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DRUGS & SUPPLEMENTS
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Bidi Gaspain
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Bidi Gaspain uses
Bidi Gaspain consists of Sodium Bicarbonate, Sodium Citrate, Sodium Phosphate Tribasic, Sodium Sulfate.Sodium Bicarbonate:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Bidi Gaspain nitrite is indicated for sequential use with Bidi Gaspain (Sodium Bicarbonate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection is indicated for sequential use with Bidi Gaspain (Sodium Bicarbonate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 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 Bidi Gaspain 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. If clinical suspicion of cyanide poisoning is high, Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection and Bidi Gaspain (Sodium Bicarbonate) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
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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.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
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 Bidi Gaspain (Sodium Bicarbonate) 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 to obtain a plasma lactate concentration.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Bidi Gaspain (Sodium Bicarbonate) thiosulfate, simultaneously with Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Bidi Gaspain (Sodium Bicarbonate) thiosulfate, with Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Bidi Gaspain Nitrite and Bidi Gaspain (Sodium Bicarbonate) Thiosulfate |
|---|---|
| Adults |
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| Children |
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Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Bidi Gaspain (Sodium Bicarbonate) nitrite, followed by Bidi Gaspain (Sodium Bicarbonate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate.
Bidi Gaspain (Sodium Bicarbonate) nitrite injection and Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) nitrite should be administered first, followed immediately by Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) Nitrite and Bidi Gaspain (Sodium Bicarbonate) Thiosulfate |
|---|---|
| Adults |
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| Children |
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NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Bidi Gaspain (Sodium Bicarbonate) 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.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Bidi Gaspain Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained 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 Bidi Gaspain (Sodium Bicarbonate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Bidi Gaspain (Sodium Bicarbonate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Bidi Gaspain (Sodium Bicarbonate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Bidi Gaspain (Sodium Bicarbonate) 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%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Bidi Gaspain (Sodium Bicarbonate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Bidi Gaspain (Sodium Bicarbonate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Bidi Gaspain (Sodium Bicarbonate) thiosulfate and Bidi Gaspain (Sodium Bicarbonate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection consists of:
- One vial of Bidi Gaspain (Sodium Bicarbonate) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Bidi Gaspain 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 oximetry or other measurements. Optimally, the Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
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. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Bidi Gaspain nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Bidi Gaspain (Sodium Bicarbonate) nitrite whenever possible. When Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite administered to an adult. Bidi Gaspain (Sodium Bicarbonate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Bidi Gaspain (Sodium Bicarbonate) nitrite should be used 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 Bidi Gaspain (Sodium Bicarbonate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Bidi Gaspain 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 Bidi Gaspain (Sodium Bicarbonate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Bidi Gaspain nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Bidi Gaspain (Sodium Bicarbonate) nitrite.
5.7 Use with Other Drugs
Bidi Gaspain (Sodium Bicarbonate) nitrite should be used 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.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Bidi Gaspain (Sodium Bicarbonate) nitrite.
The medical literature has reported the following adverse events in association with Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Bidi Gaspain nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Bidi Gaspain (Sodium Bicarbonate) 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, Bidi Gaspain (Sodium Bicarbonate) 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, Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Bidi Gaspain (Sodium Bicarbonate) 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.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Bidi Gaspain (Sodium Bicarbonate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Bidi Gaspain (Sodium Bicarbonate) 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.
8.2 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, Bidi Gaspain nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Bidi Gaspain (Sodium Bicarbonate) nitrite is excreted in human milk. Because Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Bidi Gaspain (Sodium Bicarbonate) nitrite. In studies conducted with Long-Evans rats, Bidi Gaspain (Sodium Bicarbonate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Bidi Gaspain nitrite in conjunction with Bidi Gaspain (Sodium Bicarbonate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Bidi Gaspain (Sodium Bicarbonate) 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.
Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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.
8.5 Geriatric Use
Bidi Gaspain (Sodium Bicarbonate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug 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.
