SODIUM NITRITE: 45 Adverse Event Reports & Safety Profile

Sodium nitrite has the chemical name nitrous acid sodium salt. The chemical formula is NaNO 2 and the molecular weight is 69.0. The structural formula is: Structure of Sodium Nitrite Sodium Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of sodium nitrite injection. Sodium nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of sodium nitrite in 10 mL solution (30 mg/mL). Sodium nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical

Structure

AND USAGE Sodium Nitrite Injection, an antidote, is indicated for sequential use with sodium thiosulfate for the treatment of acute cyanide poisoning that is judged to be serious or life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Sodium Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

Sodium Nitrite

Injection, an antidote, is indicated for sequential use with sodium thiosulfate for treatment of acute cyanide poisoning that is judged to be serious or life-threatening. ( 1 ) Use with caution if the diagnosis of cyanide poisoning is uncertain. ( 1 )

AND ADMINISTRATION If clinical suspicion of cyanide poisoning is high, administer Sodium Nitrite Injection without delay and in conjunction with appropriate airway, ventilatory, and circulatory support. ( 2.1 ) The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222. ( 2.1 ) Dosing : Age Intravenous Dose of Sodium Nitrite and Sodium Thiosulfate Adults 1.)

Sodium

Nitrite -10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute 2.)

Sodium

Thiosulfate - 50 mL of sodium thiosulfate immediately following administration of sodium nitrite.

Children

1.)

Sodium

Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m 2 BSA) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL 2.)

Sodium

Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m 2 of BSA) not to exceed 50 mL total dose immediately following administration of sodium nitrite. Redosing : If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate. ( 2.2 ) Monitoring : Blood pressure must be monitored during treatment. ( 2.2 ) Sodium nitrite is chemically incompatible with hydroxocobalamin and should not be administered via the same intravenous line. ( 2.4 )

2.1 Important Dosage and Administration Instructions If clinical suspicion of cyanide poisoning is high, administer Sodium Nitrite Injection without delay. Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed in order to administer sodium nitrite and sodium thiosulfate [ see Warnings and Precautions (5.1) ]. The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Identifying

Patients with Cyanide Poisoning Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to sodium nitroprusside.. The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication Table 1.

Common

Signs and Symptoms of Cyanide Poisoning Symptoms Headache Confusion Dyspnea Chest Tightness Nausea Signs Altered Mental Status (e.g., confusion, disorientation) Seizures or Coma Mydriasis Tachypnea/Hyperpnea (early) Bradypnea/Apnea (late) Hypertension (early)/ Hypotension (late)

Cardiovascular Collapse Vomiting Plasma Lactate

Concentration ≥ 8 mmol/L In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Sodium Nitrite Injection, smoke-inhalation victims should be assessed for the following: Exposure to fire or smoke in an enclosed area Presence of soot around the mouth, nose, or oropharynx Altered mental status Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed in order to obtain a plasma lactate concentration. Use with Other Cyanide Antidotes The safety of administering other cyanide antidotes simultaneously with Sodium Nitrite Injection has not been established. If a decision is made to administer another cyanide antidote with Sodium Nitrite Injection, these drugs should not be administered concurrently in the same intravenous (IV) line. [ see Dosage and Administration (2.2) ]

2.2 Recommended Dosing Sodium Nitrite Injection and Sodium Thiosulfate Injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous

Dose of Sodium Nitrite and Sodium Thiosulfate Adults 1.)

Sodium

Nitrite -10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute 2.)

Sodium

Thiosulfate - 50 mL of sodium thiosulfate immediately following administration of sodium nitrite.

Children

1.)

Sodium

Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m 2 BSA) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL 2.)

Sodium

Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m 2 of BSA) not to exceed 50 mL total dose immediately following administration of sodium nitrite. NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate. In adult and pediatric patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration. [see Warnings and Precautions (5.2) ] All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.3 Recommended Monitoring Monitor patients for at least 24-48 hours after Sodium Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, obtain hemoglobin/hematocrit when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO 2 are unreliable in the presence of methemoglobinemia. Methemoglobin level : Administrations of sodium nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of sodium nitrite do not appear to be mediated by methemoglobin formation alone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12) ]</span> and clinical responses to sodium nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of sodium nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Monitor serum methemoglobin levels during treatment using co-oximetry, and discontinue administration of sodium nitrite when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.4 Incompatibility Information Chemical incompatibility has been reported between sodium nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between sodium thiosulfate and sodium nitrite, when administered sequentially through the same IV line as described in Dosage and Administration. Simultaneous administration of sodium nitrite and blood products (whole blood, packed red cells, platelet concentrate and/or fresh frozen plasma) through the same intravenous line is not recommended. However, blood products and sodium nitrite can be administered simultaneously using separate intravenous lines (preferably on contralateral extremities, if peripheral lines are being used).

None None. ( 4 )

REACTIONS There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium nitrite. The medical literature has reported the following adverse events in association with sodium nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed. Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia Hematological: methemoglobinemia Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma Gastrointestinal system: nausea, vomiting, abdominal pain Respiratory system: tachypnea, dyspnea Body as a Whole : anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of sodium nitrite at doses less than twice those recommended for the treatment of cyanide poisoning. Most common adverse reactions are: Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS Methemoglobinemia: Sodium nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse co-oximetry or other measurements. Optimally, the sodium nitrite dose should be reduced in proportion to the oxygen carrying capacity. ( 5.2 ) Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Sodium nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the sodium nitrite dose should be reduced in proportion to the oxygen carrying capacity. ( 5.4 )

5.1 Hypotension Sodium nitrite has been associated with severe hypotension, methemoglobinemia, and death at doses less than twice recommended therapeutic doses. Hypotension may occur concurrently or separately. Sodium nitrite should be used to treat life-threatening cyanide poisoning. When the diagnosis of cyanide poisoning is uncertain and/or the patient is not in extremis, special consideration should be given to administration of sodium nitrite if the patient is known or suspected to have diminished oxygen or cardiovascular reserve (e.g., smoke inhalation victims, pre-existing anemia, substantial blood loss, cardiac or respiratory compromise) or to be at higher risk of developing methemoglobinemia (e.g., congenital methemoglobin reductase deficiency).

5.2 Methemoglobinemia Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Monitor patients closely to ensure adequate perfusion and oxygenation during treatment with sodium nitrite. Monitor methemoglobin levels and administer oxygen during treatment with sodium nitrite whenever possible. When sodium nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of sodium nitrite administered to an adult. Sodium nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Sodium nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of sodium nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia Use sodium nitrite with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a sodium nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury Use sodium nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when sodium nitrite is administered. Follow reduced dosing guidelines in pediatric patients. 5.6 G6PD Deficiency Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with sodium nitrite administration, consider alternative therapeutic approaches in these patients. Monitor patients with known or suspected G6PD deficiency for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive sodium nitrite.

5.7 Use with Other Drugs Use sodium nitrite with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

INTERACTIONS Formal drug interaction studies have not been conducted with Sodium Nitrite Injection.