Decyline Ointment

Salicylic Acid:

• Pharmacological action
• Why is Decyline Ointment (Salicylic Acid) prescribed?
• Dosage and administration
• Decyline Ointment (Salicylic Acid) side effects, adverse reactions
• Decyline Ointment contraindications
• Special instructions
• Decyline Ointment drug interactions
• Decyline Ointment (Salicylic Acid) reviews

Pharmacological action

Decyline Ointment is pharmaceytical active ingredient for topical use. Inhibits the secretion of the sebaceous and sweat glands. At low concentrations it has keratoplastic and in high doses keratolytic effect. Decyline Ointment (Salicylic Acid) has a weak antimicrobial activity.

Why is Decyline Ointment (Salicylic Acid) prescribed?

Monotherapy with Decyline Ointment (Salicylic Acid) and as part of combination therapies for inflammatory, infectious and other skin lesions, including burns, psoriasis, eczema, dyskeratosis, ichthyosis, acne vulgaris, warts, hyperkeratosis, corn, callus, oily seborrhea, scaly skin disease, hair loss, sweating feet.

Dosage and administration

Decyline Ointment is applied to the skin surface 2-3 times / day.

Decyline Ointment (Salicylic Acid) side effects, adverse reactions

Rarely: local reactions such as itching, burning, skin rashes, allergic reactions.

Decyline Ointment contraindications

Hypersensitivity to Decyline Ointment (Salicylic Acid), renal failure, infancy.

Special instructions

The composition of the solution for topical use include ethanol.

Decyline Ointment drug interactions

Decyline Ointment (Salicylic Acid) is pharmaceutically not compatible with resorcinol (forms melted mixture) and zinc oxide (forms insoluble forms of zinc salicylate).

Sodium Propionate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Decyline Ointment (Sodium Propionate) reviews

1 INDICATIONS AND USAGE

Decyline Ointment nitrite is indicated for sequential use with Decyline Ointment (Sodium Propionate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Decyline Ointment (Sodium Propionate) Nitrite Injection is indicated for sequential use with Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment 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, Decyline Ointment (Sodium Propionate) Nitrite Injection and Decyline Ointment (Sodium Propionate) 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.

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 Decyline Ointment (Sodium Propionate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Decyline Ointment (Sodium Propionate) thiosulfate, simultaneously with Decyline Ointment (Sodium Propionate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Decyline Ointment (Sodium Propionate) thiosulfate, with Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite, followed by Decyline Ointment (Sodium Propionate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate.

Decyline Ointment (Sodium Propionate) nitrite injection and Decyline Ointment (Sodium Propionate) 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. Decyline Ointment (Sodium Propionate) nitrite should be administered first, followed immediately by Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Decyline Ointment (Sodium Propionate) 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 Decyline Ointment 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 Decyline Ointment (Sodium Propionate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Decyline Ointment (Sodium Propionate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Decyline Ointment (Sodium Propionate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Decyline Ointment (Sodium Propionate) thiosulfate and Decyline Ointment (Sodium Propionate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Decyline Ointment (Sodium Propionate) Nitrite Injection consists of:

• One vial of Decyline Ointment (Sodium Propionate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Decyline Ointment nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Decyline Ointment (Sodium Propionate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Decyline Ointment (Sodium Propionate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Decyline Ointment (Sodium Propionate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Decyline Ointment nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Decyline Ointment (Sodium Propionate) nitrite whenever possible. When Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite administered to an adult. Decyline Ointment (Sodium Propionate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Decyline Ointment 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment 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 Decyline Ointment (Sodium Propionate) nitrite.

5.7 Use with Other Drugs

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite.

The medical literature has reported the following adverse events in association with Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Decyline Ointment (Sodium Propionate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Decyline Ointment nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Decyline Ointment (Sodium Propionate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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, Decyline Ointment (Sodium Propionate) 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, Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Decyline Ointment (Sodium Propionate) 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, Decyline Ointment 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 Decyline Ointment (Sodium Propionate) nitrite is excreted in human milk. Because Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Decyline Ointment (Sodium Propionate) nitrite. In studies conducted with Long-Evans rats, Decyline Ointment (Sodium Propionate) 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 Decyline Ointment nitrite in conjunction with Decyline Ointment (Sodium Propionate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Decyline Ointment (Sodium Propionate) 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.

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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

Decyline Ointment (Sodium Propionate) 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

Decyline Ointment (Sodium Propionate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Decyline Ointment (Sodium Propionate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Decyline Ointment (Sodium Propionate) nitrite has the chemical name nitrous acid Decyline Ointment (Sodium Propionate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Decyline Ointment (Sodium Propionate) Nitrite

Decyline Ointment (Sodium Propionate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Decyline Ointment (Sodium Propionate) nitrite injection.

Decyline Ointment (Sodium Propionate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Decyline Ointment (Sodium Propionate) nitrite in 10 mL solution (30 mg/mL). Decyline Ointment (Sodium Propionate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

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 Decyline Ointment nitrite and Decyline Ointment (Sodium Propionate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Decyline Ointment (Sodium Propionate) Nitrite

Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite. It has been suggested that Decyline Ointment (Sodium Propionate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Decyline Ointment (Sodium Propionate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Decyline Ointment (Sodium Propionate) 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. Decyline Ointment (Sodium Propionate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Decyline Ointment (Sodium Propionate) Nitrite

When 4 mg/kg Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Decyline Ointment (Sodium Propionate) Nitrite

Decyline Ointment (Sodium Propionate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Decyline Ointment (Sodium Propionate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Decyline Ointment nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Decyline Ointment (Sodium Propionate) 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. Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Decyline Ointment (Sodium Propionate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Decyline Ointment (Sodium Propionate) 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. Decyline Ointment (Sodium Propionate) 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. Decyline Ointment (Sodium Propionate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Decyline Ointment (Sodium Propionate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Decyline Ointment (Sodium Propionate) nitrite or 1 g/kg Decyline Ointment (Sodium Propionate) thiosulfate alone or in sequence immediately after subcutaneous injection of Decyline Ointment (Sodium Propionate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Decyline Ointment (Sodium Propionate) nitrite and/or 0.5 g/kg Decyline Ointment (Sodium Propionate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Decyline Ointment (Sodium Propionate) cyanide required to cause death, and when administered together, Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Decyline Ointment (Sodium Propionate) nitrite and Decyline Ointment (Sodium Propionate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Decyline Ointment (Sodium Propionate) nitrite, with or without Decyline Ointment (Sodium Propionate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) thiosulfate report its use in conjunction with Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) 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 Decyline Ointment (Sodium Propionate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Decyline Ointment (Sodium Propionate) nitrite injection 30 mg/mL (containing 300 mg of Decyline Ointment (Sodium Propionate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Decyline Ointment (Sodium Propionate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Decyline Ointment Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Decyline Ointment (Sodium Propionate) 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

Decyline Ointment (Sodium Propionate) 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

Undecylenic Acid:

• Uses
• Warning
• Directions
• Other information
• Other ingredients
• Decyline Ointment (Undecylenic Acid) reviews

Drug Facts

Uses

• Cures most athlete's foot, jock itch & ringworm
• Relieves itching, burning, cracking, and discomfort which accompany these conditions

Warning

• For external use only.
• Not for diaper rash

• When using this product avoid contact with eyes and mucous membrane.

• Do not use on children under 2 years of age except under the advice and supervision of a doctor.

Stop use and ask a doctor if

• Irritation occurs
• There is no improvement within 4 weeks of treatment for athlete's foot and ringworm and 2 weeks of treatment for jock itch discontinue use and consult a doctor.

KEEP OUT OF REACH OF CHILDREN.

In case of accidental ingestion seek professional assistance or contact a poison control center right away.

Directions

• Clean affected area and dry thoroughly.
• Apply a thin layer over affected area twice daily (morning & night) or as directed by a doctor.
• For athlete's foot pay special attention to the space between the toes. Wear well fitting, ventilated shoes and change shoes & socks at least once a day.
• For athlete's foot and ringworm, use daily for 4 weeks
• For jock itch use daily for 2 weeks.
• Supervise Children in use of this product.
• Product not effective in the scalp or nails.

Other Information

Store at 59° - 86° F

Other ingredients

talc

SANAFITIL^®

ANTIFUNGAL

POWDER

• Treats most Athlete's foot, Jock itch & Ringworm

NET WEIGHT / PESO

NETO : 2 OZ (57 g)

Zinc Undecylenate:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Decyline Ointment (Zinc Undecylenate) reviews

INDICATIONS AND USAGE

Decyline Ointment (Zinc Undecylenate) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Decyline Ointment (Zinc Undecylenate) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Decyline Ointment (Zinc Undecylenate) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Decyline Ointment (Zinc Undecylenate) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Decyline Ointment (Zinc Undecylenate) from a bolus injection. Administration of Decyline Ointment (Zinc Undecylenate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Decyline Ointment (Zinc Undecylenate) are suggested as a guideline for subsequent Decyline Ointment (Zinc Undecylenate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Decyline Ointment 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Decyline Ointment (Zinc Undecylenate) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Decyline Ointment chloride. It is also not known whether Decyline Ointment (Zinc Undecylenate) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Decyline Ointment (Zinc Undecylenate) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response between 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Decyline Ointment (Zinc Undecylenate) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Decyline Ointment (Zinc Undecylenate) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Decyline Ointment (Zinc Undecylenate) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Decyline Ointment (Zinc Undecylenate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Decyline Ointment (Zinc Undecylenate) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Decyline Ointment (Zinc Undecylenate) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Decyline Ointment (Zinc Undecylenate) toxicity.

DOSAGE AND ADMINISTRATION

Decyline Ointment (Zinc Undecylenate) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Decyline Ointment (Zinc Undecylenate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Decyline Ointment (Zinc Undecylenate).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. See PRECAUTIONS.

HOW SUPPLIED

Decyline Ointment (Zinc Undecylenate) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Decyline Ointment (Zinc Undecylenate)

1 mg/mL

Decyline Ointment (Zinc Undecylenate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA