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PHENAZOPYRIDINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Phenazopyridine is an azo dye compound used as a urinary tract analgesic.

Specific Substances

    1) 3-Phenylazopyridine-2,6-diyldiamine
    2) Fenazopiridina (Mexican)
    3) Phenazopyridine hydrochloride
    4) CAS 94-78-0
    5) CAS 136-40-3 (Phenazopyridine hydrochloride)

Available Forms Sources

    A) FORMS
    1) Phenazopyridine hydrochloride, an azo dye, is available as 95 mg, 97.2 mg, 97.5 mg, 100 mg, and 200 mg tablets (Prod Info Pyridium(R) oral tablets, 2014).
    B) USES
    1) Phenazopyridine is indicated to relieve symptoms such as pain, burning, urgency and/or frequency, and other discomforts due to irritation of the lower urinary tract mucosa caused by infection, trauma, surgery, endoscopic procedures, or the passage of sounds or catheters (Prod Info Pyridium(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Phenazopyridine is indicated to relieve symptoms such as pain, burning, urgency and/or frequency, and other discomforts due to irritation of the lower urinary tract mucosa caused by infection, trauma, surgery, endoscopic procedures, or the passage of sounds or catheters.
    B) PHARMACOLOGY: Phenazopyridine hydrochloride is a urinary tract analgesic agent. The precise mode of action is unknown but when excreted in the urine, it promotes topical analgesia on the mucosa of the urinary tract, thus relieving pain, burning, urgency and frequency.
    C) TOXICOLOGY: HEMOLYSIS: The mechanism is due to its chemical structure and aromatic compound-like similarities to phenylhydrazine, which is known to cause the problem. This drug has been shown through its oxidizing properties to act as an intermediate between the molecular oxygen and hemoglobin association, resulting in aggregation of oxidatively denatured hemoglobin. Red cells become rigid, have problems traversing the spleen, with resultant destruction and formation of bite cells. Patients with red blood cell glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may have an increased risk for developing hemolysis.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Gastrointestinal disturbances, transient acute renal failure (after large doses or prolonged use), methemoglobinemia, sulfhemoglobinemia, hemolysis, jaundice and elevated liver enzymes have developed. Muscle tenderness, headache, vertigo, rhabdomyolysis and renal impairment secondary to rhabdomyolysis have also been reported.
    F) WITH POISONING/EXPOSURE
    1) Methemoglobinemia and hemolytic anemia are the primary manifestations of phenazopyridine intoxication. These findings may develop after taking this drug for several days based on therapeutic use, but typically develop with overdosage or in patients with renal impairment. Methemoglobinemia usually occurs within 2 to 3 hours after ingestion, but may be delayed. In one child cyanosis was observed 17 hours after induction of emesis. Although rare, acute tubular necrosis and jaundice associated with increased liver enzymes have occurred following overdose.
    0.2.20) REPRODUCTIVE
    A) Phenazopyridine is in Pregnancy Category B.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor CBC and methemoglobin concentration in patients with cyanosis. Obtain methemoglobin levels in children who have ingested even a small number of phenazopyridine tablets.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors, and epinephrine may be required. Treat symptomatic methemoglobinemia with methylene blue. Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or infants may require exchange transfusion or treatment with hyperbaric oxygen as they may not respond to methylene blue. Monitor creatine kinase levels. If severe elevations occur and there is a concern for rhabdomyolysis, treat the patient with aggressive IV fluids and consider sodium bicarbonate.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or severe respiratory distress.
    E) ANTIDOTE
    1) Symptomatic methemoglobinemia can be treated with methylene blue.
    F) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    G) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    H) ENHANCED ELIMINATION
    1) If methemoglobinemia is not corrected with IV methylene blue in a severely symptomatic patient, exchange transfusion should be considered, especially in infants and children.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent minor exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected phenazopyridine overdose, the possibility of multidrug involvement should be considered. It is important to be aware that methemoglobinemia may recur.
    K) PHARMACOKINETICS
    1) The pharmacokinetic properties of phenazopyridine have not been determined. Rapidly excreted by the kidneys (66% excreted unchanged in the urine).
    L) PREDISPOSING CONDITIONS
    1) Patients with G6PD deficiency may develop hemolysis secondary to methemoglobinemia and may not respond to methylene blue therapy.
    M) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis includes other drugs or substances that can cause methemoglobinemia (eg, nitrites, nitrates, local anesthetics, sulfonamides, and aniline dyes) or rhabdomyolysis (eg, LSD, cocaine, amphetamines).

