DRUGS & SUPPLEMENTS
Ossiplex usesOssiplex consists of Sodium Fluoride, Vitamin C (Ascorbic Acid).
1 INDICATIONS AND USAGE
Ossiplex nitrite is indicated for sequential use with Ossiplex (Sodium Fluoride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
Ossiplex (Sodium Fluoride) Nitrite Injection is indicated for sequential use with Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex 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, Ossiplex (Sodium Fluoride) Nitrite Injection and Ossiplex (Sodium Fluoride) Thiosulfate Injection should be administered without delay.
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.
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 Ossiplex (Sodium Fluoride) 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.
1.3 Use with Other Cyanide Antidotes
Caution should be exercised when administering cyanide antidotes, other than Ossiplex (Sodium Fluoride) thiosulfate, simultaneously with Ossiplex (Sodium Fluoride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Ossiplex (Sodium Fluoride) thiosulfate, with Ossiplex (Sodium Fluoride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
2 DOSAGE AND ADMINISTRATION
Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite, followed by Ossiplex (Sodium Fluoride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate.
Ossiplex (Sodium Fluoride) nitrite injection and Ossiplex (Sodium Fluoride) 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. Ossiplex (Sodium Fluoride) nitrite should be administered first, followed immediately by Ossiplex (Sodium Fluoride) 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.
NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Ossiplex (Sodium Fluoride) 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 Ossiplex 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 Ossiplex (Sodium Fluoride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Ossiplex (Sodium Fluoride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Ossiplex (Sodium Fluoride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Ossiplex (Sodium Fluoride) thiosulfate and Ossiplex (Sodium Fluoride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
3 DOSAGE FORMS AND STRENGTHS
Ossiplex (Sodium Fluoride) Nitrite Injection consists of:
Administration of the contents of one vial constitutes a single dose.
5 WARNINGS AND PRECAUTIONS
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 Ossiplex nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Ossiplex (Sodium Fluoride) nitrite whenever possible. When Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite administered to an adult. Ossiplex (Sodium Fluoride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite, and infusion rates should be slowed if hypotension occurs.
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
5.4 Smoke Inhalation Injury
Ossiplex 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 Ossiplex (Sodium Fluoride) 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 Ossiplex 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 Ossiplex (Sodium Fluoride) nitrite.
5.7 Use with Other Drugs
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite.
The medical literature has reported the following adverse events in association with Ossiplex (Sodium Fluoride) 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
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 Ossiplex (Sodium Fluoride) 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.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been conducted with Ossiplex (Sodium Fluoride) Nitrite Injection.
8 USE IN SPECIFIC POPULATIONS
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Ossiplex (Sodium Fluoride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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, Ossiplex (Sodium Fluoride) 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, Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Ossiplex (Sodium Fluoride) 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, Ossiplex 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 Ossiplex (Sodium Fluoride) nitrite is excreted in human milk. Because Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Ossiplex (Sodium Fluoride) nitrite. In studies conducted with Long-Evans rats, Ossiplex (Sodium Fluoride) 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 Ossiplex nitrite in conjunction with Ossiplex (Sodium Fluoride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Ossiplex (Sodium Fluoride) 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.
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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
Ossiplex (Sodium Fluoride) 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
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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.
Ossiplex (Sodium Fluoride) nitrite has the chemical name nitrous acid Ossiplex (Sodium Fluoride) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Ossiplex (Sodium Fluoride) Nitrite
Ossiplex (Sodium Fluoride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Ossiplex (Sodium Fluoride) nitrite injection.
Ossiplex (Sodium Fluoride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Ossiplex (Sodium Fluoride) nitrite in 10 mL solution (30 mg/mL). Ossiplex (Sodium Fluoride) 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 Ossiplex nitrite and Ossiplex (Sodium Fluoride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Ossiplex (Sodium Fluoride) Nitrite
Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite. It has been suggested that Ossiplex (Sodium Fluoride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Ossiplex (Sodium Fluoride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Ossiplex (Sodium Fluoride) 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. Ossiplex (Sodium Fluoride) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:
12. 2 Pharmacodynamics
Ossiplex (Sodium Fluoride) Nitrite
When 4 mg/kg Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite is estimated to be 55 minutes.
Ossiplex (Sodium Fluoride) Nitrite
Ossiplex (Sodium Fluoride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Ossiplex (Sodium Fluoride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Ossiplex (Sodium Fluoride) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.
The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) 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.
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 Ossiplex nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Ossiplex (Sodium Fluoride) 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. Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Ossiplex (Sodium Fluoride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Ossiplex (Sodium Fluoride) 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. Ossiplex (Sodium Fluoride) 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. Ossiplex (Sodium Fluoride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Ossiplex (Sodium Fluoride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Ossiplex (Sodium Fluoride) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.
Clinical studies to evaluate the potential effects of Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Ossiplex (Sodium Fluoride) nitrite or 1 g/kg Ossiplex (Sodium Fluoride) thiosulfate alone or in sequence immediately after subcutaneous injection of Ossiplex (Sodium Fluoride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Ossiplex (Sodium Fluoride) nitrite and/or 0.5 g/kg Ossiplex (Sodium Fluoride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Ossiplex (Sodium Fluoride) cyanide required to cause death, and when administered together, Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Ossiplex (Sodium Fluoride) nitrite and Ossiplex (Sodium Fluoride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Ossiplex (Sodium Fluoride) nitrite, with or without Ossiplex (Sodium Fluoride) thiosulfate, was found not to be effective in the same setting.
14 CLINICAL STUDIES
The human data supporting the use of Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) thiosulfate report its use in conjunction with Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) 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 Ossiplex (Sodium Fluoride) Nitrite carton (NDC 60267-311-10) consists of the following:
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: Ossiplex (Sodium Fluoride) Thiosulfate must be obtained separately.)
