Nithiodote

Since sodium nitrite and sodium thiosulfate is given by a healthcare professional in an emergency setting, you are not likely to miss a dose.

Sodium nitrite and sodium thiosulfate injection are used together to treat cyanide poisoning. Cyanide poisoning is a life-threatening condition that requires immediate medical attention.

This medicine is to be given only by or under the direct supervision of a doctor.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Bluish color of the fingernails, lips, skin, palms, or nail beds
• blurred vision
• change in consciousness
• confusion
• dark urine
• difficult or labored breathing
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drowsiness
• fainting
• fast, slow, pounding, or irregular heartbeat or pulse
• fever
• headache
• lightheadedness
• loss of consciousness
• nausea
• numbness and tingling sensation
• pale skin
• rapid heart rate
• rapid shallow breathing
• seizures
• shortness of breath
• sore throat
• sweating
• tightness in the chest
• troubled breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• anxiety
• confusion about identity, place, and time
• headache
• hives or welts
• increased sweating
• itching
• redness of the skin
• salty taste in your mouth
• skin rash
• tingling sensation at the injection site
• warm sensation over your body

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Nithiodote, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Nithiodote. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Nithiodote.

Review Date: October 4, 2017

Nithiodote Injection consists of:

• One vial of sodium nitrite injection, USP 300 mg/10mL (30 mg/mL) and
• One vial of sodium thiosulfate injection USP 12.5 grams/50 mL (250 mg/mL)

Administration of one vial of each medication constitutes a single dose.

Mechanism of Action

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.

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.

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.

Each NITHIDOTE 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.

Applies to sodium nitrite / sodium thiosulfate: intravenous solution

Cardiovascular

Cardiovascular side effects have included syncope, hypotension, tachycardia, palpitations, and dysrhythmia[Ref]

Hematologic

Hematologic side effects have included methemoglobinemia and prolonged bleeding time.[Ref]

Nervous system

Nervous system side effects have included headache, dizziness, blurred vision, seizures, confusion, coma, anxiety, lightheadedness, fatigue, weakness, disorientation, generalized numbness and tingling.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, abdominal pain, and salty taste in mouth.[Ref]

Respiratory

Respiratory side effects have included tachypnea, cyanosis, and dyspnea.[Ref]

Dermatologic

Dermatologic side effects have included urticaria, diaphoresis, and a warm sensation over the body.[Ref]

Local

Local side effects have included injection site tingling.[Ref]

Some side effects of Nithiodote may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Both sodium nitrite and sodium thiosulfate have been formally assigned to pregnancy category C by the FDA. Sodium nitrite has caused fetal death in humans as well as animals. There are no controlled data in human pregnancy. Sodium nitrite-sodium thiosulfate are only recommended for use during pregnancy when there are no alternatives and benefit outweighs risk.

There are no data on the excretion of sodium nitrite or sodium thiosulfate into human milk. Because sodium nitrite and sodium thiosulfate may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. The manufacturer recommends caution be used when administering sodium nitrite- sodium thiosulfate to nursing women.