8.6 Renal Disease
Bidi Gaspain (Sodium Bicarbonate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug 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.
10 OVERDOSAGE
Large doses of Bidi Gaspain (Sodium Bicarbonate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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.
11 DESCRIPTION
Bidi Gaspain (Sodium Bicarbonate) nitrite has the chemical name nitrous acid Bidi Gaspain (Sodium Bicarbonate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Bidi Gaspain (Sodium Bicarbonate) Nitrite
Bidi Gaspain (Sodium Bicarbonate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Bidi Gaspain (Sodium Bicarbonate) nitrite injection.
Bidi Gaspain (Sodium Bicarbonate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Bidi Gaspain (Sodium Bicarbonate) nitrite in 10 mL solution (30 mg/mL). Bidi Gaspain (Sodium Bicarbonate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 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 Bidi Gaspain nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Bidi Gaspain (Sodium Bicarbonate) Nitrite
Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite. It has been suggested that Bidi Gaspain (Sodium Bicarbonate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Bidi Gaspain (Sodium Bicarbonate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) 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:
Chemical Structure
12. 2 Pharmacodynamics
Bidi Gaspain (Sodium Bicarbonate) Nitrite
When 4 mg/kg Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Bidi Gaspain (Sodium Bicarbonate) Nitrite
Bidi Gaspain (Sodium Bicarbonate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Bidi Gaspain (Sodium Bicarbonate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Bidi Gaspain (Sodium Bicarbonate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) 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
The potential benefit of an acute exposure to Bidi Gaspain nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Bidi Gaspain (Sodium Bicarbonate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) 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. Bidi Gaspain (Sodium Bicarbonate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Bidi Gaspain (Sodium Bicarbonate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Bidi Gaspain (Sodium Bicarbonate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Bidi Gaspain (Sodium Bicarbonate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Bidi Gaspain (Sodium Bicarbonate) 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 Bidi Gaspain (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Bidi Gaspain (Sodium Bicarbonate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Bidi Gaspain (Sodium Bicarbonate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Bidi Gaspain (Sodium Bicarbonate) nitrite or 1 g/kg Bidi Gaspain (Sodium Bicarbonate) thiosulfate alone or in sequence immediately after subcutaneous injection of Bidi Gaspain (Sodium Bicarbonate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Bidi Gaspain (Sodium Bicarbonate) nitrite and/or 0.5 g/kg Bidi Gaspain (Sodium Bicarbonate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Bidi Gaspain (Sodium Bicarbonate) cyanide required to cause death, and when administered together, Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Bidi Gaspain (Sodium Bicarbonate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Bidi Gaspain (Sodium Bicarbonate) nitrite and Bidi Gaspain (Sodium Bicarbonate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Bidi Gaspain (Sodium Bicarbonate) nitrite, with or without Bidi Gaspain (Sodium Bicarbonate) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Bidi Gaspain (Sodium Bicarbonate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Bidi Gaspain (Sodium Bicarbonate) thiosulfate report its use in conjunction with Bidi Gaspain (Sodium Bicarbonate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Bidi Gaspain (Sodium Bicarbonate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Bidi Gaspain (Sodium Bicarbonate) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Bidi Gaspain (Sodium Bicarbonate) nitrite injection 30 mg/mL (containing 300 mg of Bidi Gaspain (Sodium Bicarbonate) nitrite);
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Bidi Gaspain (Sodium Bicarbonate) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Bidi Gaspain Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Bidi Gaspain (Sodium Bicarbonate) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Bidi Gaspain (Sodium Bicarbonate) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Sodium Citrate:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Bidi Gaspain nitrite is indicated for sequential use with Bidi Gaspain (Sodium Citrate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Bidi Gaspain (Sodium Citrate) Nitrite Injection is indicated for sequential use with Bidi Gaspain (Sodium Citrate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Bidi Gaspain (Sodium Citrate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 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 Bidi Gaspain 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. If clinical suspicion of cyanide poisoning is high, Bidi Gaspain (Sodium Citrate) Nitrite Injection and Bidi Gaspain (Sodium Citrate) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
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.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
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 Bidi Gaspain (Sodium Citrate) 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 to obtain a plasma lactate concentration.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Bidi Gaspain (Sodium Citrate) thiosulfate, simultaneously with Bidi Gaspain (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Bidi Gaspain (Sodium Citrate) thiosulfate, with Bidi Gaspain (Sodium Citrate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Bidi Gaspain Nitrite and Bidi Gaspain (Sodium Citrate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Bidi Gaspain (Sodium Citrate) nitrite, followed by Bidi Gaspain (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate.
