An over-the-counter omission.

Abstract: Despite the widespread use of over-the-counter (OTC) medications, their utilization is rarely ascertained at hospital admission. Presented here is an interesting case of acute renal failure and hemolytic anemia attributable to a commonly utilized OTC medication. The chronic use of phenazopyridine accounted for all of these findings. Upon discontinuation, everything normalized within one month. Although the differential diagnosis for renal failure and hemolytic anemia is extensive, scleral icterus, normal bilirubin, and orange-colored urine raised the suspicion of phenazopyridine use. This case report highlights overuse of common OTC medications, as well as a lack of knowledge of potential adverse reactions. With history-taking vigilance and patient education, adverse events from OTC medications can be minimized.

Key Words: over-the-counter medications, phenazopyridine, acute renal failure, hemolytic anemia

**********

Despite the widespread use of over-the-counter (OTC) medications by patients, their utilization is rarely ascertained at the time of hospital admission. Presented here is an interesting case of acute renal failure and hemolytic anemia attributable to a commonly utilized OTC medication.

Case Report

The patient was a 58-year-old white female with no significant past medical history who presented to her primary care physician with a two-week history of severe fatigue. Although usually active, she had become progressively more fatigued to the point of requiring wheelchair assistance in the airport the day before presentation. She was admitted to the hospital for acute renal failure (creatinine of 3.0 mg/dL with baseline 0.9 mg/dL two months prior) and anemia (hematocrit of 27.9 with baseline 37.5 two months prior). She had no prior history of renal failure. She denied any change in her urinary habits (no dysuria, hematuria, or frequency). She denied recent nausea, vomiting, or change in her bowel habits. She also denied any known recent blood loss, but did have a total abdominal hysterectomy/bilateral salpingo-oophorechomy three months prior, requiring two units of packed red blood cells. She denied recent changes in any of her prescription medications. Her review of symptoms was otherwise completely negative.

Her past medical history included irritable bowel syndrome, migraine headaches, depression, anxiety, reflux, and hypothyroidism. Her prescription medications included Wellbutrin, Xanax, Synthroid, and Prilosec, and her OTC medications included Tylenol and Motrin for her migraines. Social and family histories were unremarkable.

Physical examination was remarkable for scleral icterus but was otherwise normal. Laboratory findings were significant for a hemoglobin of 8.9, elevated reticulocyte count, elevated LDH, undetectable haptoglobin, and a creatinine of 3.0 mg/dL. Urine studies revealed dark orange urine, but were otherwise normal. Renal ultrasound was also normal.

Upon further questioning of her OTC medications, it was discovered that the chronic use of phenazopyridine accounted for all of the above-mentioned findings. Upon discontinuation of the medication, the patient's laboratory and examination findings returned to normal within one month without any other intervention (Table).

Discussion

The patient's presentation was consistent with overuse of phenazopyridine, an OTC medication available as several products including Azo-Gesic 95 mg, Azo-Standard 95 mg, Prodium 95 mg, Pyridium 100 mg and 200 mg, ReAzo 97 mg, Uristat 95 mg, and UTI Relief 97.2 mg. Its mechanism of action is unknown, but is an azo dye which appears to exert a local anesthetic action on urinary tract mucosa. Its reported adverse reactions include acute renal failure, hemolytic anemia, hepatitis, and methemoglobinemia. There have been a variety of case reports outlining the spectrum of diseases that can present as a result of phenazopyridine ingestion. The first paper recorded in 1964 outlined a case of severe hemolytic anemia (1) and the spectrum of methemoglobinemia, hemolytic anemia and acute renal failure has been reported after an acute ingestion, (2-5) after a chronic overdose, (6) and after chronically appropriate doses. (7) The mechanism of these adverse reactions is not well understood, but the renal failure has been postulated to occur in response to triaminopyridine, a metabolite of phenazopyridine that causes vacuolization and necrosis of renal distal tubules. (8) Although the differential diagnosis for renal failure and hemolytic anemia is extensive, the scleral icterus in the setting of a normal bilirubin level, combined with orange-colored urine, raised the suspicion of phenazopyridine use in this patient. She did not initially divulge this medication use because she considered it irrelevant.

