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DRUGS & SUPPLEMENTS
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Sodium Benzoate:
Bronquidiazina CR nitrite is indicated for sequential use with Bronquidiazina CR (Sodium Benzoate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
Bronquidiazina CR (Sodium Benzoate) Nitrite Injection is indicated for sequential use with Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.
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 Bronquidiazina CR 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, Bronquidiazina CR (Sodium Benzoate) Nitrite Injection and Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:
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.
Caution should be exercised when administering cyanide antidotes, other than Bronquidiazina CR (Sodium Benzoate) thiosulfate, simultaneously with Bronquidiazina CR (Sodium Benzoate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Bronquidiazina CR (Sodium Benzoate) thiosulfate, with Bronquidiazina CR (Sodium Benzoate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
Age | Intravenous Dose of Bronquidiazina CR Nitrite and Bronquidiazina CR (Sodium Benzoate) Thiosulfate |
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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 Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Bronquidiazina CR (Sodium Benzoate) nitrite, followed by Bronquidiazina CR (Sodium Benzoate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate.
Bronquidiazina CR (Sodium Benzoate) nitrite injection and Bronquidiazina CR (Sodium Benzoate) 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. Bronquidiazina CR (Sodium Benzoate) nitrite should be administered first, followed immediately by Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) Nitrite and Bronquidiazina CR (Sodium Benzoate) Thiosulfate |
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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 Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Bronquidiazina CR (Sodium Benzoate) 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.
Patients should be monitored for at least 24-48 hours after Bronquidiazina CR 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 Bronquidiazina CR (Sodium Benzoate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Bronquidiazina CR (Sodium Benzoate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Bronquidiazina CR (Sodium Benzoate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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.
Chemical incompatibility has been reported between Bronquidiazina CR (Sodium Benzoate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Bronquidiazina CR (Sodium Benzoate) thiosulfate and Bronquidiazina CR (Sodium Benzoate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
Bronquidiazina CR (Sodium Benzoate) Nitrite Injection consists of:
Administration of the contents of one vial constitutes a single dose.
None
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 Bronquidiazina CR nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Bronquidiazina CR (Sodium Benzoate) nitrite whenever possible. When Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite administered to an adult. Bronquidiazina CR (Sodium Benzoate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite, and infusion rates should be slowed if hypotension occurs.
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
Bronquidiazina CR 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.
Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Bronquidiazina CR (Sodium Benzoate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.
Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Bronquidiazina CR 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 Bronquidiazina CR (Sodium Benzoate) nitrite.
Bronquidiazina CR (Sodium Benzoate) 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.
There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Bronquidiazina CR (Sodium Benzoate) nitrite.
The medical literature has reported the following adverse events in association with Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.
Most common adverse reactions are:
To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Formal drug interaction studies have not been conducted with Bronquidiazina CR (Sodium Benzoate) Nitrite Injection.
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Bronquidiazina CR (Sodium Benzoate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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, Bronquidiazina CR (Sodium Benzoate) 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, Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Bronquidiazina CR (Sodium Benzoate) 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.
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, Bronquidiazina CR nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.
It is not known whether Bronquidiazina CR (Sodium Benzoate) nitrite is excreted in human milk. Because Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Bronquidiazina CR (Sodium Benzoate) nitrite. In studies conducted with Long-Evans rats, Bronquidiazina CR (Sodium Benzoate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.
There are case reports in the medical literature of Bronquidiazina CR nitrite in conjunction with Bronquidiazina CR (Sodium Benzoate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Bronquidiazina CR (Sodium Benzoate) 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.
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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.
Bronquidiazina CR (Sodium Benzoate) 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.
Bronquidiazina CR (Sodium Benzoate) 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.
Large doses of Bronquidiazina CR (Sodium Benzoate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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.
Bronquidiazina CR (Sodium Benzoate) nitrite has the chemical name nitrous acid Bronquidiazina CR (Sodium Benzoate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Bronquidiazina CR (Sodium Benzoate) Nitrite
Bronquidiazina CR (Sodium Benzoate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Bronquidiazina CR (Sodium Benzoate) nitrite injection.
Bronquidiazina CR (Sodium Benzoate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Bronquidiazina CR (Sodium Benzoate) nitrite in 10 mL solution (30 mg/mL). Bronquidiazina CR (Sodium Benzoate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.
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 Bronquidiazina CR nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Bronquidiazina CR (Sodium Benzoate) Nitrite
Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite. It has been suggested that Bronquidiazina CR (Sodium Benzoate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Bronquidiazina CR (Sodium Benzoate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Bronquidiazina CR (Sodium Benzoate) 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. Bronquidiazina CR (Sodium Benzoate) 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
Bronquidiazina CR (Sodium Benzoate) Nitrite
When 4 mg/kg Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite is estimated to be 55 minutes.