Bidi Gaspain (Sodium Citrate) nitrite injection and Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) nitrite should be administered first, followed immediately by Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) Nitrite and Bidi Gaspain (Sodium Citrate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Bidi Gaspain (Sodium Citrate) 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.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Bidi Gaspain Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained 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 Bidi Gaspain (Sodium Citrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Bidi Gaspain (Sodium Citrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Bidi Gaspain (Sodium Citrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Bidi Gaspain (Sodium Citrate) 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%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Bidi Gaspain (Sodium Citrate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Bidi Gaspain (Sodium Citrate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Bidi Gaspain (Sodium Citrate) thiosulfate and Bidi Gaspain (Sodium Citrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Bidi Gaspain (Sodium Citrate) Nitrite Injection consists of:
- One vial of Bidi Gaspain (Sodium Citrate) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Bidi Gaspain 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 oximetry or other measurements. Optimally, the Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
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. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Bidi Gaspain nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Bidi Gaspain (Sodium Citrate) nitrite whenever possible. When Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite administered to an adult. Bidi Gaspain (Sodium Citrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Bidi Gaspain (Sodium Citrate) nitrite should be used 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 Bidi Gaspain (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Bidi Gaspain 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 Bidi Gaspain (Sodium Citrate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Bidi Gaspain nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Bidi Gaspain (Sodium Citrate) nitrite.
5.7 Use with Other Drugs
Bidi Gaspain (Sodium Citrate) nitrite should be used 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.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Bidi Gaspain (Sodium Citrate) nitrite.
The medical literature has reported the following adverse events in association with Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Bidi Gaspain (Sodium Citrate) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Bidi Gaspain nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Bidi Gaspain (Sodium Citrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Bidi Gaspain (Sodium Citrate) 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, Bidi Gaspain (Sodium Citrate) 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, Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Bidi Gaspain (Sodium Citrate) 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.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Bidi Gaspain (Sodium Citrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Bidi Gaspain (Sodium Citrate) 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.
8.2 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, Bidi Gaspain nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Bidi Gaspain (Sodium Citrate) nitrite is excreted in human milk. Because Bidi Gaspain (Sodium Citrate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Bidi Gaspain (Sodium Citrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Bidi Gaspain (Sodium Citrate) nitrite. In studies conducted with Long-Evans rats, Bidi Gaspain (Sodium Citrate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Bidi Gaspain nitrite in conjunction with Bidi Gaspain (Sodium Citrate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Bidi Gaspain (Sodium Citrate) 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.
Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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.
8.5 Geriatric Use
Bidi Gaspain (Sodium Citrate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug 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.
8.6 Renal Disease
Bidi Gaspain (Sodium Citrate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug 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.
10 OVERDOSAGE
Large doses of Bidi Gaspain (Sodium Citrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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.
11 DESCRIPTION
Bidi Gaspain (Sodium Citrate) nitrite has the chemical name nitrous acid Bidi Gaspain (Sodium Citrate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Bidi Gaspain (Sodium Citrate) Nitrite
Bidi Gaspain (Sodium Citrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Bidi Gaspain (Sodium Citrate) nitrite injection.