Conclusion

This case report highlights patients' overuse of common OTC medications, as well as their pervasive lack of knowledge of potential adverse reactions. (9-10) Although phenazopyridine is widely used, 50% of product consumers do not know that it is a urinary tract analgesic, and 80% of product consumers do not know either the cause of their symptoms or the action of the drug. (11) In addition, although OTC medication use is reported by two-thirds of all hospitalized patients, (12-13) documentation of them is present in only 10% of admission paperwork. Given that drug-related hospitalizations account for 5 to 8% of all hospital stays, (14-15) it is essential that a complete OTC medication list be included as a routine part of the history obtained from all patients during outpatient visits and at the time of hospital admission. With history-taking vigilance and patient education, adverse events from OTC medications can be minimized.

References

1. Gabor EP, Lowenstein L, De Leeuw NK. Hemolytic anemia induced by Phenylazo-Diamino-Pyridine (Pyridium). Can Med Assoe J 1964;91:756-759.

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

3. 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.

4. Vega J. Acute renal failure caused by phenazopyridine. Rev Med Chile 2003;131:541-544.

5. Kornowski R, Averbuch M, Jaffe A, et al. Sedural toxicity. Harefuah 1991;120:324-325.

6. Thomas RJ, Doddabele S, Karnad AB. Chronic severe hemolytic anemia related to surreptitious phenazopyridine abuse. Ann Intern Med 1994: 121:308.

7. Landman J, Kavaler E, Waterhouse Jr. RL. Acquired methemoglobinemia possibly related to phenazopyridine in a woman with normal renal function. J Urol 1997;158:1520-1521.

8. Munday R, Manns E. 2,3,6-triaminopyridine, a metabolite of the urinary tract analgesic phenazopyridine. causes muscle necrosis and renal damage in rats. J Appl Toxicol 1998;18:161-165.

9. Batty GM, Oborne CA, Swift CG, et al. The use of over-the-counter medication by elderly medical in-patients. Postgrad Med J 1997;73:720-722.

10. Oborne CA, Luzac ML. Over-the-counter medicine use prior to and during hospitalization. Ann Pharmacother 2005;39:268-273.

11. Shi CW, Asch SM, Fielder E, et al. Consumer knowledge of over-the-counter phenazopyridine. Ann Fam Med 2004;2:240-244.

12. Chrischilles EA, Foley DJ, Wallace RB, et al. Use of medications by persons 65 and over; data from the established populations for epidemiologic studies of the elderly. J Gerontol 1992;47:M137-M144.

13. Simons LA, Tett S, Simons J, et al. Multiple medication use in the elderly. Use of prescription and non-prescription drugs in an Australian community setting. Med J Aust 1992;157:242-246.

14. Hallas J, Jensen KB, Grodum E, et al. Drug-related admissions to a department of medical gastroenterology. The role of self-medicated and prescribed drugs. Scand J Gastroenterol 1991;26:174-180.

15. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18.820 patients. BMJ 2004;329:15-19.

Danielle Bowen Scheurer, MD, MSCR 

From the Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Reprint requests to Danielle Scheurer, MD, Brigham and Women's Hospital, Department of Medicine, 75 Francis Street, PB/B4/424, Boston, MA 02115. Email: [e-mail]

Accepted January 25, 2006.

RELATED ARTICLE: Key Points

* Over-the-counter medication use is common.

* Patient's knowledge of adverse reactions from over-the-counter medications is limited.

Table. Laboratory trends

            6 months prior  Admit  Hospital  Hospital  Hospital
Date        to admit        date   day 2     day 3     day 4

BUN         11              41     34        27        18
Creatinine   0.9             3.0    2.8       2.3       1.9
Hemoglobin  12.2             8.9    7.6 (a)   9.3       8.9 (a)
Hematocrit  37.5            27.9   24.3 (a)  29.2      27.6 (a)

            Hospital  1 month after
Date        day 5     discharge

BUN         28        25
Creatinine   1.7       1.3
Hemoglobin  10.3      12.2
Hematocrit  32.4      36.4

(a) Days on which I unit packed red blood cells was received.