Multiple adverse effects of pyridium: a case report.

Abstract: Pyridium (phenazopyridine hydrochloride) is often prescribed as an analgesic in patients following trauma, surgery, or infections of the urinary tract. Pyridium toxicity has been previously reported, however, most cases result in a single adverse effect. Herein the authors describe an elderly patient who presented with simultaneous multiple adverse effects, including a previously undocumented myelosuppressive pancytopenia.

Key Words: Pyridium, myelosuppressive pancytopenia, geriatrics

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Pyridium (phenazopyridine hydrochloride), marketed in 1914 as a treatment for urinary tract infections (UTIs), is currently indicated as a urinary analgesic to relieve dysuric symptoms associated with UTIs, trauma, or surgery. (1) A literature search using the terms Pyridium and phenazopyridine revealed 183 articles on the subject. Less than one-third of these articles described adverse effects of the drug and very few reported more than one adverse event in a single patient. (2-7) There have been two documented cases of multiple adverse effects. (8-9) Most often the reported side effects include methemoglobinemia, acute renal failure, hemolytic anemia, and yellowing of the skin, although others have also been documented (Table). (10) Herein, we describe a patient who presented with myelosuppressive pancytopenia which has not been reported with Pyridium use.

Case Report

An 87-year-old Caucasian male presented to his primary care physician (PCP) with a chief complaint of fatigue and yellow skin. The patient's urologist had prescribed Pyridium tid three days earlier to treat dysuria. The patient's past medical history was significant for coronary artery bypass, congestive heart failure, asthma, radiation for prostate cancer Stage 0 ten years prior, and bladder carcinoma in situ. His medications included prednisone, digoxin, Lasix, Ditropan, and Pyridium. The patient did admit noncompliance with the Pyridium, taking the medication four times a day, rather than the prescribed three to alleviate his significant dysuria.

The patient was sent to the Emergency Room after the PCP suspected hepatotoxicity with jaundice. Upon further evaluation the patient was admitted to a medical floor. On physical examination the patient was found to be cachectic but in no apparent distress. He was afebrile, with a normal blood pressure, heart rate, and respiratory rate. His skin was bright yellow and slightly tinted. Capillary refill was less than two seconds. His sclerae were nonicteric. Mucous membranes were cracked and his tongue was parched, however there was no evidence of yellow pigmentation on the undersurface. Heart and lung examinations were within normal limits. There was no appreciable hepatosplenomegaly or hepatojugular reflex.

A urinalysis reported the urine as orange with a leukocyte esterase level of 100 leu/uL, positive for nitrates and bacteria 1+. At admission, abnormal laboratory values were white blood count (WBC) 2.7 (nl = 4.5-10.0/uL), hemoglobin 9.5 (nl = 13.1-18.0 g/dL), platelet count 72 (nl = 140-440/uL), creatinine 2.2 mg/dL (nl = 0.6-1.4 mg/dL), and BUN 46 mg/dL. All other values were within normal limits including total bilirubin 1.0 (nl = 0.1-1.5 mg/dL), alkaline phosphatase 59 (nl = 39-117 U/L), SGOT 18 (nl = 0-37 U/L), and SGPT 10 (nl = 0-45 U/L). Haptoglobin was 181 (nl = 62-171 mg/dL), and reticulocyte count and index were 1.2% (nl = 0.2-2.1%) and 0.4 (nl = 2.5-9.5 10e4/[micro]L), respectively. A PSA level was 0.1 ng/mL.

The patient was initially rehydrated and the Pyridium was discontinued. His renal function responded well to fluid challenges, with BUN and creatinine levels returning to premorbid values of 23 mg/dL and 1.2 mg/dL, respectively, after five days. During hospitalization the patient's WBC dropped to 2.1, platelet count to 67, and hemoglobin 7.4. On hospital day two, two units of packed red blood cells were infused. At time of discharge, his WBC was 4.4, platelet count 82, and hemoglobin 10.0. Premorbid values for this patient were a WBC 8.8, platelet count 240, and hemoglobin of 13.1. On hospital day five, the patient was discharged in satisfactory condition to a subacute rehabilitation facility. His skin had returned to normal color and his urine showed no evidence of the orange discoloration seen earlier. Lab results performed two months after the patient's discharge revealed all serum levels had returned to normal limits.

Discussion

Since the first report of an adverse effect of Pyridium was published in 1951, (11) there have been very few cases involving more than a single adverse event occurring. Thrombocytopenia and neutropenia have been reported with the use of Azo-Granatol (sulfamethoxazole-Pyridium), but it is unknown which component was the causative agent. (10) The patient outlined in this case presented with five manifestations of Pyridium toxicity. Upon admission he was diagnosed with acute renal failure, skin discoloration, thrombocytopenia, neutropenia, and anemia.