Range Of Toxicity

    A) TOXICITY: PEDIATRIC: Methemoglobinemia developed in a 13-month-old following an acute ingestion of 2.5 to 3 g of phenazopyridine, and in a 2-year-old after ingesting 800 to 1200 mg of phenazopyridine. ADULT: Symptoms typically occur following the ingestion of several grams. However, methemoglobinemia and acute renal failure developed in a 17-year-old female following a single 1200 mg ingestion.
    B) THERAPEUTIC DOSE: ADULT: One 200-mg tablet or two 100-mg tablets orally 3 times daily. CHILDREN 6 TO 12 YEARS: 12 mg/kg/day in divided doses 3 times daily for 2 days.

Clinical Effects

Summary Of Exposure

    A) USES: Phenazopyridine is indicated to relieve symptoms such as pain, burning, urgency and/or frequency, and other discomforts due to irritation of the lower urinary tract mucosa caused by infection, trauma, surgery, endoscopic procedures, or the passage of sounds or catheters.
    B) PHARMACOLOGY: Phenazopyridine hydrochloride is a urinary tract analgesic agent. The precise mode of action is unknown but when excreted in the urine, it promotes topical analgesia on the mucosa of the urinary tract, thus relieving pain, burning, urgency and frequency.
    C) TOXICOLOGY: HEMOLYSIS: The mechanism is due to its chemical structure and aromatic compound-like similarities to phenylhydrazine, which is known to cause the problem. This drug has been shown through its oxidizing properties to act as an intermediate between the molecular oxygen and hemoglobin association, resulting in aggregation of oxidatively denatured hemoglobin. Red cells become rigid, have problems traversing the spleen, with resultant destruction and formation of bite cells. Patients with red blood cell glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may have an increased risk for developing hemolysis.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Gastrointestinal disturbances, transient acute renal failure (after large doses or prolonged use), methemoglobinemia, sulfhemoglobinemia, hemolysis, jaundice and elevated liver enzymes have developed. Muscle tenderness, headache, vertigo, rhabdomyolysis and renal impairment secondary to rhabdomyolysis have also been reported.
    F) WITH POISONING/EXPOSURE
    1) Methemoglobinemia and hemolytic anemia are the primary manifestations of phenazopyridine intoxication. These findings may develop after taking this drug for several days based on therapeutic use, but typically develop with overdosage or in patients with renal impairment. Methemoglobinemia usually occurs within 2 to 3 hours after ingestion, but may be delayed. In one child cyanosis was observed 17 hours after induction of emesis. Although rare, acute tubular necrosis and jaundice associated with increased liver enzymes have occurred following overdose.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) PIGMENTATION: Yellow discoloration of the sclera may occur after phenazopyridine poisoning (Sharon et al, 1986).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Sulfhemoglobinemia secondary to phenazopyridine overdose may be associated with dyspnea.
    b) CASE REPORT: A 57-year-old woman developed cyanosis and dyspnea following the use of phenazopyridine for several years. Vital signs were: blood pressure 135/65 mmHg, pulse 105 bpm, respiratory rate 22/minute; pulse oximetry 86% on room air. The ECG revealed only sinus tachycardia. A sulfhemoglobin level of 13.9% was reported. Following supportive therapy for seven days, she was discharged without any sequelae (Barrueto et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) Methemoglobinemia secondary to phenazopyridine overdose may be associated with dyspnea.
    b) CASE REPORT: A 21-year-old woman ingesting an unknown amount developed cyanosis, dyspnea, a decreased PO2, and a methemoglobin level of 80% (O'Mahony et al, 1985).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported with the use of phenazopyridine (Prod Info Pyridium(R) oral tablets, 2014).
    2) WITH POISONING/EXPOSURE
    a) Headache may occur.
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Vertigo may be noted.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL SYMPTOM
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal disturbances are reported with phenazopyridine administration (Prod Info Pyridium(R) oral tablets, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH THERAPEUTIC USE
    a) Hepatotoxicity has been reported in patients taking phenazopyridine (Prod Info Pyridium(R) oral tablets, 2014).
    b) Cases of recurrent bouts of jaundice and elevated liver enzymes after repeated brief courses of treatment have been reported. Also, two cases of hepatitis believed to be from hypersensitivity to this drug have been reported (Vega, 2003; Badley, 1976; Goldfinger & Marx, 1972).
    2) WITH POISONING/EXPOSURE
    a) Hepatotoxicity has been reported following an overdose (Prod Info Pyridium(R) oral tablets, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Transient acute renal failure may result from large doses or prolonged use (Prod Info Pyridium(R) oral tablets, 2014; Tomlinson et al, 1983; Sharon et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) Transient acute renal failure may result from large doses or prolonged use (Tomlinson et al, 1983; Sharon et al, 1986), but also occurred following a single 1200 mg dose in a teenage girl (Onder et al, 2006).
    b) CASE REPORT: A 17-year-old girl with perinatally acquired HIV with no history of nephropathy, intentionally ingested 1200 mg of phenazopyridine, and developed methemoglobinemia and acute renal failure. Progressive nonoliguric renal failure occurred several days after exposure. Serum creatinine peaked at 4.2 mg/dL; liver function remained normal. Percutaneous renal biopsy was suggestive of acute tubular necrosis, with no significant glomerular changes or evidence of chronic injury. Following treatment with oral N-acetylcysteine, IV L-carnitine, and sodium bicarbonate for alkalinization the patient was discharged on day 8 with normal renal function (Onder et al, 2006).
    c) CASE REPORT: A 27-year-old woman developed oliguric acute renal failure after ingesting 2 grams of phenazopyridine. She experienced abdominal cramps, jaundice, markedly orange-colored urine, and oligoanuria. At the 6th hospital day, her serum creatinine and urea nitrogen were 13.5 and 72.4 mg/dL, respectively. Following supportive care, she recovered completely without further sequelae (Vega, 2003).
    d) CASE REPORT: Acute tubular necrosis was reported in a 13-year-old girl following acute ingestion of 2 grams of phenazopyridine without evidence of methemoglobinemia nor hemolytic anemia (Feinfeld et al, 1978).
    e) CASE REPORT: Muscle tenderness, rhabdomyolysis, and renal dysfunction were reported in a 19-year-old woman after ingestion of 6 grams (Gavish et al, 1986).
    B) URINE COLOR ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Phenazopyridine colors the urine and feces orange to red and also stains clothing (Prod Info Pyridium(R) oral tablets, 2014; Block & Lamy, 1968).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolysis has been associated with some cases of methemoglobinemia due to phenazopyridine toxicity (Greenberg & Wong, 1964; Greenberg, 1976; Jeffery et al, 1982; Cohen & Bovasso, 1971).
    b) CASE REPORT: The delayed development of hemolysis 7 days postingestion and after normalization of methemoglobinemia in a patient with renal failure was attributed to methylene blue therapy in one case (Sharon et al, 1986).
    2) WITH POISONING/EXPOSURE
    a) Hemolysis has been associated with some cases of methemoglobinemia due to phenazopyridine toxicity (Greenberg & Wong, 1964; Greenberg, 1976; Jeffery et al, 1982; Cohen & Bovasso, 1971).
    b) Patients with red blood cell glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may have an increased risk for developing hemolysis (Prod Info Pyridium(R) oral tablets, 2014).
