The Poison Control Center

Phenazopyridine

Case
Introduction
Hemolytic anemia
Methemoglobinemia
Renal failure
Hepatotoxicity
Summary
References

Case

An 18-month-old female ingested up to ten 200 mg. phenazopyridine tablets in the evening. She slept through the night without incident but was noted eight hours later to have pink urine and vomitus. Twelve hours after ingestion she presented to the emergency department with cyanosis and lethargy. A methemoglobin level drawn on admission was 60.9 percent. Therapy with methylene blue, 10 mg. (0.83 mg./kg.) given over 30 minutes and oxygen was instituted. An arterial blood gas on 100 percent oxygen revealed a pH 7.39, pO2 36.8 mm Hg, pCO2 36.8 mm Hg, HCO3 20.6 meq/L. It is very possible that this was a mixed-venous blood sample. A repeat methemoglobin determination, thirty minutes later, revealed a level of 22.5 percent, which declined to 13.5 percent 13 hours post admission. The remaining clinical course was uneventful and the child was discharged approximately 24 hours after admission.

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Introduction

This case illustrates the potential for delayed onset of profound methemoglobinemia after an accidental ingestion of two grams of phenazopyridine by a toddler.

Phenazopyridine is an AZO dye that has been used as a genitourinary analgesic since the 1920's.¹ It is currently available as a single agent and in combination products with antiinfective agents such as sufisoxazole and sulfamethoxazole and with antispasmodic agents. Despite fairly widespread use of phenazopyridine, reports of serious toxicity are relatively uncommon. It should be noted that toxicity may occur with acute accidental or intentional overdoses as well as with chronic administration of therapeutic doses.

Phenazopyridine toxicity most commonly manifests as hemolytic anemia,^2-7 and/or methemoglobinemia^1,3,7-10 in patients with acute overdose or during chronic therapeutic use. Because neonates have both an immature NADH-dependent methemoglobin reductase system and higher levels of fetal hemoglobin,^11-12 they are more susceptible to the oxidative stresses which can be seen with phenazopyridine. Acute renal failure and hepatitis have also been reported.^13-16

Hemolytic Anemia

Hemolytic anemia has been reported with chronic therapeutic use^2-6 and with acute overdoses⁷ of phenazopyridine and may be the only sign of toxicity. It has been observed in patients with^2,5 and without^4,7 glucose-6-phosphate dehydrogenase (G6PD) deficiency and is characterized by the presence of Heinz bodies. A peripheral smear may reveal the presence of "bite" cells or degmacytes. The mechanism for hemolytic anemia with phenazopyridine use has not been described.

The resulting anemia may be severe enough to require replacement transfusions.¹ A baseline hemoglobin/hematocrit and peripheral smear may be warranted to monitor for the occurrence of hemolytic anemia.

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Methemoglobinemia

Methemoglobinemia is a serious complication which can occur with acute phenazopyridine ingestions. Phenazopyridine is metabolized to aniline which, in turn, is metabolized to three compounds which are strong oxidants. These metabolites cause hemoglobin to be oxidized to methemoglobin which is unable to transport oxygen.³ The presence of significant amounts of methemoglobin causes normal hemoglobin to hold on tighter to oxygen. This results in less oxygen release to tissues, and therefore hypoxia. This is reflected in a leftward shift of the oxyhemoglobin dissociation curve.¹⁷ Therefore, in cases of methemoglobinemia, a normal pO2 should be expected even in patients with cyanosis. However, a decrease in pO2 as well as oxygen saturation has been noted.^7-9 Patients with G6PD deficiency appear to be more susceptible to methemoglobinemia.¹

If methemoglobin levels are analyzed soon after sampling, levels may correlate with clinical signs and symptoms.

Methemoglobinemia is treated with methylene blue which converts methemoglobin to oxyhemoglobin. Supplemental oxygen should be instituted while preparing for methylene blue therapy. The criteria for methylene blue therapy include symptomatic patients and asymptomatic patients with methemoglobin levels greater than 30 percent. Intravenous methylene blue is given slowly over several minutes in a dose of 1 to 2 mg./kg. of a 1percent solution. This can be repeated every four hours as necessary. The blue color of methylene blue may impart a transitory cyanosis to the patient which clears as the methylene blue is converted to the active and colorless leukomethylene blue.1 It is theoretically possible that repeat doses may be required in phenazopyridine ingestions due to persistent and prolonged production of toxic metabolites. If a patient does not respond to methylene blue therapy, the occurrence of G6PD deficiency or an overdose of methylene blue should be suspected. Patients with G6PD deficiency, with severe symptoms, may require exchange transfusion. Methylene blue in high doses is itself an oxidant. Therefore, if too much methylene blue is given to a patient it can actually cause methemoglobinemia.