Interestingly, it appears that the anemia was myelosuppressive and not hemolytic in etiology. This hypothesis is supported by virtue of all three cell lines being suppressed, an elevated haptoglobin level, a normal total bilirubin and a diminished reticulocyte count, even after correction for hematocrit. Although hemolytic anemia has been described as an adverse reaction to Pyridium, myelosuppressive anemia has not. The myelosuppressive anemia in our case was not confirmed with a bone marrow biopsy. Although the patient had a history of prostate cancer, bone metastasis as an etiology for the myelosuppression is highly unlikely given the extremely low PSA.

The patient's myelosuppression, acute renal failure, and skin and urine discoloration reversed upon discontinuation of the Pyridium. These observations are consistent with previous studies.

Conclusions

Pyridium is an oral analgesic prescribed occasionally for dysuria associated with trauma, surgery and infections of the urinary tract. It must be stressed that serious side effects may occur, especially if therapeutic doses are exceeded. In this case, the patient exhibited multiple simultaneous adverse effects of Pyridium, including a previously undocumented myelosuppressive pancytopenia. Clinicians who prescribe Pyridium should educate their patients to monitor for side effects and to stay within the daily recommended dose. This case report also provides an excellent example of the potential for rapidly occurring toxicity in the geriatric population. Clinicians should be reminded to "start low, go slow" when prescribing medications to the elderly.

References

1. Product Information. Pyridium (phenazopyridine) Morris Plains, NJ: Parke-Davis, 1992.

2. Wander HJ, Pascoe DJ. Phenazopyridine hydrochloride poisoning. Report of a case and review of the literature. Am J Dis Child 1965;110:105-107.

3. Nathan DM, Seigel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med 1977;137:1636-1638.

4. Cohen BL, Bovaso GJ Jr. Acquired methemoglobinemia and hemolytic anemia following excessive pyridium (phenazopyridine hydrochloride) ingestion. Clin Pediatr 1971;10:537-540.

5. Greenberg MS, Wong H. Methemoglobinemia and Heinz body hemolytic anemia due to Phenazopyridine hydrochloride. N Engl J Med 1964;271:431-435.

6. Eybel CE, Armbruster KF, Ing TS. Skin pigmentation and acute renal-failure in a patient receiving phenazophyridine therapy. J Am Med Assoc 1974;228:1027-1028.

7. Alano FA Jr., Webster GD Jr. Acute renal failure and pigmentation due to phenazopyridine (Pyridium). Ann Intern Med 1970; 72:89-91.

8. Gavish D, Knobler H, Gottehrer N, et al. Methemoglobinemia, muscle damage and renal failure complicating phenazopyridine overdose. Isr J Med Sci 1986; 22: 45-47. [Medline].

9. Kornowski R. Averbuch M. Jaffe A, et al. Sedural Toxicity. Harefuah 1991; 120: 324-325. [Medline].

10. MICROMEDEX[R] Healthcare Series. Available at: http://www.micromedex.com.

11. Crawford SE, Moon AE Jr., Panos TC, et al. Methemoglobinemia associated with pyridium administration; Report of a case. J Am Med Assoc 1951; 146: 24-25.</p> <pre> The only creatures that are evolved enough to convey pure love are dogs and infants. --Johnny Depp </pre> <p>Charles Haigh, MD, MSC, and James C. Dewar, MD

From Forum Health, Family Practice Center, and Department of Clinical Medicine, Northeastern Ohio Universities College of Medicine, Roots-town, OH.

Reprint requests to Charles Haigh, MD, MSc, Forum Health--Family Practice Center, 500 Gypsy Lane, Youngstown, OH 44501. Email: [e-mail]

Accepted August 24, 2005.

RELATED ARTICLE: Key Points

* Pyridium (phenazopyridine hydrochloride) is often prescribed as an analgesic in patients following trauma, surgery, or infections of the urinary tract.

* Myelosuppressive pancytopenia has not been previously reported as an adverse effect of Pyridium. Upon discontinuation of the drug this condition rapidly reversed.

* Since elderly patients are highly prone to developing drug toxicity, they should be counseled and monitored accordingly when starting new medications.

Table. Adverse effects of pyridium

Acute renal failure
Hemolytic anemia
  patients with G6PD
Nephrolithiasis
  patients without G6PD
Methemoglobinemia
Yellow skin discoloration
Orange urine discoloration
Aseptic meningitis
Hepatitis
Keratoconjunctivitis sicca
Local anesthesia
Acute Porphyria
Hemolytic anemia + methemoglobinemia
Hemolytic anemia + acute renal failure
Skin discoloration + acute renal failure

G6PD, glucose 6 phosphatase deficiency.