    B) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Methemoglobinemia has been reported following therapeutic doses (Prod Info Pyridium(R) oral tablets, 2014; Jeffery et al, 1982), and is the primary manifestation of intoxication (Onder et al, 2006; Randazzo et al, 1975).
    b) ONSET: Methemoglobinemia usually occurs within 2 to 3 hours after ingestion, but may be delayed. In one child, cyanosis was reported 17 hours after induction of emesis (Wieland et al, 1983).
    c) CASE REPORT: A 73-year-old woman with G6PD concentrations within normal limits developed methemoglobinemia without hemolytic anemia associated with phenazopyridine 100 to 200 mg orally three times daily for three months. A rate constant for methemoglobin disappearance of 0.0326 days (-1) was reported, corresponding to a half-life of 21 days (Terrell et al, 1988).
    d) CASE REPORT: Chronic administration of phenazopyridine 200 mg TID in a 72-year-old man with normal renal function and no evidence of G6PD deficiency was associated with development of methemoglobinemia (Chakraborty et al, 1987).
    e) CASE REPORT/SUPRATHERAPEUTIC: A 46-year-old man ingested 3 to 4 grams/day (normal dosing 200 mg orally 3 times daily) over a week and presented with yellow pigmentation of the sclerae, mucous membranes, skin, cyanosis, and a methemoglobin level of 26% (Sharon et al, 1986).
    f) CASE REPORT: A case of methemoglobinemia and hemolytic anemia was reported in an adult patient with end stage renal disease taking a therapeutic dose of phenazopyridine (Fincher & Campbell, 1989)
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-month-old toddler developed severe, refractory methemoglobinemia (initial methemoglobin, 26%) after ingestion of approximately 23 Pyridium Plus(R) tablets, a preparation containing phenazopyridine in addition to hyoscyamine and butalbital. He required 6.5 mg/kg methylene blue and 2 exchange transfusions, with methemoglobinemia levels declining to 3.7% over 1 week (Truman et al, 1994).
    b) CASE REPORT: A 2-year-old child developed methemoglobinemia (methemoglobin level 29.1%; normal 1% to 3%) after ingesting a maximum of three phenazopyridine 200 mg tablets (equivalent of approximately 50 mg/kg). Following supportive care, she recovered completely without further sequelae. The authors suggested that patients should be observed for 4 to 6 hours after phenazopyridine overdose or methemoglobin levels should be obtained in all children who have ingested even a small number of phenazopyridine tablets (Gold & Bithoney, 2003).
    C) SULFHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Sulfhemoglobinemia has been reported in a 84-year-old woman while taking phenazopyridine 100 mg four times daily. A methemoglobin level of 50.3% measured by co-oximeter (which does not differentiate between sulfhemoglobin and methemoglobin) was unaffected following two separate IV doses of methylene blue (2 mg/kg). The patient was inadvertently rechallenged with the same dosage which resulted in a methemoglobin level of 30%; again unresponsive to methylene blue. The lack of response to methylene blue, no decrease in methemoglobin with the addition of cyanide to a patient blood sample, and persistence of methemoglobinemia for 22 days following discontinuation of the drug suggests the presence of sulfhemoglobin (Halvorsen & Dull, 1991).
    b) CASE REPORT: A 57-year-old woman developed cyanosis and dyspnea following the use of phenazopyridine for several years. Vital signs were: blood pressure 135/65 mmHg, pulse 105 bpm, respiratory rate 22/minute; pulse oximetry 86% on room air. The ECG revealed only sinus tachycardia. A sulfhemoglobin level of 13.9% was reported. Following supportive therapy for seven days, she was discharged without any sequelae (Barrueto et al, 2002).
    c) CASE REPORT: A 63-year-old woman presented with fatigue and bluish discoloration of the body for 6 to 8 weeks. She had been taking phenazopyridine over-the-counter for 4 months for dysuria. Cyanosis did not improve with methylene blue and sulfhemoglobinemia was observed by spectrophotometer analysis (Gopalachar et al, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Yellow skin pigmentation may result from large doses or prolonged use (Prod Info Pyridium(R) oral tablets, 2014; Sharon et al, 1986; Truman et al, 1994).
    b) Discoloration or staining of contact lens may also occur (Prod Info Pyridium(R) oral tablets, 2014).
    2) WITH POISONING/EXPOSURE
    a) Yellow skin pigmentation may result from large doses or prolonged use (Sharon et al, 1986; Truman et al, 1994).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash and pruritus have been reported in patients taking phenazopyridine (Prod Info Pyridium(R) oral tablets, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Muscle tenderness, rhabdomyolysis, and renal dysfunction were reported in a 19-year-old woman after ingestion of 6 grams (Gavish et al, 1986).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) An anaphylactoid-like reaction has been reported in patients taking phenazopyridine (Prod Info Pyridium(R) oral tablets, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Phenazopyridine is in Pregnancy Category B.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    PHENAZOPYRIDINEB
    Reference: Briggs et al, 1998.
    B) LACK OF EFFECT
    1) Phenazopyridine is not contraindicated in pregnancy due to many years of use in pregnancy with no reported complications (Briggs et al, 1998).
    a) Animal data are nonexistent, but 1 prospective human study showed little risk of malformations.
    2) The Collaborative Perinatal Project studied 50,282 pregnancies between 1959 and 1965.
    a) Of 219 mother-child pairs exposed to phenazopyridine during the first 4 months of pregnancy, a total of 7 children were malformed, less than what was expected from the hospital background incidence.
    b) The relative risk of minor malformations was slightly greater than expected (1:24) and inguinal hernia occurred twice as often as was expected (6 children) (Heinonen et al, 1977).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor CBC and methemoglobin concentration in patients with cyanosis. Obtain methemoglobin levels in children who have ingested even a small number of phenazopyridine tablets.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzymes in symptomatic patients.
    2) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    B) HEMATOLOGIC
    1) Monitor CBC and methemoglobin concentration in patients with cyanosis.
    2) One report suggested that methemoglobin levels should be obtained in all children who have ingested even a small number of phenazopyridine tablets (Gold & Bithoney, 2003).
    3) Significant RETICULOCYTOSIS is demonstrated in some cases, with ranges anywhere from 9% to 21%.
    4) The peripheral smear on these patients may show a normochromic-normocytic red cell with occasional helmet cells, fragment red cells and the presence of bite cells and Heinz body being diagnostic. "Bite cells" are also called degmacytes. They result from the destruction of red cells due to oxidative stress, making them appear as though a bite has been taken out of them (Zimmerman et al, 1980; Greenberg, 1976).
    5) G-6-PD is usually normal in most case reports, but it is known that this agent can induce the problem in G-6-PD deficient patients (Mercieca et al, 1982).
    4.1.3) URINE
    A) URINALYSIS
    1) Urinalysis, including signs of hemolysis or myoglobinuria, should be obtained.
    2) Pigmented urine casts and crystals in the urine may appear if the patient has renal disease and has received large doses of phenazopyridine.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent minor exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
    B) One report suggested that patients should be observed for 4 to 6 hours after phenazopyridine overdose or methemoglobin levels should be obtained in all children who have ingested even a small number of phenazopyridine tablets (Gold & Bithoney, 2003).