Bronquidiazina CR (Sodium Benzoate) Nitrite
Bronquidiazina CR (Sodium Benzoate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Bronquidiazina CR (Sodium Benzoate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) 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.
The potential benefit of an acute exposure to Bronquidiazina CR nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Bronquidiazina CR (Sodium Benzoate) 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. Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Bronquidiazina CR (Sodium Benzoate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Bronquidiazina CR (Sodium Benzoate) 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. Bronquidiazina CR (Sodium Benzoate) 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. Bronquidiazina CR (Sodium Benzoate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Bronquidiazina CR (Sodium Benzoate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).
Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Bronquidiazina CR (Sodium Benzoate) nitrite or 1 g/kg Bronquidiazina CR (Sodium Benzoate) thiosulfate alone or in sequence immediately after subcutaneous injection of Bronquidiazina CR (Sodium Benzoate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Bronquidiazina CR (Sodium Benzoate) nitrite and/or 0.5 g/kg Bronquidiazina CR (Sodium Benzoate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Bronquidiazina CR (Sodium Benzoate) cyanide required to cause death, and when administered together, Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Bronquidiazina CR (Sodium Benzoate) nitrite and Bronquidiazina CR (Sodium Benzoate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Bronquidiazina CR (Sodium Benzoate) nitrite, with or without Bronquidiazina CR (Sodium Benzoate) thiosulfate, was found not to be effective in the same setting.
The human data supporting the use of Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) thiosulfate report its use in conjunction with Bronquidiazina CR (Sodium Benzoate) 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 Bronquidiazina CR (Sodium Benzoate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
Each Bronquidiazina CR (Sodium Benzoate) Nitrite carton (NDC 60267-311-10) consists of the following:
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: Bronquidiazina CR (Sodium Benzoate) Thiosulfate must be obtained separately.)
Bronquidiazina CR 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.
When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.
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
Bronquidiazina CR (Sodium Benzoate) 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
Bronquidiazina CR (Sodium Benzoate) 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
Sulfamethoxazole:
Indication: For the treatment bacterial infections causing bronchitis, prostatitis and urinary tract infections.
Bronquidiazina CR (Sulfamethoxazole) is a sulfonamide drug that inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA) for binding to dihydropteroate synthetase (dihydrofolate synthetase). Bronquidiazina CR (Sulfamethoxazole) is bacteriostatic in nature. Inhibition of dihydrofolic acid synthesis decreases the synthesis of bacterial nucleotides and DNA. Bronquidiazina CR (Sulfamethoxazole) is normally given in combination with Trimethoprim, a dihydrofolate reductase inhibitor, which inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid. Studies have shown that bacterial resistance develops more slowly with the combination of the two drugs than with either Trimethoprim or Bronquidiazina CR (Sulfamethoxazole) alone.
Trimethoprim:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bronquidiazina CR (Trimethoprim) tablets, USP and other antibacterial drugs, Bronquidiazina CR (Trimethoprim) tablets, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.
Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to Bronquidiazina CR (Trimethoprim). Therapy may be initiated prior to obtaining the results of these tests.
Bronquidiazina CR (Trimethoprim) is contraindicated in individuals hypersensitive to Bronquidiazina CR (Trimethoprim) and in those with documented megaloblastic anemia due to folate deficiency.
Serious hypersensitivity reactions have been reported rarely in patients on Bronquidiazina CR (Trimethoprim) therapy. Bronquidiazina CR (Trimethoprim) has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.
The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders (see OVERDOSAGE, Chronic).
Complete blood counts should be obtained if any of these signs are noted in a patient receiving Bronquidiazina CR (Trimethoprim) and the drug discontinued if a significant reduction in the count of any formed blood element is found.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Bronquidiazina CR (Trimethoprim) tablets, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antiobiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Prescribing Bronquidiazina CR tablets, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Bronquidiazina CR (Trimethoprim) should be given with caution to patients with possible folate deficiency. Folates may be administered concomitantly without interfering with the antibacterial action of Bronquidiazina CR (Trimethoprim). Bronquidiazina CR (Trimethoprim) should also be given with caution to patients with impaired renal or hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Patients should be counseled that antibacterial drugs including Bronquidiazina CR (Trimethoprim) tablets, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Bronquidiazina CR (Trimethoprim) tablets, USP are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Bronquidiazina CR (Trimethoprim) tablets, USP or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with and without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Bronquidiazina CR may inhibit the hepatic metabolism of phenytoin. Bronquidiazina CR (Trimethoprim), given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Bronquidiazina CR (Trimethoprim) can interfere with a serum methotrexate assay as determined by the Competitive Binding Protein Technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of Bronquidiazina CR (Trimethoprim) may also interfere with the Jaffé alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with Bronquidiazina CR.
