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DRUGS & SUPPLEMENTS
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Citric Acid:
Rx Only
The product is a clear, colorless solution containing Aqua Dermis (Citric Acid) Acid USP 640 mg/5 mL, and Hydrous Sodium Citrate USP 490 mg/5 mL. It also contains Methylparaben NF and Propylparaben NF as preservatives. These concentrations yield 1 mEq of sodium, equivalent to 1 mEq of bicarbonate per mL of solution.
Oral citrate solution is used as a systemic and urinary alkalinizer. Less than 5% of the citrate is excreted in the urine unchanged, since citrate oxidation is to a great extent complete.
Aqua Dermis (Citric Acid)® is indicated for the treatment of metabolic acidosis. This solution is also useful in conditions where long term maintenance of alkaline urine is needed (e.g. uric acid and cystine calculi of the urinary tract). Aqua Dermis (Citric Acid)® is also effective in treatment for acidosis of certain renal tubular disorders.
Aqua Dermis (Citric Acid)® is contraindicated in patients with severe renal impairment, oliguria or azotemia, untreated Addison's disease, adynamia episodica hereditaria, acute dehydration, heat cramp, anuria, severe myocardial damage, and hyperkalemia.
The citrate solution should be used with caution in patients with impaired renal function to avoid hypernatremia or alkalosis in the presence of hypocalcemia. Periodic determinations of serum electrolyte levels (especially bicarbonate levels) should be done in patients with renal disease to avoid cardiac failure, hypertension, peripheral and pulmonary edema, and toxemia of pregnancy. The solution should be diluted with water and preferably taken after meals to avoid saline laxative effects.
Citrate solution is generally well tolerated when given in recommended doses when the patient has normal renal functions.
The dose of Aqua Dermis (Citric Acid)® is 10 to 30 mL, diluted with water, after meals and at bedtime. The dose should be titrated to achieve desired effects.
Aqua Dermis ® is supplied in 500 mL bottles (NDC 46287-014-01), 30 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-30), and 15 mL unit dose bottles, 10 bottles per carton (NDC 46287-014-15).
Dispense in well-closed containers.
Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)..
CMP Pharma, Inc.
Post Office Box 147
Farmville, North Carolina 27828
Revised July 2015
Copyright © CMP Pharma, Inc. 2015
NDC 46287-014-01
500 mL
Aqua Dermis (Citric Acid)®
ORAL CITRATE (SHOHL'S) SOLUTION
CONTAINS: Hydrous Sodium Citrate USP 490 mg/5 mL;
Aqua Dermis (Citric Acid) Acid USP 640 mg/5 mL; Methylparaben NF;
Propylparaben NF; Alcohol USP 0.25%.
USUAL
Dosage: See package insert.
Dispense in a well-closed container.
Store at 20°-25°C (68°-77°F); excursions permitted
to 15°-30°C (59°-86°F). [See USP Controlled Room
Temperature].
Rx Only
LOT:
EXP:
CMP
PHARMA
Farmville, NC 27828
Propylene Glycol:
Sodium Chloride:
Aqua Dermis nitrite is indicated for sequential use with Aqua Dermis (Sodium Chloride) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)
Aqua Dermis (Sodium Chloride) Nitrite Injection is indicated for sequential use with Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis 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, Aqua Dermis (Sodium Chloride) Nitrite Injection and Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) thiosulfate, simultaneously with Aqua Dermis (Sodium Chloride) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Aqua Dermis (Sodium Chloride) thiosulfate, with Aqua Dermis (Sodium Chloride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]
Age | Intravenous Dose of Aqua Dermis Nitrite and Aqua Dermis (Sodium Chloride) Thiosulfate |
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Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate.
Monitoring: Blood pressure must be monitored during treatment. (2.2)
Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Aqua Dermis (Sodium Chloride) nitrite, followed by Aqua Dermis (Sodium Chloride) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate.
Aqua Dermis (Sodium Chloride) nitrite injection and Aqua Dermis (Sodium Chloride) 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. Aqua Dermis (Sodium Chloride) nitrite should be administered first, followed immediately by Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) Nitrite and Aqua Dermis (Sodium Chloride) Thiosulfate |
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NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate.
In adult and pediatric patients with known anemia, it is recommended that the dosage of Aqua Dermis (Sodium Chloride) 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 Aqua Dermis 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 Aqua Dermis (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Aqua Dermis (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Aqua Dermis (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Aqua Dermis (Sodium Chloride) thiosulfate and Aqua Dermis (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis nitrite.