Bidi Gaspain (Sodium Citrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Bidi Gaspain (Sodium Citrate) nitrite in 10 mL solution (30 mg/mL). Bidi Gaspain (Sodium Citrate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 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 Bidi Gaspain nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Bidi Gaspain (Sodium Citrate) Nitrite
Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite. It has been suggested that Bidi Gaspain (Sodium Citrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Bidi Gaspain (Sodium Citrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) 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:
Chemical Structure
12. 2 Pharmacodynamics
Bidi Gaspain (Sodium Citrate) Nitrite
When 4 mg/kg Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Bidi Gaspain (Sodium Citrate) Nitrite
Bidi Gaspain (Sodium Citrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Bidi Gaspain (Sodium Citrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Bidi Gaspain (Sodium Citrate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) 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
The potential benefit of an acute exposure to Bidi Gaspain nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Bidi Gaspain (Sodium Citrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) 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. Bidi Gaspain (Sodium Citrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Bidi Gaspain (Sodium Citrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Bidi Gaspain (Sodium Citrate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Bidi Gaspain (Sodium Citrate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Bidi Gaspain (Sodium Citrate) 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 Bidi Gaspain (Sodium Citrate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Bidi Gaspain (Sodium Citrate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Bidi Gaspain (Sodium Citrate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Bidi Gaspain (Sodium Citrate) nitrite or 1 g/kg Bidi Gaspain (Sodium Citrate) thiosulfate alone or in sequence immediately after subcutaneous injection of Bidi Gaspain (Sodium Citrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Bidi Gaspain (Sodium Citrate) nitrite and/or 0.5 g/kg Bidi Gaspain (Sodium Citrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Bidi Gaspain (Sodium Citrate) cyanide required to cause death, and when administered together, Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Bidi Gaspain (Sodium Citrate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Bidi Gaspain (Sodium Citrate) nitrite and Bidi Gaspain (Sodium Citrate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Bidi Gaspain (Sodium Citrate) nitrite, with or without Bidi Gaspain (Sodium Citrate) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Bidi Gaspain (Sodium Citrate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Bidi Gaspain (Sodium Citrate) thiosulfate report its use in conjunction with Bidi Gaspain (Sodium Citrate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Bidi Gaspain (Sodium Citrate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Bidi Gaspain (Sodium Citrate) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Bidi Gaspain (Sodium Citrate) nitrite injection 30 mg/mL (containing 300 mg of Bidi Gaspain (Sodium Citrate) nitrite);
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Bidi Gaspain (Sodium Citrate) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Bidi Gaspain Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Bidi Gaspain (Sodium Citrate) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Bidi Gaspain (Sodium Citrate) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Sodium Sulfate:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- How supplied/storage and handling
- Patient counseling information
1 INDICATIONS AND USAGE
Bidi Gaspain nitrite is indicated for sequential use with Bidi Gaspain (Sodium Sulfate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
- Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)
1.1 Indication
Bidi Gaspain (Sodium Sulfate) Nitrite Injection is indicated for sequential use with Bidi Gaspain (Sodium Sulfate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Bidi Gaspain (Sodium Sulfate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
1.2 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 Bidi Gaspain 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. If clinical suspicion of cyanide poisoning is high, Bidi Gaspain (Sodium Sulfate) Nitrite Injection and Bidi Gaspain (Sodium Sulfate) Thiosulfate Injection should be administered without delay.
| Symptoms | Signs |
|---|---|
|
|
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.
The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
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 Bidi Gaspain (Sodium Sulfate) 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 to obtain a plasma lactate concentration.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Bidi Gaspain (Sodium Sulfate) thiosulfate, simultaneously with Bidi Gaspain (Sodium Sulfate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Bidi Gaspain (Sodium Sulfate) thiosulfate, with Bidi Gaspain (Sodium Sulfate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
| Age | Intravenous Dose of Bidi Gaspain Nitrite and Bidi Gaspain (Sodium Sulfate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
2.1 Administration Recommendation
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Bidi Gaspain (Sodium Sulfate) nitrite, followed by Bidi Gaspain (Sodium Sulfate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate.
