patients were questioned and observed for any signs of toxicity, but none were identified. It is unknown what laboratory monitoring, if any, was done to identify ADRs. Of the included cases, there were 75 patients with cystitis and pyelonephritis who were assessed for symptoms of frequency, dysuria, burning, and nocturia. For each of these symptoms, treatment with phenazopyridine demonstrated improvement in 85.7%, 96.4%, 94.2%, and 88.8% of patients, respectively. Although a longer duration of phenazopyridine was utilized in this study, the lack of well-defined methods for capturing efficacy or safety events is a major limitation.¹⁰ While both Kirwin et al. and Gould provide some perspective on the ADR profile of phenazopyridine, neither study addresses the safety of use beyond 14 days or includes patients with radiation cystitis.^9,10

Limitations

This study was limited by its retrospective design and the limited availability of laboratory data during the time of presumed drug exposure. However, the post-hoc sensitivity analysis demonstrated similar results among patients with the most appropriately timed data set. Presumed phenazopyridine exposure was based on pharmacy dispensation data and adherence could not be verified. Additionally, patients may have received medical care at an outside institution, the details of which may not have been readily available to investigators. While we are not aware of this occurring in any of the included patients, it has been previously estimated that 46% of Medicare-eligible veterans utilize services from both the VA and the private-sector.¹¹ Lastly, a power calculation was unable to be performed due to the absence of previously published literature on long-term safety with phenazopyridine.

Furthermore, patients had varying lengths of surveillance for new diagnoses of hepatocellular and colorectal cancer, depending on when the patient received phenazopyridine during the nine-year study period. Although there was no difference in new diagnoses of hepatocellular or colorectal cancer between groups, the risk of new cancer diagnoses cannot be excluded. A large, matched comparator study with extended follow up may be able to provide a more meaningful quantification of risk. While this study focused on patients receiving long-term phenazopyridine for radiation cystitis, phenazopyridine may be used in extended durations for other indications in clinical practice.

Conclusion

There was no difference in ADRs among patients receiving phenazopyridine for greater than 14 days compared to a matched comparator group. The incidence of identified renal, hepatic, hematologic, and dermatologic ADRs was very low in both phenazopyridine and comparator groups.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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