Included as part of the "PRECAUTIONS" Section
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).
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. Use sodium nitrite with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic
sequelae. Monitor hemodynamics closely during and after administration of sodium nitrite and sodium thiosulfate, and reduce infusion rates if hypotension
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
Smoke Inhalation Injury
Use sodium nitrite with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to
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.
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.
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.
Sodium thiosulfate drug product may contain trace impurities of sodium sulfite. The presence of a trace amount of sulfites in this product should not deter
administration of the drug for treatment of emergency situations, even if the patient is sulfite-sensitive.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The potential benefit of an acute exposure to sodium nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent
studies. Sodium nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150
mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of
tumor in either male or female rats. Sodium nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for
males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female
mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice.
Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there
were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that sodium nitrite may react in vivo with
secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to sodium nitrite and secondary amines in feed or drinking water
resulted in an increase in the incidence of tumors in rodents.
Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.
Sodium nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98,
TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Sodium nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse
lymphoma assay, both assays conducted in the absence of metabolic activation. Sodium nitrite was negative in the in vitro chromosomal aberrations assay using
human peripheral blood lymphocytes. Acute administration of sodium nitrite to male rats or male mice did not produce an increased incidence of micronuclei in
bone marrow. Likewise, sodium nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
The mutagenic potential of sodium thiosulfate has been examined in the in vitro Bacterial Reverse Mutation Assay (Ames Assay). Sodium thiosulfate was not
mutagenic in the absence of metabolic activation in S. typhimurium strains TA98, TA100, TA1535, TA537, or TA1538. Sodium thiosulfate was not mutagenic
in the presence of metabolic activation in strains TA 98, TA1535, TA1537, TA1538 or E. coli strain WP2.
Impairment Of Fertility
Clinical studies to evaluate the potential effects of either sodium nitrite or sodium thiosulfate intake on fertility of either males or females have not been
In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of
sodium nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted
in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of sodium
nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
There are no preclinical studies examining the effects of sodium thiosulfate on fertility.
Use In Specific Populations
Both sodium nitrite and sodium thiosulfate are Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. NITHIODOTE
should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Sodium nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential
reproductive toxicity of sodium nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for
congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a
case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate were ≥ 26 ppm (not
The potential reproductive toxicity of sodium nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no
evidence of teratogenicity in guinea pigs, mice, or rats. However, 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).
Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with sodium nitrite at
concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in
dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of sodium nitrite that would be used to treat cyanide poisoning, based
on a body surface area comparison).
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. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting
in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.
There are no reported epidemiological studies of congenital anomalies in infants born to women treated with sodium thiosulfate during
pregnancy. In animal studies, there are no teratogenic effects in offspring of hamsters treated during pregnancy with sodium thiosulfate in doses similar to those
given intravenously to treat cyanide poisoning in humans. Other studies suggest that treatment with sodium thiosulfate ameliorates the teratogenic effects of
maternal cyanide poisoning in hamsters. In other studies, sodium thiosulfate was not embryotoxic or teratogenic in mice, rats, hamsters, or rabbits at maternal
doses of up to 550, 400, 400 and 580 mg/kg/day, respectively.
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 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.
Labor And Delivery
Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult,
sodium nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
It is not known whether sodium nitrite or sodium thiosulfate is excreted in human milk. Because NITHIODOTE may be administered in life-threatening situations,
breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, exercise caution following NITHIODOTE administration to a
nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of sodium nitrite and sodium thiosulfate. In
studies conducted with Long-Evans rats, sodium nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth
and increased mortality in the offspring.
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 thiosulfate or 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.
Use Sodium nitrite 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. [see DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS , ADVERSE REACTIONS]
Sodium nitrite and sodium thiosulfate are known to be substantially excreted by the kidney, and the risk of adverse reactions to these drugs may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
Sodium nitrite and sodium thiosulfate are known to be substantially excreted by the kidney, and the risk of toxic reactions to these drugs may be greater in
patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it
may be useful to monitor renal function.