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Renal Failure

Transient acute oliguric^13,14 or nonoliguric^15,16 renal failure may be seen with large doses^13,15,16 or prolonged use¹⁴ of phenazopyridine. This most commonly occurs in elderly patients with diminished renal function. Rarely have patients with normal renal function developed acute renal failure.^13,16 Renal toxicity due to phenazopyridine may be a direct effect of the drug and/or its metabolites, or may be secondary to hypoxic injury when methemoglobinemia occurs.¹³ Treatment is usually supportive. Peritoneal dialysis has not been found to be useful in removing phenazopyridine.¹³

Hepatotoxicity

Jaundice, liver function test abnormalities,¹⁸ and hypersensitivity hepatitis¹⁹ due to phenazopyridine have been reported. Discontinuation of the drug and supportive care usually results in resolution of symptoms.

Summary

Although toxicity with phenazopyridine is relatively uncommon, when it does occur, it may present with a varied and potentially serious clinical picture. Acute overdoses or prolonged use of therapeutic doses may present with hemolytic anemia, methemoglobinemia or acute renal failure.

In the case presented, the only symptom of phenazopyridine toxicity observed was cyanosis with profound methemoglobinemia. Methemoglobinemia responded rapidly to methylene blue therapy. The delay in onset of methemoglobinemia in this case, which has been reported only to a limited extent,¹⁰ is noteworthy and suggests that a prolonged observation period may be necessary.

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References

1. Green ED, Zimmerman RC, Ghurabi WH et al. Phenazopyridine hydrochloride toxicity: a cause of drug-induced methemoglobinemia. JACEP 1979 Oct;8(10):426-31.
2. Galun E, Oren R, Glikson M, Friedlander M, Heyman A . Phenazopyridine-induced hemolytic anemia in G-6-PD deficiency. Drug Intell Clin Pharm 1987 Nov;21(11):921-2.
3. Jeffrey WH, Zelicoff AP, Hardy WR. Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine. Drug Intell Clin Pharm 1982;16:157.
4. Noonan HM, Kimbrell M, Ben Johnson WB, Reuler JB. Phenazopyridine-induced hemolytic anemia. Urology 1983 Jun;21(6):623-624
5. Mercieca JE, Clarke MF, Phillips ME, Curtis JR. Acute haemolytic anaemia due to phenazopyridine hydrochloride in G-6-PD deficiency subject. Lancet 1982 Sep 4;2(8297):564.
6. Tishler M, Abramov A. Phenazopyridine-induced hemolytic anemia in a patient with G6PD deficiency. Acta Haematol. 1983;70(3):208-9.
7. Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med 1977 Nov;137(11):1636-8.
8. O'Mahoney S, Finucane P, Hinds D. Phenazopyridine-induced methemoglobinemia. Ir J Med Sci 1985 Nov;154(11):433-4.
9. Sharon M, Puente G, Cohen LB. Phenazopyridine (Pyridium) poisoning: possible toxicity of methylene blue administration in renal failure. Mt. Sinai J Med 1986 Apr;53(4):280-1.
10. Weiland MJ, Ebrahimi JM, Krenzelok EP. Methemoglobinemia secondary to phenazopyridine ingestion. Vet Hum Toxicol 1983;25:53.
11. Gosselin RE, Hodge HC, Smith RP, et al. Clinical toxicology of commercial products. Fourth edition. Baltimore, Williams and Wilkins, 1976.
12. Ross JD. Deficient activity of DPNH-dependent methemoglobinimia diaphorase in cord blood eythrocytes. Blood 1963;21:51-62.
13. Tomlinson B, Cohen SL, Smith MR et al. Nephrotoxicity of phenazopyridine. Human Toxicol 1983;3:539-543.
14. Zimmerman RC, Green ED, Ghurabi W, Colohan DP. Methemoglobinemia from overdose of phenazopyridine hydrochloride. Ann Emerg Med 1980 Mar;9(3):147-9.
15. Feinfeld DA, Ranieri R, Lipner HI, Avram MM. Renal failure in phenazopyridine overdose. JAMA 1978 Dec;240(24):2661.
16. Quershi N, Hedger RW. Phenazopyridine (Pyridium) and acute renal failure. Ann Intern Med 1979;90:443.
17. Bodansky O, Gutmann H. Treatment of methemoglobinemia. J Pharm Exp Ther 1947;90:46-56.
18. Hood JW, Toth WN. Jaundice caused by phenazopyridine. JAMA 1966 Dec 26;198(13):1366-7.
19. Goldfiner SE, Marx S. Hypersensitivity hepatitis due to phenazopyridine hydrochloride. N Engl J Med 1972 May 18;286(20):1090-1.

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