Phenazopyridine-Induced Toxicity in an Elderly Patient Receiving a Prolonged Regimen of Therapeutic Doses

Design

Case presentation

A 74-year-old female was admitted to the intensive care unit with respiratory and acute renal failure (admission serum creatinine 4.5 mg/dL and blood urea nitrogen 80 mg/dL). She had a past medical history of stage 3 non-small-cell lung cancer status post chemotherapy and radiation, chronic obstructive pulmonary disease, hypertension, and hyperlipidemia. Prior to admission, the patient reported persistent bladder pain and urinary urgency for the past month for which she was taking phenazopyridine 200 mg orally TID for 3 weeks prior to admission. Since starting the medication, the patient experienced dark urine, decreased urine output, fatigue, and worsening shortness of breath. Pertinent physical examination and laboratory findings included yellow skin pigmentation, methemoglobinemia (methemoglobin level 18.8%), hemolytic anemia (hemoglobin 6.9 g/dL), reticulocyte count 5.1%, and peripheral blood smear showing Heinz body hemolysis. Upon admission, phenazopyridine was discontinued. The patient received intravenous methylene blue for methemoglobinemia and supportive care for acute renal failure, yellow skin discoloration, and hemolytic anemia. After five days, laboratory values and respiratory status returned to baseline, and the patient was discharged. According to the Naranjo probability scale, phenazopyridine leading to acute renal failure was possible and to methemoglobinemia and hemolytic anemia was probable.

Study Author Conclusions

Phenazopyridine Associated Acute Interstitial Nephritis and Review of Literature

Design

Case presentation

A 78-year-old while male with a past medical history of prostate cancer with treatment completed in January, on lisinopril, hydrochlorothiazide, and tamsulosin was started on phenazopyridine 100 mg TID in February for complaints of dysuria. In June he presented to the emergency department with a 2-week history of dull lower abdominal pain, 1 week history of burning urination, and a transient rash that had already dissipated. His vitals were stable, with no signs of uremia. His serum creatinine was 3.5 mg/dL and blood urea nitrogen was 54 mg/dL with negative cultures on urinalysis. His serologic workup for glomerulonephritis was negative. His 3 medications were stopped (including phenazopyridine) and he was treated with ceftriaxone for urinary tract infection. His serum creatinine trended down to 2.8 mg/dL and symptoms improved so he was discharged and resumed home medications.

Within 2 weeks, his serum creatinine was 5.8 mg/dL and phenazopyridine was stopped again with resulting serum creatinine dropping to 3.6 mg/dL. Renal biopsy revealed significant underlying changes of acute interstitial process with nephrosclerosis. He was treated with prednisone and his serum creatinine steadily dropped to 2.8 mg/dL in one week and 0.8 mg/dL at his 4-week follow-up. 

Study Author Conclusions

A Case of Severe Hypoxia Caused by Phenazopyridine-Induced Methemoglobinemia: A near Fatal Event from Over-the-Counter Medication Use

Design

Case presentation

An 89-year-old female patient with history of hypothyroidism, hyperlipidemia, hypertension, chronic kidney disease stage III, and recurrent urinary tract infection (UTI) presented with progressive shortness of breath x 1 week. The patient reported experiencing symptoms at rest, which worsened with activity. Despite using BiPAP, her oxygen saturation (SpO2) was 89–90%, and ABG revealed very high PaO2, suggestive of refractory hypoxia. Based on her lab and testing results, the patient was diagnosed with severe hypoxia due to methemoglobinemia. 

The patient's medications were reviewed, and it was found that she was prescribed phenazopyridine (Pyridium), used at a dose of one tablet (200 mg) by mouth three times daily as needed for urinary discomfort. The patient admitted she had been using one tablet (200 mg) three times daily regularly for two weeks, mentioning that phenazopyridine helped with urinary discomfort but did not fully resolve dysuria. A urine analysis revealed pus cells (WBC 10–20/HPF), with the resulting culture growing Pseudomonas aeruginosa and Enterococcus faecalis. The patients UTI was treated with piperacillin-tazobactam, while methemoglobinemia-induced hypoxia was treated with two doses of methylene blue 1 mg/kg dose. Symptoms subsequently resolved, with fully resolution by one-week post-discharge. 

Study Author Conclusions

This patient had chronic kidney disease stage III with a CrCl of 44 mL/min, which put her at a higher risk of developing methemoglobinemia from phenazopyridine. Hence, physicians should take utmost care when prescribing phenazopyridine in patients with reduced renal function, and patients should be strongly advised not to take the medication for more than two days.

Phenazopyridine is a commonly used over-the-counter medication for urinary discomfort but could lead to severe methemoglobinemia with hypoxia that could potentially be fatal if not promptly diagnosed. Therefore, this case highlights the need to strongly advise patients not to take phenazopyridine for more than two days and to have a high index of suspicion of phenazopyridine-induced methemoglobinemia in a patient presenting with unexplained shortness of breath with a history of phenazopyridine use.

