5 WARNINGS AND PRECAUTIONS

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. 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 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 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.

5.8 Sulfites

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.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium nitrite or sodium thiosulfate.

The medical literature has reported the following adverse events in association with sodium nitrite or sodium thiosulfate 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.

Sodium Nitrite

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.

Sodium Thiosulfate

Cardiovascular system: hypotension

Central nervous system: headache, disorientation

Gastrointestinal system: nausea, vomiting

Hematological: prolonged bleeding time

Body as a Whole: salty taste in mouth, warm sensation over body

In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and administration of large doses of sodium thiosulfate have been associated with a higher incidence of nausea and vomiting. However, administration of 0.1 g sodium thiosulfate per pound up to a maximum of 15 g in a 10-15% solution over 10-15 minutes was associated with nausea and vomiting in 7 of 26 patients without concomitant cyanide intoxication.

In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate was associated with increases in clotting time 1-3 days after administration. However, no significant changes were observed in other hematological parameters.

10 OVERDOSAGE

Sodium Nitrite

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.

Sodium Thiosulfate

There is limited information about the effects of large doses of sodium thiosulfate in humans. Oral administration of 3 g sodium thiosulfate per day for 1-2 weeks in humans resulted in reductions in room air arterial oxygen saturation to as low as 75%, which was due to a rightward shift in the oxygen hemoglobin dissociation curve. The subjects returned to baseline oxygen saturations 1 week after discontinuation of sodium thiosulfate. A single intravenous administration of 20 mL of 10% sodium thiosulfate reportedly did not change oxygen saturations.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cyanide is an extremely toxic poison. In the absence of rapid and adequate treatment, exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well. Signs and symptoms of acute systemic cyanide poisoning may develop rapidly within minutes, depending on the route and extent of cyanide exposure.

The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Sodium Nitrite

Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO2 + Hemoglobin → Methemoglobin
HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Sodium Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Sodium thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

12. 2 Pharmacodynamics

Sodium Nitrite

When 4 mg/kg sodium nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of sodium nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of sodium nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered sodium nitrite and sodium thiosulfate is estimated to be 55 minutes.

Sodium Thiosulfate

In dogs, pretreatment with sodium thiosulfate to achieve a steady state level of 2 μmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold.

12.3 Pharmacokinetics

Sodium Nitrite

Sodium nitrite is a strong oxidant and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free sodium nitrite in humans have not been well studied. It has been reported that approximately 40% of sodium nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Sodium Thiosulfate

Thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with sodium nitrite and sodium thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

Sodium Nitrite

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.

Sodium Thiosulfate

Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.

Mutagenesis:

Sodium Nitrite

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.

Sodium Thiosulfate

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:

Sodium Nitrite

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).

Sodium Thiosulfate

There are no preclinical studies examining the effects of sodium thiosulfate on fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each NITHIODOTE carton (NDC 60267-812-00) consists of the following:

• One 10 mL glass vial of sodium nitrite injection 30 mg/mL (containing 300 mg of sodium nitrite);
• One 50 mL glass vial of sodium thiosulfate injection 250 mg/mL (containing 12.5 grams of sodium thiosulfate);
• One package insert.

Storage

Store at controlled room temperature between 20°C and 25°C (68°F - 77°F); excursions permitted to 15-30°C (59 to 86°F).

Protect from direct light. Do not freeze.

17 PATIENT COUNSELING INFORMATION

NITHIODOTE is indicated for cyanide poisoning and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life- threatening hypotension and methemoglobin formation.

Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Lactation

Advise women that breastfeeding is not recommended during treatment with NITHIODOTE [see Use in Specific Populations (8.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

• If clinical suspicion of cyanide poisoning is high, administer NITHIODOTE 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.

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 NITHIODOTE, 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 NITHIODOTE has not been established. If a decision is made to administer another cyanide antidote with NITHIODOTE, 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 serious or 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.

**Sodium Nitrite**-10 mL of sodium nitrite at the rate of 2.5 to 5 mL/minute

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

**Sodium Nitrite -** 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of sodium nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL

**Sodium Thiosulfate -**1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 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)]

Visually inspect all parenteral drug products for particulate matter and discoloration prior to administration.

2.3 Recommended Monitoring

Monitor patients for at least 24-48 hours after NITHIODOTE 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 PO2 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 [see Clinical Pharmacology (12)] 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 NITHIODOTE 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 NITHIODOTE 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 NITHIODOTE can be administered simultaneously using separate intravenous lines (preferably on contralateral extremities, if peripheral lines are being used).