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor CBC and methemoglobin concentration in patients with cyanosis. Obtain methemoglobin levels in children who have ingested even a small number of phenazopyridine tablets.
    D) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors, and epinephrine may be required. Treat symptomatic methemoglobinemia with methylene blue. Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or infants may require exchange transfusion or treatment with hyperbaric oxygen as they may not respond to methylene blue. Monitor creatine kinase levels. If severe elevations occur and there is a concern for rhabdomyolysis, treat the patient with aggressive IV fluids and consider sodium bicarbonate.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and liver enzymes in symptomatic patients.
    3) Monitor CBC and methemoglobin concentration in patients with cyanosis. Obtain methemoglobin levels in children who have ingested even a small number of phenazopyridine tablets.
    4) Monitor CK, renal function, and urine output in patients with rhabdomyolysis.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    4) CASE REPORT: Usual doses of methylene blue (1 mg/kg) were associated with development of hemolysis in a patient with phenazopyridine-induced methemoglobinemia and renal failure. Although the possibility of direct hemolysis secondary to phenazopyridine could not be excluded, the author recommended adjusting the dose of methylene blue in patients with renal impairment (Sharon et al, 1986).
    E) ACUTE RENAL FAILURE SYNDROME
    1) Monitor renal function and urine output. Intravenous hydration may be needed to maintain urine output. Renal insufficiency secondary to phenazopyridine overdose is usually reversible (Onder et al, 2006).
    2) CASE REPORT: Urinary alkalinization, oral N-acetylcysteine (NAC) and an L-carnitine infusion were used to treat acute renal failure in a young adult women following a 1200 mg ingestion. NAC can improve renal function, reduce interstitial injury and replenish intracellular glutathione in experimental acute renal failure and L-carnitine can support mitochondrial metabolism, which may be disrupted by free-oxygen radicals (Onder et al, 2006).
    F) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) EXCHANGE TRANSFUSION
    1) Exchange transfusion may be useful in severely symptomatic patients, especially in infants and children, if methemoglobinemia is not corrected with intravenous methylene blue (Cohen & Bovasso, 1971).