Bronquidiazina CR (Trimethoprim) was demonstrated to be nonmutagenic in the Ames assay. In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of Bronquidiazina CR (Trimethoprim) up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of Bronquidiazina CR (Trimethoprim) in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.
No adverse effects on fertility or general reproductive performance were observed in rats given Bronquidiazina CR in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.
Bronquidiazina CR has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.
While there are no large, well-controlled studies on the use of Bronquidiazina CR (Trimethoprim) in pregnant women, Brumfitt and Pursell,3 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or Bronquidiazina CR (Trimethoprim) in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving Bronquidiazina CR (Trimethoprim) and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received Bronquidiazina CR (Trimethoprim) and sulfamethoxazole at the time of conception or shortly thereafter.
Because Bronquidiazina CR (Trimethoprim) may interfere with folic acid metabolism, Bronquidiazina CR (Trimethoprim) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The oral administration of Bronquidiazina CR (Trimethoprim) to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.
Bronquidiazina CR is excreted in human milk. Because Bronquidiazina CR (Trimethoprim) may interfere with folic acid metabolism, caution should be exercised when Bronquidiazina CR (Trimethoprim) is administered to a nursing woman.
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of Bronquidiazina CR (Trimethoprim) as a single agent has not been established in pediatric patients under 12 years of age.
Clinical studies of Bronquidiazina CR (Trimethoprim) tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience4,5 has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published.6 Bronquidiazina CR (Trimethoprim) 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 potassium concentrations and to monitor renal function by calculating creatinine clearance.
The adverse effects encountered most often with Bronquidiazina CR were rash and pruritus.
Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of Bronquidiazina CR (Trimethoprim), an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.
Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis have been received.
Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.
Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.
Hyperkalemia, hyponatremia.
Aseptic meningitis has been rarely reported.
Fever, and increases in BUN and serum creatinine levels.
Signs of acute overdosage with Bronquidiazina CR may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronic subsection).
Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of Bronquidiazina CR (Trimethoprim). Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating the drug.
Use of Bronquidiazina CR (Trimethoprim) at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depression occur, Bronquidiazina CR (Trimethoprim) should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.
The usual oral adult dosage is 100 mg of Bronquidiazina CR (Trimethoprim) every 12 hours or 200 mg of Bronquidiazina CR (Trimethoprim) every 24 hours, each for 10 days. The use of Bronquidiazina CR (Trimethoprim) in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.
Bronquidiazina CR (Trimethoprim) tablets, USP, 100 mg: White, round, convex tablet, debossed “9”, scored, “3” on one side and debossed “21 58” on the other, in bottles of 100.
Store at 20° to 25°C (68° to 77°F).
Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required).
Manufactured In Canada By:
TEVA CANADA LIMITED
Toronto, Canada M1B 2K9
Manufactured For:
TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454
Rev. K 6/2016
NDC 0093-2158-01
Bronquidiazina CR (Trimethoprim)
Tablets USP
100 mg
Rx only
100 TABLETS
TEVA
Depending on the reaction of the Bronquidiazina CR after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Bronquidiazina CR not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Bronquidiazina CR addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Visitors | % | ||
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Useful | 4 | 100.0% |
Visitors | % | ||
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No side effects | 3 | 50.0% | |
It has side effects | 3 | 50.0% |
Visitors | % | ||
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Not expensive | 3 | 100.0% |
Visitors | % | ||
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3 times in a day | 7 | 53.8% | |
Twice in a day | 4 | 30.8% | |
Once in a day | 2 | 15.4% |
Visitors | % | ||
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6-10mg | 5 | 45.5% | |
1-5mg | 3 | 27.3% | |
11-50mg | 2 | 18.2% | |
101-200mg | 1 | 9.1% |
Visitors | % | ||
---|---|---|---|
1 day | 3 | 25.0% | |
2 days | 3 | 25.0% | |
3 days | 3 | 25.0% | |
5 days | 2 | 16.7% | |
1 week | 1 | 8.3% |
Visitors | % | ||
---|---|---|---|
With a meal | 1 | 33.3% | |
Before food | 1 | 33.3% | |
Empty stomach | 1 | 33.3% |
Visitors | % | ||
---|---|---|---|
> 60 | 12 | 34.3% | |
30-45 | 6 | 17.1% | |
1-5 | 5 | 14.3% | |
46-60 | 4 | 11.4% | |
16-29 | 3 | 8.6% | |
< 1 | 3 | 8.6% | |
6-15 | 2 | 5.7% |
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The information was verified by Dr. Rachana Salvi, MD Pharmacology