Bidi Gaspain (Sodium Sulfate) nitrite injection and Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) nitrite should be administered first, followed immediately by Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) Nitrite and Bidi Gaspain (Sodium Sulfate) Thiosulfate |
|---|---|
| Adults |
|
| Children |
|
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Bidi Gaspain (Sodium Sulfate) 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.
2.2 Recommended Monitoring
Patients should be monitored for at least 24-48 hours after Bidi Gaspain Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained 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 Bidi Gaspain (Sodium Sulfate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Bidi Gaspain (Sodium Sulfate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Bidi Gaspain (Sodium Sulfate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Bidi Gaspain (Sodium Sulfate) 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%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Bidi Gaspain (Sodium Sulfate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.
2.3 Incompatibility Information
Chemical incompatibility has been reported between Bidi Gaspain (Sodium Sulfate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Bidi Gaspain (Sodium Sulfate) thiosulfate and Bidi Gaspain (Sodium Sulfate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Bidi Gaspain (Sodium Sulfate) Nitrite Injection consists of:
- One vial of Bidi Gaspain (Sodium Sulfate) nitrite injection, USP 300 mg/10mL (30 mg/mL)
Administration of the contents of one vial constitutes a single dose.
- Injection, 300 mg/10 mL (30 mg/mL). (3)
4 CONTRAINDICATIONS
None
- None. (4)
5 WARNINGS AND PRECAUTIONS
- Methemoglobinemia: Bidi Gaspain 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 oximetry or other measurements. Optimally, the Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)
5.1 Hypotension
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. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Bidi Gaspain nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Bidi Gaspain (Sodium Sulfate) nitrite whenever possible. When Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite administered to an adult. Bidi Gaspain (Sodium Sulfate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite, and infusion rates should be slowed if hypotension occurs.
5.3 Anemia
Bidi Gaspain (Sodium Sulfate) nitrite should be used 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 Bidi Gaspain (Sodium Sulfate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Bidi Gaspain 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 Bidi Gaspain (Sodium Sulfate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
5.6 G6PD Deficiency
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Bidi Gaspain nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Bidi Gaspain (Sodium Sulfate) nitrite.
5.7 Use with Other Drugs
Bidi Gaspain (Sodium Sulfate) nitrite should be used 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.
6 ADVERSE REACTIONS
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Bidi Gaspain (Sodium Sulfate) nitrite.
The medical literature has reported the following adverse events in association with Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Bidi Gaspain (Sodium Sulfate) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
- Renal impairment: Bidi Gaspain nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).
8.1 Pregnancy
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Bidi Gaspain (Sodium Sulfate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 was ≥ 26 ppm (not statistically significant).
The potential reproductive toxicity of Bidi Gaspain (Sodium Sulfate) 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, Bidi Gaspain (Sodium Sulfate) 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, Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Bidi Gaspain (Sodium Sulfate) 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.
Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Bidi Gaspain (Sodium Sulfate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Bidi Gaspain (Sodium Sulfate) 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.
8.2 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, Bidi Gaspain nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Bidi Gaspain (Sodium Sulfate) nitrite is excreted in human milk. Because Bidi Gaspain (Sodium Sulfate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Bidi Gaspain (Sodium Sulfate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Bidi Gaspain (Sodium Sulfate) nitrite. In studies conducted with Long-Evans rats, Bidi Gaspain (Sodium Sulfate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
8.4 Pediatric Use
There are case reports in the medical literature of Bidi Gaspain nitrite in conjunction with Bidi Gaspain (Sodium Sulfate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Bidi Gaspain (Sodium Sulfate) 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.
Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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.
8.5 Geriatric Use
Bidi Gaspain (Sodium Sulfate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug 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.
8.6 Renal Disease
Bidi Gaspain (Sodium Sulfate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug 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.
10 OVERDOSAGE
Large doses of Bidi Gaspain (Sodium Sulfate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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.