Abstracts

Case Reports

    A) ADULT
    1) Methemoglobinemia developed in a 43-year-old patient following an approximate ingestion of 7 1/2 g in an attempted suicide gesture. The patient was noted to develop a confusional state with a hyperpyrexia of 100.8 degrees F and a pulse of 130/min. Lethargy, cyanosis, and a bright orange-colored urine were also noted in association with the methemoglobin level of about 3.5 g/dL. This patient was also noted to have a hematocrit which fell to 38% in association with a hemoglobin saturation of 23.7%. Administration of methylene blue in a dose of 70 to 90 mg IV for 2 doses resulted in rapid improvement. Subsequent recovery was rapid and complete (Randazzo et al, 1975).
    B) PEDIATRIC
    1) INFANT
    a) A 13-month-old infant accidentally ingested 25 to 30 tablets of phenazopyridine (2500 to 3000 mg) and subsequently developed methemoglobinemia and hemolytic anemia. Three days following ingestion the patient became lethargic and once was noted to have cyanotic lips associated with shallow and rapid respiration. Her extremities were noted to be mottled purple with a purplish hue of the oral mucosa and tongue. Her heart rate was noted to be 148/minute. Initially the patient was found to have a methemoglobin content of 2.84 g/dL which at 14 hours had fallen to 1.65 g/dL. It was also noted that the patient's hemoglobin fell to 6.6 g/dL in association with an elevated reticulocyte count. Peripheral smear demonstrated anisocytosis, poikilocytosis, and occasional burr cells. Following gastric decontamination and 1 mg/kg of methylene blue IV for 2 doses, along with a transfusion of whole blood and packed cells, the patient had a satisfactory recovery (Cohen & Bovasso, 1971).

