Sodium Nitrite Drug Information

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. Use with caution if the diagnosis of cyanide poisoning is uncertain.

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. 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.

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. 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. All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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 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.

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).

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 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.

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

Pregnancy Risk Summary Life-sustaining therapy should not be withheld. Cyanide poisoning is a medical emergency in pregnancy, which can be fatal for the pregnant woman and fetus if left untreated (see Clinical Considerations ). Therefore, if a pregnant woman has known or suspected cyanide poisoning, Sodium Nitrite Injection for sequential use with Sodium Thiosulfate Injection is recommended.

There are no available data on Sodium Nitrite Injection use in pregnant women to establish a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. If available, consider alternative therapies not associated with methemoglobinemia. There are no intravenous animal studies to evaluate the effect of sodium nitrite on embryofetal development.

In published animal studies, fetal mortality was reported when pregnant guinea pigs were subcutaneously administered sodium nitrite at 1.7 times the maximum recommended human dose (MRHD) of 450 mg sodium nitrite when maternal and fetal methemoglobin concentrations were at their peak. In other published studies, no evidence of malformations were reported in guinea pigs, mice, or rats; however, severe anemia, reduced growth, and increased pup mortality was reported when pregnant rats were treated with 4.7 times the MRHD of sodium nitrite via drinking water during gestation and throughout lactation (see Data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Cyanide readily crosses the placenta.

Treatment for cyanide poisoning should not be withheld because of potential concerns regarding the effects of Sodium Nitrite Injection on the fetus. Fetal/neonatal adverse reactions Sodium nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin.

In addition, the fetus has lower levels of methemoglobin reductase than adults. Based on animal studies, prenatal exposure to sodium nitrite resulted in impaired neural development likely the result of prenatal hypoxia (see Data ). If available, consider alternative therapy not known to be associated with methemoglobinemia.

Data Animal Data There are no intravenous toxicology studies of sodium nitrite that evaluate the potential for reproductive and developmental toxicity. In a published study, sodium nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, sodium nitrite died within 60 minutes of treatment.

Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of sodium nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

In a published study, treatment of pregnant rats via drinking water with sodium nitrite at concentrations of either 2000 or 3000 mg/L during gestation and throughout lactation resulted in severe anemia, reduced growth and increased mortality in the offspring. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (4.7 and 6.5 times the highest clinical dose of sodium nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison). In a published study, treatment of pregnant mice with approximately 243 mg/kg sodium nitrite daily (2.6 times the maximum recommended daily dose of 450 mg/day based on body surface are) via the drinking water (1000 mg/L) from Gestation Day 7-18 did not result in evidence of malformations or embryofetal toxicity or maternal toxicity.

Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to sodium nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to sodium nitrite (2000 mg/L via drinking water) demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups.

These changes have been attributed to prenatal hypoxia following nitrite exposure.

Pediatric Use There are case reports in the medical literature of sodium nitrite in conjunction with sodium thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of sodium nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports. Sodium nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults.

The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk. Mortality attributed to sodium nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Large doses of sodium nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse. Sodium nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to sodium nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of sodium nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.