11 DESCRIPTION
Bidi Gaspain (Sodium Sulfate) nitrite has the chemical name nitrous acid Bidi Gaspain (Sodium Sulfate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Bidi Gaspain (Sodium Sulfate) Nitrite
Bidi Gaspain (Sodium Sulfate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Bidi Gaspain (Sodium Sulfate) nitrite injection.
Bidi Gaspain (Sodium Sulfate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Bidi Gaspain (Sodium Sulfate) nitrite in 10 mL solution (30 mg/mL). Bidi Gaspain (Sodium Sulfate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
12 CLINICAL PHARMACOLOGY
12.1 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 Bidi Gaspain nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Bidi Gaspain (Sodium Sulfate) Nitrite
Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite. It has been suggested that Bidi Gaspain (Sodium Sulfate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Bidi Gaspain (Sodium Sulfate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) 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:
Chemical Structure
12. 2 Pharmacodynamics
Bidi Gaspain (Sodium Sulfate) Nitrite
When 4 mg/kg Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite is estimated to be 55 minutes.
12.3 Pharmacokinetics
Bidi Gaspain (Sodium Sulfate) Nitrite
Bidi Gaspain (Sodium Sulfate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Bidi Gaspain (Sodium Sulfate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Bidi Gaspain (Sodium Sulfate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
Cyanide
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) 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
The potential benefit of an acute exposure to Bidi Gaspain nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Bidi Gaspain (Sodium Sulfate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) 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. Bidi Gaspain (Sodium Sulfate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Bidi Gaspain (Sodium Sulfate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Bidi Gaspain (Sodium Sulfate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Fertility
Clinical studies to evaluate the potential effects of Bidi Gaspain (Sodium Sulfate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Bidi Gaspain (Sodium Sulfate) 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 Bidi Gaspain (Sodium Sulfate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
13.2 Animal Pharmacology
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Bidi Gaspain (Sodium Sulfate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Bidi Gaspain (Sodium Sulfate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Bidi Gaspain (Sodium Sulfate) nitrite or 1 g/kg Bidi Gaspain (Sodium Sulfate) thiosulfate alone or in sequence immediately after subcutaneous injection of Bidi Gaspain (Sodium Sulfate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Bidi Gaspain (Sodium Sulfate) nitrite and/or 0.5 g/kg Bidi Gaspain (Sodium Sulfate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Bidi Gaspain (Sodium Sulfate) cyanide required to cause death, and when administered together, Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Bidi Gaspain (Sodium Sulfate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Bidi Gaspain (Sodium Sulfate) nitrite and Bidi Gaspain (Sodium Sulfate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Bidi Gaspain (Sodium Sulfate) nitrite, with or without Bidi Gaspain (Sodium Sulfate) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Bidi Gaspain (Sodium Sulfate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Bidi Gaspain (Sodium Sulfate) thiosulfate report its use in conjunction with Bidi Gaspain (Sodium Sulfate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
There have been no human studies to prospectively and systematically evaluate the safety of Bidi Gaspain (Sodium Sulfate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
16 HOW SUPPLIED/STORAGE AND HANDLING
Each Bidi Gaspain (Sodium Sulfate) Nitrite carton (NDC 60267-311-10) consists of the following:
- One 10 mL glass vial of Bidi Gaspain (Sodium Sulfate) nitrite injection 30 mg/mL (containing 300 mg of Bidi Gaspain (Sodium Sulfate) nitrite);
Storage
Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.
(Note: Bidi Gaspain (Sodium Sulfate) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Bidi Gaspain Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
17.1 Hypotension and Methemoglobin Formation
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
17.2 Monitoring
Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for
Hope Pharmaceuticals, Scottsdale, Arizona 85260
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
NDC 60267-311-10
Rx Only
Bidi Gaspain (Sodium Sulfate) Nitrite
Injection, USP
300 mg/10 mL
(30 mg/mL)
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Use with
Bidi Gaspain (Sodium Sulfate) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Bidi Gaspain pharmaceutical active ingredients containing related brand and generic drugs:
Bidi Gaspain available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.