Side Effects of Phenazopyridine
Phenazopyridine can cause serious and potentially life-threatening side effects including methemoglobinemia, acute renal failure, hemolytic anemia, and severe skin reactions, even at therapeutic doses.
Common and Expected Side Effects
- Orange discoloration of urine is the most common and expected effect, occurring in virtually all patients taking phenazopyridine 1, 2, 3
- Gastrointestinal symptoms including nausea, vomiting, and mild anorexia occur frequently at standard doses 1
- Yellowish skin discoloration can develop during treatment 3, 4
Serious and Life-Threatening Side Effects
Methemoglobinemia (Most Critical)
- Methemoglobinemia is an uncommon but potentially fatal complication where oxygen delivery to tissues is severely impaired 1, 5
- Risk increases significantly when dosage and duration exceed manufacturer specifications 1
- Presents with refractory hypoxia (pulse oximetry in high 80s despite 100% oxygen), generalized dusky skin, headache, weakness, lightheadedness, dyspnea, and can progress to arrhythmias, confusion, seizures, and multiorgan failure 1, 5
- Can occur even with therapeutic doses taken for as little as 2 weeks 5
- Methemoglobin levels >20-30% require immediate treatment 1
Acute Renal Failure
- Acute kidney injury can occur through multiple mechanisms: acute tubular necrosis, acute interstitial nephritis, or pigment-induced nephropathy 3, 4
- Can develop even at therapeutic doses without preexisting kidney disease 3
- Progressive nonoliguric renal failure may develop within 3 days of ingestion 4
- Risk is particularly elevated in patients with preexisting renal insufficiency 3, 4
Hematologic Complications
- Hemolytic anemia can occur, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency 3, 4
- Pigment-induced nephropathy may result from hemolytic anemia 3
Severe Skin Reactions
- Severe skin ulcers and necrosis have been reported, even after short-term use (as little as 3 days) 2
- Bluish discoloration may develop first, progressing to blisters and deep ulcers 2
- These reactions can occur without concurrent methemoglobinemia or renal dysfunction 2
Hepatotoxicity
- Hepatitis has been reported as a rare complication 3
Critical Clinical Pitfalls
- Over-the-counter availability leads to underestimation of toxicity risk—patients may exceed recommended doses or duration without medical supervision 1, 5
- Refractory hypoxia should always prompt consideration of methemoglobinemia in patients with phenazopyridine exposure, even at therapeutic doses 1, 5
- Chronic use (beyond 2 days as typically recommended) dramatically increases risk of serious complications 1
- Patients taking serotonergic medications (MAOIs, SSRIs, SNRIs, TCAs) cannot receive methylene blue (first-line treatment for methemoglobinemia) due to risk of serotonin syndrome—vitamin C must be used instead 1
Management of Serious Side Effects
- Immediate discontinuation of phenazopyridine is the first step for all serious adverse effects 1, 3
- For methemoglobinemia with levels >30% or symptomatic patients with levels >20%: administer methylene blue 1-2 mg/kg IV, unless contraindicated 1
- If methylene blue is contraindicated (concurrent serotonergic medications or G6PD deficiency): use vitamin C/ascorbic acid as alternative treatment 1
- For acute interstitial nephritis: early steroid administration improves renal recovery and decreases progression to chronic kidney disease 3
- For acute tubular necrosis: supportive care with N-acetylcysteine, intravenous carnitine, and urine alkalinization may be beneficial 4