17 PATIENT COUNSELING INFORMATION
Ossiplex 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.
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
Ossiplex (Sodium Fluoride) Nitrite
300 mg/10 mL
FOR INTRAVENOUS USE
SINGLE USE ONLY
Any unused portion of a vial
should be discarded.
Ossiplex (Sodium Fluoride) Thiosulfate
for Treatment of
CANGENE bioPharma, Inc.
Baltimore, MD for
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Vitamin C (Ascorbic Acid):
Ossiplex ) (vitamin c) is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Ossiplex (Vitamin C (Ascorbic Acid)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Ossiplex (Vitamin C (Ascorbic Acid)) has antioxidant properties.
With intravaginal application of Ossiplex (Vitamin C (Ascorbic Acid)) lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).
After oral administration Ossiplex (Vitamin C (Ascorbic Acid)) is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.
The concentration of Ossiplex (Vitamin C (Ascorbic Acid)) in blood plasma in normal amounts to approximately 10-20 mg / ml.
The concentration of Ossiplex (Vitamin C (Ascorbic Acid)) in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.
Plasma protein binding is about 25%.
Ossiplex (Vitamin C (Ascorbic Acid)) is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.
Ossiplex (Vitamin C (Ascorbic Acid)) taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.
Why is Ossiplex ) prescribed?
For systemic use of Ossiplex (Vitamin C (Ascorbic Acid)) RiteMED Phils: prevention and treatment of hypo- and avitaminosis of vitamin C; providing increased need for vitamin C during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.
For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.
Dosage and administration
This medication administered orally, IM, IV, intravaginally.
For the prevention of deficiency conditions Ossiplex ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.
For intravaginal used Ossiplex (Vitamin C (Ascorbic Acid)) drugs in appropriate dosage forms.
Ossiplex (Vitamin C (Ascorbic Acid)) side effects, adverse reactions
CNS: headache, fatigue, insomnia.
Digestive system: stomach cramps, nausea and vomiting.
Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.
Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.
Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.
Ossiplex ) contraindications
Increased sensitivity to Ossiplex (Vitamin C (Ascorbic Acid)).
Using during pregnancy and breastfeeding
The minimum daily requirement of Ossiplex ) in the II and III trimester of pregnancy is about 60 mg.
Ossiplex (Vitamin C (Ascorbic Acid)) crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of Ossiplex (Vitamin C (Ascorbic Acid)), which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take Ossiplex (Vitamin C (Ascorbic Acid)) in high doses, except in cases where the expected benefit outweighs the potential risk.
The minimum daily requirement during lactation (breastfeeding) is 80 mg. Ossiplex (Vitamin C (Ascorbic Acid)) is excreted in breast milk. A mother's diet that contains adequate amounts of Ossiplex (Vitamin C (Ascorbic Acid)), is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of Ossiplex (Vitamin C (Ascorbic Acid)) in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to Ossiplex (Vitamin C (Ascorbic Acid)), except when the expected benefit outweighs the potential risk.
Ossiplex (Vitamin C (Ascorbic Acid)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because Ossiplex (Vitamin C (Ascorbic Acid)) increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.
Patients with high content body iron should apply Ossiplex (Vitamin C (Ascorbic Acid)) in minimal doses.
Ossiplex (Vitamin C (Ascorbic Acid)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.
The use of Ossiplex (Vitamin C (Ascorbic Acid)) in high doses can cause exacerbation of sickle cell anemia.
Data on the diabetogenic action of Ossiplex (Vitamin C (Ascorbic Acid)) are contradictory. However, prolonged use of Ossiplex (Vitamin C (Ascorbic Acid)) should periodically monitor your blood glucose levels.
It is believed that the use of Ossiplex (Vitamin C (Ascorbic Acid)) in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in Ossiplex (Vitamin C (Ascorbic Acid)) in patients with advanced cancer.
Absorption of Ossiplex (Vitamin C (Ascorbic Acid)) decreased while use of fresh fruit or vegetable juices, alkaline drinking.
Ossiplex ) drug interactions
In an application with barbiturates, primidone increases the excretion of Ossiplex (Vitamin C (Ascorbic Acid)) in the urine.
With the simultaneous use of oral contraceptives reduces the concentration of Ossiplex (Vitamin C (Ascorbic Acid)) in blood plasma.
In an application of Ossiplex (Vitamin C (Ascorbic Acid)) with iron preparations Ossiplex (Vitamin C (Ascorbic Acid)), due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.
Ossiplex (Vitamin C (Ascorbic Acid)) in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.
With the simultaneous use of aspirin reduces the absorption of Ossiplex (Vitamin C (Ascorbic Acid)) by about a third.
Ossiplex (Vitamin C (Ascorbic Acid)) in an application with warfarin may decrease effects of warfarin.
With the simultaneous application of Ossiplex (Vitamin C (Ascorbic Acid)) increases the excretion of iron in patients receiving deferoxamine. In the application of Ossiplex (Vitamin C (Ascorbic Acid)) at a dose of 500 mg / day possibly left ventricular dysfunction.
In an application with tetracycline is increased excretion of Ossiplex (Vitamin C (Ascorbic Acid)) in the urine.
There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with Ossiplex (Vitamin C (Ascorbic Acid)) 500 mg 2 times / day.
May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.
Ossiplex ) in case of emergency / overdose
Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).
Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).
When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.
Ossiplex pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Ossiplex available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
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.
Ossiplex destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Ossiplex Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Ossiplex pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Ossiplex?
Depending on the reaction of the Ossiplex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ossiplex 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 Ossiplex 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.
Reviewsdrugs.com conducted a study on Ossiplex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Ossiplex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
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The information was verified by Dr. Arunabha Ray, MD Pharmacology