Range Of Toxicity

Summary

    A) TOXICITY: PEDIATRIC: Methemoglobinemia developed in a 13-month-old following an acute ingestion of 2.5 to 3 g of phenazopyridine, and in a 2-year-old after ingesting 800 to 1200 mg of phenazopyridine. ADULT: Symptoms typically occur following the ingestion of several grams. However, methemoglobinemia and acute renal failure developed in a 17-year-old female following a single 1200 mg ingestion.
    B) THERAPEUTIC DOSE: ADULT: One 200-mg tablet or two 100-mg tablets orally 3 times daily. CHILDREN 6 TO 12 YEARS: 12 mg/kg/day in divided doses 3 times daily for 2 days.

Therapeutic Dose

    7.2.1) ADULT
    A) One 200-mg tablet or two 100-mg tablets orally 3 times daily (Prod Info Pyridium(R) oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) 6 TO 12 YEARS OF AGE: 12 mg/kg/day orally daily in 3 divided doses for maximum 2 days (Gunn et al, 2002)

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) Transient methemoglobinemia and acute renal failure developed in a 17-year-old female after ingesting a single 1200 mg dose (Onder et al, 2006).
    b) Methemoglobinemia associated with hemolytic anemia and acute renal failure have been reported in an 18-year-old woman who self-administered twelve 200-milligram tablets over a 24-hour period (Nathan et al, 1977).
    c) Methemoglobinemia, hemolysis, renal failure, and rhabdomyolysis were reported in a 19-year-old who ingested 6 grams (Gavish et al, 1986).
    2) CHILDREN
    a) Methemoglobinemia developed in a 13-month-old female following acute ingestion of 2.5 to 3 grams of phenazopyridine (Cohen & Bovasso, 1971). She recovered following methylene blue therapy and exchange transfusion.
    b) A 2-year-old child was reported to develop a methemoglobin level of 32 percent after ingestion of 800 to 1200 milligrams (Wieland et al, 1983).
    c) A 2-year-old child developed methemoglobinemia (methemoglobin level 29.1%; normal 1% to 3%) after ingesting a maximum of three phenazopyridine 200 mg tablets (equivalent of approximately 50 mg/kg). Following supportive care, she recovered completely without further sequelae (Gold & Bithoney, 2003).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Phenazopyridine hydrochloride is a urinary tract analgesic agent. The precise mode of action is unknown but when excreted in the urine, it promotes topical analgesia on the mucosa of the urinary tract, thus relieving pain, burning, urgency and frequency (Prod Info PYRIDIUM(R) oral tablet, 2002).
    B) Although phenazopyridine inhibits, in vitro, the growth of staphylococci, streptococci, gonococci, and E coli, it imparts little or no antibacterial activity to the urine. Its chief value lies in its local anesthetic effect on urinary tract mucosa.

Toxicologic Mechanism

    A) HEMOLYSIS
    1) The mechanism is due to its chemical structure and aromatic compound-like similarities to phenylhydrazine, which is known to cause the problem (Greenberg & Wong, 1964).
    2) This drug has been shown through its oxidizing properties to act as an intermediate between the molecular oxygen and hemoglobin association, resulting in aggregation of oxidatively denatured hemoglobin.
    a) Red cells become rigid, have problems traversing the spleen, with resultant destruction and formation of bite cells (Noonan et al, 1983).
    3) The most common patient characteristic in most of the case reports is impaired renal function which seems to allow accumulation of the drug and increase the potential for side effect.
    a) Other inherent patient sensitivities have not been identified other than impaired renal function and deficiency of G-6-PD (Greenberg & Wong, 1964; Mercieca et al, 1982; Johnson & Chartrand, 1976; DeLeeuw, 1963).

Physicochemical

Physical Characteristics

    A) crystalline powder, colored light red, dark red, or dark violet

Molecular Weight

    A) 213.24

References

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