Phenazopyridine-induced hemolytic anemia in advanced kidney disease

Design

Case presentation

An 86-year-old male with a history of diabetic nephropathy, stage 5 chronic kidney disease (CKD), congestive heart failure and benign prostatic hyperplasia presented with recurrent fatigue and exertional dyspnea for over 2 months. His medication regimen included clopidogrel, aspirin, terazosin, furosemide, digoxin and insulin. 

He was initially admitted for severe anemia, presumed to be due to CKD. His hemoglobin was 6 g/dL, with a usual baseline of 9 g/dL. Of note, the patient reported recently completing a course of phenazopyridine 100 mg three times daily for 10 days for a urinary tract infection (UTI). He was treated inpatient with blood transfusions and instructed to start erythropoietin 6,000 IU weekly administration. 

Two months later, he was readmitted and noted resuming phenazopyridine to treat his UTI symptoms just 10 days prior to readmission. The physical exam was unremarkable, except for pale conjunctiva without sclera icterus. Abnormal lab findings were as follows: low hemoglobin 6 g/dL, high lactate dehydrogenase 354 U/L, and low haptoglobin 22 mg/dL. A peripheral blood smear showed hyperchromic blood cells, schistocytes and bite cells. All remaining labs were normal. He was treated with blood transfusions and phenazopyridine was discontinued. After treatment, hemoglobin improved and remained stable at 9 g/dL and there was an absence of fragmented red blood cells on the blood smear. 

Study Author Conclusions

The management of phenazopyridine-induced hemolytic anemia relies on early recognition with prompt withdrawal of the drug. Because of its vague symptoms and other causes of anemia in individuals with CKD, the diagnosis may be easily overlooked, as was the case here. Phenazopyridine-induced hemolytic anemia was diagnosed because of the extended use of phenazopyridine without dose adjustment for CKD and resolution of the hemolytic anemia upon withdrawal of the offending agent. The dose must be lower in individuals with impaired renal function, although specific dose adjustment based on renal function is not available.

Safety Analysis of Long-Term Phenazopyridine Use for Radiation Cystitis

Design

Retrospective cohort study

N= 90

Objective

Study Groups

Phenazopyridine (n= 90)

Comparator (n= 90)

Inclusion Criteria

Received radiation and treated with at least one chronic medication during study period, > 14 day supply of phenazopyridine

Exclusion Criteria

Did not have established primary care at a Veterans Affair Medical Center or had history of hepatocellular or colorectal cancer prior to study time frame

Methods

Patient data were collected via review of electronic medical records. Patients receiving phenazopyridine were matched to comparators based on gender, age, cancer diagnosis, and treatment intent (curative vs. palliative). Drug exposure was assessed based on duration of initiation prescription plus refills with less than 6 months elapsed between fills. Data was collected at baseline and during time of drug exposure or start of radiation plus 2 weeks.

Duration

Treated with radiation therapy between July 1, 2008 to June 30, 2017

Outcome Measures

Primary: incidence of composite ADRs

Secondary: evaluating incidence and changes from baseline of individual ADRs and incidence of emergency department (ED) visits and hospitalizations

Baseline Characteristics

Phenazopyridine (n= 90)

Comparator (n= 90)

Age, years

Male

Race

African American

Caucasian

Other

65.6%

34.4%

0

61.1%

36.7%

2.2%

Cancer diagnosis

Prostate

Other

97.8%

2.2%

97.8%

2.2%

Mean radiation dose, cGy

67.5

Phenazopyridine regimens used

200 mg TID

100 mg TID

42%

34%

-

-

Phenazopyridine use duration

< 30 days

30-59 days

60-90 days

> 90 days

4.4%

67.8%

14.4%

13.3%

-

-

-

-

Results

Endpoint

Phenazopyridine (n= 90)

Comparator (n= 90)

p-Value

ADR

Increased SCr

Increased AST

Increased ALT

Decreased Hb

Decreased Plt

Rash

Skin discoloration

Composite

3

1

2

3

4

0

0

13 

4

2

5

0

6

1

0

18 

0.69

0.56

0.25

0.08

0.52

0.31

N/A

0.32

In addition to composite ADRs, no significant difference was found between groups for distribution of individual ADRs. Post-hoc sensitivity analysis was conducted with 31 patients from phenazopyridine group and 29 from the comparator group, again finding no significant difference. Rates for ED visits and hospitalizations were similar. 

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

Adverse Events

Study Author Conclusions

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.

InpharmD Researcher Critique

Included patients were of a specific demographic, limited to males treated at a VA hospital, hindering generalizability. Patients were not given phenazopyridine for treatment of urinary tract infections, but did include patients on average > 65 years old and treated with what was considered to be long term phenazopyridine. However, the majority of patients utilized phenazopyridine for 30-59 days. Data and results are all based on electronic medical records, which may potentially limit accuracy.