Sodium Nitrite and Sodium Thiosulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [combination package]:

Nithiodote: Sodium nitrite 300 mg/10 mL (10 mL) and sodium thiosulfate 12.5 g/50 mL (50 mL)

Pharmacology

Mechanism of Action

Sodium nitrite: Promotes the formation of methemoglobin which competes with cytochrome oxidase for the cyanide ion. Cyanide combines with methemoglobin to form cyanomethemoglobin, thereby freeing the cytochrome oxidase and allowing aerobic metabolism to continue.

Sodium thiosulfate: Serves as a sulfur donor in rhodanese-catalyzed formation of thiocyanate (much less toxic than cyanide).

Pharmacokinetics/Pharmacodynamics

Distribution

Sodium thiosulfate: IV: V_d: Thiosulfate: 0.15 L/kg (Howland 2011); Thiocyanate: 0.25 L/kg.

Metabolism

Sodium nitrite: To ammonia and other metabolites.

Excretion

Sodium nitrite: Urine (~40% as unchanged drug).

Sodium thiosulfate: Urine (~20% to 50% thiosulfate as unchanged drug).

Onset of Action

Sodium nitrite: Methemoglobinemia: Peak methemoglobin concentration, mean (7%): 30 to 60 minutes.

Duration of Action

Sodium nitrite: Methemoglobinemia: Half-life (conversion of methemoglobin to normal hemoglobin): ~55 minutes.

Half-Life Elimination

Sodium thiosulfate: Thiosulfate: ~3 hours (Howland 2011); Thiocyanate: 2.7 days; Prolonged with renal impairment to ~9 days.

Use: Labeled Indications

Cyanide poisoning: Treatment of acute, life-threatening cyanide poisoning.

Note: The preferred antidote for the treatment of acute cyanide poisoning is hydroxocobalamin, especially in patients who have concurrent carbon monoxide poisoning (eg, smoke inhalation), significant anemia, or G6PD deficiency (Anseeuw 2013). Sodium nitrite and sodium thiosulfate should be considered only if hydroxocobalamin is unavailable, there is a contraindication to the use of hydroxocobalamin, or if the patient has a known sensitivity to hydroxocobalamin or vitamin B₁₂ analogues. Consider consultation with a poison control center at 1-800-222-1222.

Contraindications

There are no contraindications listed within the manufacturer’s labeling.

Dosage and Administration

Dosing: Adult

Cyanide poisoning: IV: Note: Administer sodium nitrite first, followed immediately by the administration of sodium thiosulfate.

Sodium nitrite: 300 mg (10 mL of a 3% solution); may repeat at one-half of the original dose if symptoms of cyanide toxicity return

Alternatively, in patients who are unable to tolerate significant methemoglobinemia (eg, patients with comorbidities that compromise oxygen delivery, such as heart disease, lung disease), dosing may be based on hemoglobin levels (when rapid bedside testing is available) to prevent fatal methemoglobinemia; see table (Berlin, 1970):

Table has been converted to the following text.

Dose of Sodium Nitrite Solution 3% (maximum dose: 10 mL) based on Hemoglobin Level (g/dL)

Hemoglobin level 7 g/dL: Dose of 3% sodium nitrite solution: 0.19 mL/kg

Hemoglobin level 8 g/dL: Dose of 3% sodium nitrite solution: 0.22 mL/kg

Hemoglobin level 9 g/dL: Dose of 3% sodium nitrite solution: 0.25 mL/kg

Hemoglobin level 10 g/dL: Dose of 3% sodium nitrite solution: 0.27 mL/kg

Hemoglobin level 11 g/dL: Dose of 3% sodium nitrite solution: 0.3 mL/kg

Hemoglobin level 12 g/dL: Dose of 3% sodium nitrite solution: 0.33 mL/kg

Hemoglobin level 13 g/dL: Dose of 3% sodium nitrite solution: 0.36 mL/kg

Hemoglobin level 14 g/dL: Dose of 3% sodium nitrite solution: 0.39 mL/kg

Sodium thiosulfate: 12.5 g (50 mL of a 25% solution); may repeat at one-half the original dose if symptoms of cyanide toxicity return

Note: Monitor the patient for 24-48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.

Dosing: Geriatric

Refer to adult dosing; use with caution due to the likelihood of decreased renal function.

Dosing: Pediatric

Note: Dosing in pediatric patients expressed in multiple units (mg/kg, mL/kg, mL/m²), use extra precaution.

Cyanide poisoning: Infants, Children, and Adolescents: Note: Administer in conjunction with sodium thiosulfate. Administer sodium nitrite first, followed immediately by the administration of sodium thiosulfate. Monitor the patient for 24 to 48 hours following doses. Sodium nitrite is generally discontinued for methemoglobin levels >30%.

Sodium nitrite (30 mg/mL, 3%): IV: 6 mg/kg (0.2 mL/kg or 6 to 8 mL/m² of a 3% solution); maximum dose: 300 mg (10 mL of a 3% solution) (Howland 2019; manufacturer's labeling). Monitor patients for 24 to 48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.

Dosage adjustment for patients who are unable to tolerate significant methemoglobinemia (eg, patients with comorbidities that compromise oxygen delivery, such as heart disease, lung disease, etc): Hemoglobin-dependent dosing (when rapid bedside testing is available) to prevent fatal methemoglobinemia (Berlin 1970):

Table has been converted to the following text.

Dose of Sodium Nitrite Solution 3% based on Hemoglobin Level (g/dL)

Hemoglobin level 7 g/dL: Dose of 3% sodium nitrite solution: 0.19 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 8 g/dL: Dose of 3% sodium nitrite solution: 0.22 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 9 g/dL: Dose of 3% sodium nitrite solution: 0.25 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 10 g/dL: Dose of 3% sodium nitrite solution: 0.27 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 11 g/dL: Dose of 3% sodium nitrite solution: 0.3 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 12 g/dL: Dose of 3% sodium nitrite solution: 0.33 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 13 g/dL: Dose of 3% sodium nitrite solution: 0.36 mL/kg; maximum dose: 10 mL/dose.

Hemoglobin level 14 g/dL: Dose of 3% sodium nitrite solution: 0.39 mL/kg; maximum dose: 10 mL/dose.

Sodium thiosulfate: IV: 250 mg/kg (1 mL/kg or 30 to 40 mL/m² of a 25% solution); maximum dose: 12.5 g/dose (50 mL of a 25% solution) (Howland 2019; manufacturer's labeling). Monitor the patient for 24 to 48 hours; if symptoms return, repeat both sodium nitrite and sodium thiosulfate at one-half the original doses.

Administration

IV: Administer via slow IV injection as soon as possible after diagnosis of acute, life-threatening cyanide poisoning. Administer sodium nitrite first at a rate of 2.5 to 5 mL/minute, followed immediately by sodium thiosulfate over 10 to 30 minutes (Howland, 2015). Decrease the rate of infusion in the event of significant hypotension. Simultaneous administration of blood products (whole blood, packed red cells, platelet concentrate, and/or fresh frozen plasma) should preferentially be done using separate lines (use contralateral extremities if peripheral lines are used).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Protect from direct light.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Methemoglobinemia Associated Agents: May enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Adverse Reactions

Frequency not defined.

Sodium nitrite:

Cardiovascular: Cardiac arrhythmia, flushing, hypotension, palpitations, syncope, tachycardia

Central nervous system: Anxiety, coma, confusion, dizziness, fatigue, headache, numbness, paresthesia, seizure, tingling of skin (injection site)

Dermatologic: Diaphoresis, urticaria

Endocrine & metabolic: Acidosis

Gastrointestinal: Abdominal pain, nausea, vomiting

Hematologic & oncologic: Methemoglobinemia

Neuromuscular & skeletal: Weakness

Ophthalmic: Blurred vision

Respiratory: Cyanosis, dyspnea, tachypnea

Sodium thiosulfate:

Cardiovascular: Hypotension

Central nervous system: Disorientation, flushing sensation, headache, salty taste

Gastrointestinal: Nausea, vomiting

Hematologic & oncologic: Prolonged bleeding time

Warnings/Precautions

Concerns related to adverse effects:

• Hypotension: [US Boxed Warning]: Sodium nitrite may cause severe hypotension resulting in diminished oxygen-carrying capacity; serious adverse effects may occur at doses less than twice the recommended therapeutic dose. Monitor for adequate perfusion and oxygenation; ensure patient is euvolemic. Use with caution in patients where the diagnosis of cyanide poisoning is uncertain, patients with pre-existing diminished oxygen or cardiovascular reserve (eg, smoke inhalation victims [due to the presence of carbon monoxide], anemia, substantial blood loss, and cardiac or respiratory compromise) and in patients who may be susceptible to injury from vasodilation; the use of hydroxocobalamin is recommended in these patients.
• Methemoglobinemia: [US Boxed Warning]: Sodium nitrite may cause methemoglobin formation resulting in diminished oxygen-carrying capacity; serious adverse effects may occur at doses less than twice the recommended therapeutic dose. Monitor for adequate perfusion and oxygenation. Use with caution in patients where the diagnosis of cyanide poisoning is uncertain, patients with pre-existing diminished oxygen or cardiovascular reserve (eg, smoke inhalation victims [due to the presence of carbon monoxide], anemia, substantial blood loss, and cardiac or respiratory compromise), and in patients at greater risk for developing methemoglobinemia (eg, congenital methemoglobin reductase deficiency); the use of hydroxocobalamin is recommended in these patients. Use with caution with concomitant medications known to cause methemoglobinemia (eg, nitroglycerin, phenazopyridine). Sodium nitrite is generally discontinued for methemoglobin levels >30%. Intravenous methylene blue and exchange transfusion have been used to treat life-threatening methemoglobinemia.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Disease-related concerns:

• Anemia: Use with caution; patients with anemia will form more methemoglobin. Dosage reduction in proportion to oxygen-carrying capacity is recommended.
• Glucose-6-phosphate dehydrogenase deficiency: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially children, are at an increased risk for hemolytic crisis following sodium nitrite administration; consider alternative treatment options (eg, hydroxocobalamin) if possible. Monitor for an acute drop in hematocrit; exchange transfusion may be necessary.
• Renal impairment: Use with caution; sodium nitrite and sodium thiosulfate undergo substantial renal excretion. Risk for adverse events may be increased.

Special populations:

• Elderly: Use with caution due to the likelihood of decreased renal function.
• Fire victims: Fire victims may present with both cyanide and carbon monoxide poisoning. In this scenario, hydroxocobalamin is the agent of choice for cyanide intoxication since the induction of methemoglobinemia (due to sodium nitrite) is contraindicated until carbon monoxide levels return to normal due to the risk of severe tissue hypoxia. Methemoglobinemia decreases the oxygen-carrying capacity of hemoglobin and the presence of carbon monoxide prevents hemoglobin from releasing oxygen to the tissues. In these patients, sodium thiosulfate may be used alone to promote the clearance of cyanide; however, hydroxocobalamin is still the preferred cyanide antidote because sodium thiosulfate has a slow onset of action.
• Pediatric: Methemoglobin reductase, which is responsible for converting methemoglobin back to hemoglobin, has reduced activity in pediatric patients. In addition, infants and young children have some proportion of fetal hemoglobin which forms methemoglobin more readily than adult hemoglobin. Therefore, pediatric patients (eg, neonates and infants <6 months of age) are more susceptible to excessive nitrite-induced methemoglobinemia. Hydroxocobalamin will circumvent this problem and may be a more effective and rapid alternative.
• Pregnancy: Nitrites should be avoided due to fetal hemoglobin's susceptibility to oxidative stress.
• Sulfite hypersensitivity: The presence of sulfite hypersensitivity should not preclude the use of this medication.

Other warnings/precautions:

• Appropriate use: Cyanide poisoning: Due to the risk for serious adverse effects, use with caution in patients where the diagnosis of cyanide poisoning is uncertain. However, if clinical suspicion of cyanide poisoning is high, treatment should not be delayed. Signs of cyanide poisoning may include altered mental status, cardiovascular collapse, chest tightness, mydriasis, nausea/vomiting, dyspnea, hyper-/hypotension, plasma lactate ≥8 mmol/L. Treatment of cyanide poisoning should include external decontamination and supportive therapy. Consider immediate consultation with a poison control center at 1-800-222-1222.
• Initiation of treatment: Collection of pretreatment blood cyanide concentrations does not preclude administration and should not delay administration in the emergency management of highly suspected or confirmed cyanide toxicity. Pretreatment levels may be useful as postinfusion levels may be inaccurate.
• Return of symptoms: Patients receiving treatment for acute cyanide poisoning must be monitored for return of symptoms for 24-48 hours; repeat treatment (one-half the original dose) should be administered if symptoms return.
• Smoke inhalation: Use nitrites cautiously in patients with cyanide poisoning related to smoke inhalation because methemoglobinemia and carboxyhemoglobinemia (from carbon monoxide) may worsen oxygen-carrying capacity.

Monitoring Parameters

Monitor for at least 24-48 hours after administration; blood pressure and heart rate during and after infusion; hemoglobin/hematocrit; co-oximetry; serum lactate levels; venous-arterial PO₂ gradient; serum methemoglobin and oxyhemoglobin. Pretreatment cyanide levels may be useful diagnostically, but if the patient is acutely ill, do not delay sodium nitrite therapy while awaiting laboratory results.

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Teratogenic effects have been observed following maternal exposure to high concentrations of sodium nitrite in drinking water. Teratogenic effects were not observed in animal reproduction studies of sodium nitrite or sodium thiosulfate. Embryotoxic and nonteratogenic effects were observed in animal reproduction studies of sodium nitrite. Methemoglobin reductase is lower in the fetus compared to adults and may result in adverse effects due to nitrite-induced prenatal hypoxia. There are no adequate and well-controlled studies of Nithiodote in pregnant women. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience flushing, headache, bad taste, vomiting, or nausea. Have patient report immediately to prescriber severe dizziness, passing out, fast heartbeat, confusion, blurred vision, numbness or tingling, or signs of methemoglobinemia (blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.