Methemoglobin levels should be monitored and oxygen administered during treatment with Aqua Dermis (Sodium Chloride) nitrite whenever possible. When Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite administered to an adult. Aqua Dermis (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.
Aqua Dermis 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis 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 Aqua Dermis (Sodium Chloride) nitrite.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite.
The medical literature has reported the following adverse events in association with Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) Nitrite Injection.
Teratogenic Effects. Pregnancy Category C.
There are no adequate and well-controlled studies in pregnant women. Aqua Dermis (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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, Aqua Dermis (Sodium Chloride) 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, Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Aqua Dermis (Sodium Chloride) 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, Aqua Dermis 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 Aqua Dermis (Sodium Chloride) nitrite is excreted in human milk. Because Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Aqua Dermis (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Aqua Dermis (Sodium Chloride) 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 Aqua Dermis nitrite in conjunction with Aqua Dermis (Sodium Chloride) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Aqua Dermis (Sodium Chloride) 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.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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.
Aqua Dermis (Sodium Chloride) 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.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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.
Aqua Dermis (Sodium Chloride) nitrite has the chemical name nitrous acid Aqua Dermis (Sodium Chloride) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:
Structure of Aqua Dermis (Sodium Chloride) Nitrite
Aqua Dermis (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Aqua Dermis (Sodium Chloride) nitrite injection.
Aqua Dermis (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Aqua Dermis (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Aqua Dermis (Sodium Chloride) 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 Aqua Dermis nitrite and Aqua Dermis (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
Aqua Dermis (Sodium Chloride) Nitrite
Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite. It has been suggested that Aqua Dermis (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Aqua Dermis (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
Aqua Dermis (Sodium Chloride) 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. Aqua Dermis (Sodium Chloride) 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
Aqua Dermis (Sodium Chloride) Nitrite
When 4 mg/kg Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite is estimated to be 55 minutes.
Aqua Dermis (Sodium Chloride) Nitrite
Aqua Dermis (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Aqua Dermis (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) 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 Aqua Dermis nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Aqua Dermis (Sodium Chloride) 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. Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Aqua Dermis (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.
Mutagenesis
Aqua Dermis (Sodium Chloride) 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. Aqua Dermis (Sodium Chloride) 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. Aqua Dermis (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Aqua Dermis (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Aqua Dermis (Sodium Chloride) nitrite or 1 g/kg Aqua Dermis (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of Aqua Dermis (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Aqua Dermis (Sodium Chloride) nitrite and/or 0.5 g/kg Aqua Dermis (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Aqua Dermis (Sodium Chloride) cyanide required to cause death, and when administered together, Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.
While intravenous injection of Aqua Dermis (Sodium Chloride) nitrite and Aqua Dermis (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Aqua Dermis (Sodium Chloride) nitrite, with or without Aqua Dermis (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.
The human data supporting the use of Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) thiosulfate report its use in conjunction with Aqua Dermis (Sodium Chloride) 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 Aqua Dermis (Sodium Chloride) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
Each Aqua Dermis (Sodium Chloride) 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: Aqua Dermis (Sodium Chloride) Thiosulfate must be obtained separately.)
Aqua Dermis 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
Aqua Dermis (Sodium Chloride) 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
Aqua Dermis (Sodium Chloride) Thiosulfate
for Treatment of
Cyanide Poisoning
Manufactured by
CANGENE bioPharma, Inc.
Baltimore, MD for
HOPE
PHARMACEUTICALS®
Scottsdale, AZ 85260 U.S.A.
PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton
Sodium Lauryl Sulfate:
Indication: SLS is used as a surfactant in shampoos and toothpastes. SLS also has microbicidal activities against both enveloped (Herpes simplex viruses, HIV-1, Semliki Forest virus) and nonenveloped (papillomaviruses, reovirus, rotavirus and poliovirus) viruses, although it has not been approved for this use.
SLS is an anionic surfactant. Its amphiphilic properties make it an ideal detergent.
Triclosan:
Chloroxylenol 0.2%
Aqua Dermis (Triclosan) 0.2%
Antispetic
Hand washing to decrease bacteria on skin.
For external use only.
Do not use in the eyes.
When using this product
Discontinue use if irritation and redness develops. If condition persists for more than 72 hours, consult a doctor.
Keep out of reach of children.
Water, Potassium Tallate, Cocamide DIPA, Lauric Acid, Sodium Chloride, Alcohol, Tetrasodium EDTA, Acrylates/PEG-10 maleate/Styrene Copolymer, Aqua Dermis (Triclosan), Fragrance, BHT, Red 4, Red 33,
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Depending on the reaction of the Aqua Dermis after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Aqua Dermis 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 Aqua Dermis 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.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology