Zincoren

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Zincoren uses

Zincoren consists of Boric Acid, Sodium Chloride, Sulfacetamide Sodium, Zinc Sulfate.

Sodium Chloride:


1 INDICATIONS AND USAGE

Zincoren nitrite is indicated for sequential use with Zincoren (Sodium Chloride) 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

Zincoren (Sodium Chloride) Nitrite Injection is indicated for sequential use with Zincoren (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 Zincoren (Sodium Chloride) 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 Zincoren 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, Zincoren (Sodium Chloride) Nitrite Injection and Zincoren (Sodium Chloride) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

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 Zincoren (Sodium Chloride) 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 Zincoren (Sodium Chloride) thiosulfate, simultaneously with Zincoren (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 Zincoren (Sodium Chloride) thiosulfate, with Zincoren (Sodium Chloride) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

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2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Zincoren Nitrite and Zincoren (Sodium Chloride) Thiosulfate
Adults
  • Zincoren (Sodium Chloride) Nitrite -10 mL of Zincoren (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Zincoren (Sodium Chloride) Thiosulfate - 50 mL of Zincoren (Sodium Chloride) thiosulfate immediately following administration of Zincoren (Sodium Chloride) nitrite.
Children
  • Zincoren (Sodium Chloride) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Zincoren (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Zincoren (Sodium Chloride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Zincoren (Sodium Chloride) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Zincoren (Sodium Chloride) nitrite and Zincoren (Sodium Chloride) 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 Zincoren (Sodium Chloride) nitrite, followed by Zincoren (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 Zincoren (Sodium Chloride) nitrite and Zincoren (Sodium Chloride) thiosulfate.

Zincoren (Sodium Chloride) nitrite injection and Zincoren (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. Zincoren (Sodium Chloride) nitrite should be administered first, followed immediately by Zincoren (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 Zincoren (Sodium Chloride) Nitrite and Zincoren (Sodium Chloride) Thiosulfate
Adults
  • Zincoren (Sodium Chloride) Nitrite -10 mL of Zincoren (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute
  • Zincoren (Sodium Chloride) Thiosulfate - 50 mL of Zincoren (Sodium Chloride) thiosulfate immediately following administration of Zincoren (Sodium Chloride) nitrite.
Children
  • Zincoren (Sodium Chloride) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Zincoren (Sodium Chloride) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Zincoren (Sodium Chloride) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Zincoren (Sodium Chloride) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Zincoren (Sodium Chloride) nitrite and Zincoren (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Zincoren (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.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Zincoren 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 Zincoren (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Zincoren (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Zincoren (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Zincoren (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 Zincoren (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.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Zincoren (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 Zincoren (Sodium Chloride) thiosulfate and Zincoren (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

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3 DOSAGE FORMS AND STRENGTHS

Zincoren (Sodium Chloride) Nitrite Injection consists of:

  • One vial of Zincoren (Sodium Chloride) 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: Zincoren 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 Zincoren (Sodium Chloride) 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. Zincoren (Sodium Chloride) 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 Zincoren (Sodium Chloride) 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 Zincoren nitrite.

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

5.3 Anemia

Zincoren (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 Zincoren (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Zincoren 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 Zincoren (Sodium Chloride) 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 Zincoren 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 Zincoren (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Zincoren (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.

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6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Zincoren (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with Zincoren (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 Zincoren (Sodium Chloride) 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.

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7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Zincoren (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Zincoren 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. Zincoren (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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

Zincoren (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 Zincoren (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Zincoren (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.

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, Zincoren 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 Zincoren (Sodium Chloride) nitrite is excreted in human milk. Because Zincoren (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 Zincoren (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Zincoren (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, Zincoren (Sodium Chloride) 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 Zincoren nitrite in conjunction with Zincoren (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 Zincoren (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.

Zincoren (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 Zincoren (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.

8.5 Geriatric Use

Zincoren (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.

8.6 Renal Disease

Zincoren (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.

10 OVERDOSAGE

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

Zincoren (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 Zincoren (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 Zincoren (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.

11 DESCRIPTION

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

Structure of Zincoren (Sodium Chloride) Nitrite

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

Zincoren (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Zincoren (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). Zincoren (Sodium Chloride) 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 Zincoren nitrite and Zincoren (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Zincoren (Sodium Chloride) Nitrite

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

Zincoren (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. Zincoren (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

12. 2 Pharmacodynamics

Zincoren (Sodium Chloride) Nitrite

When 4 mg/kg Zincoren (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 Zincoren (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 Zincoren (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 Zincoren (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Zincoren (Sodium Chloride) Nitrite

Zincoren (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Zincoren (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of Zincoren (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 Zincoren (Sodium Chloride) nitrite and Zincoren (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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

  • One 10 mL glass vial of Zincoren (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of Zincoren (Sodium Chloride) 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: Zincoren (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Zincoren 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

Zincoren (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

Zincoren (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

Sulfacetamide Sodium:


DESCRIPTION

Zincoren ® ophthalmic suspension is a sterile, topical anti-inflammatory/anti-infective combination product for ophthalmic use.

Structural Formulas

MW=254.24 C8H9N2NaO3S·H2O MW=402.49 C23H30O6

Structural Formulas

Chemical Names

Zincoren (Sulfacetamide Sodium) sodium: N-sulfanilylacetamide monosodium salt monohydrate.

Prednisolone acetate: 11ß, 17, 21-trihydroxypregna-1, 4-diene-3, 20-dione 21-acetate.

Each mL of Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension contains:

Actives: Zincoren (Sulfacetamide Sodium) sodium 10%, prednisolone acetate (microfine suspension) 0.2%.

Inactives: benzalkonium chloride (0.004%); edetate disodium; polysorbate 80; polyvinyl alcohol 1.4%; potassium phosphate, monobasic; purified water; sodium phosphate, dibasic; sodium thiosulfate; hydrochloric acid and/or sodium hydroxide to adjust pH (6.6 to 7.2).

CLINICAL PHARMACOLOGY

Corticosteroids suppress the inflammatory response to a variety of agents and they probably delay or slow healing. Since corticosteroids may inhibit the body's defense mechanism against infection, a concomitant antibacterial drug may be used when this inhibition is considered to be clinically significant in a particular case.

When a decision to administer both a corticosteroid and an antibacterial is made, the administration of such drugs in combination has the advantage of greater patient compliance and convenience, with the added assurance that the appropriate dosage of both drugs is administered. When both types of drugs are in the same formulation, compatibility of ingredients is assured and the correct volume of drug is delivered and retained. The relative potency of corticosteroids depends on the molecular structure, concentration and release from the vehicle.

Microbiology

Zincoren (Sulfacetamide Sodium) sodium exerts a bacteriostatic effect against susceptible bacteria by restricting the synthesis of folic acid required for growth through competition with p-aminobenzoic acid.

Some strains of these bacteria may be resistant to Zincoren (Sulfacetamide Sodium) or resistant strains may emerge in vivo.

The anti-infective component in these products is included to provide action against specific organisms susceptible to it. Zincoren (Sulfacetamide Sodium) sodium is active in vitro against susceptible strains of the following microorganisms: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, and Serratia marcescens.

INDICATIONS AND USAGE

Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension is a steroid/anti-infective combination drug indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.

Ocular corticosteroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe where the inherent risk of corticosteroid use in certain infective conjunctivitides is accepted to obtain diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns or penetration of foreign bodies.

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular antibacterial drug in this product is active against the following common bacterial eye pathogens: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, and Serratia marcescens.

A significant percentage of staphylococcal isolates are completely resistant to sulfa drugs.

CONTRAINDICATIONS

Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation, to other sulfonamides and to other corticosteroids. (Hypersensitivity to the antimicrobial component occurs at a higher rate than for other components.)

WARNINGS

NOT FOR INJECTION INTO THE EYE.

Prolonged use of corticosteroids may result in posterior subcapsular cataract formation and may increase intraocular pressure in susceptible individuals, resulting in ocular hypertension/glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision.

If the product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Corticosteroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently.

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with the use of topical corticosteroids.

In acute purulent conditions of the eye, corticosteroids may mask infection or enhance existing infection.

The use of ocular corticosteroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of corticosteroid medication in the treatment of herpes simplex requires great caution.

Prolonged use of Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension may suppress the host response and thus increase the hazard of secondary ocular infections.

Prolonged use of topical anti-bacterial agents may give rise to overgrowth of nonsusceptible organisms including fungi.

A significant percentage of staphylococcal isolates are completely resistant to sulfonamides.

Acute anterior uveitis may occur in susceptible individuals, primarily Blacks.

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered, irrespective of the route of administration.

If signs of hypersensitivity, skin rash, or other serious reactions occur, discontinue use of this preparation. Cross-sensitivity among corticosteroids has been demonstrated.

PRECAUTIONS

General

The initial prescription and renewal of the medication order beyond 20 milliliters of the suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

The possibility of fungal infections of the cornea should be considered after prolonged corticosteroid dosing. Fungal cultures should be taken when appropriate.

Use with caution in patients with severe dry eye.

The p-aminobenzoic acid present in purulent exudates competes with sulfonamides and can reduce their effectiveness.

Information for Patients

If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician.

Contact lenses should not be worn during the use of this product.

This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the applicator tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Protect from light. Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity. Keep out of the reach of children.

Laboratory Tests

Eyelid cultures and tests to determine the susceptibility of organisms to Zincoren (Sulfacetamide Sodium) may be indicated if signs and symptoms persist or recur in spite of the recommended course of treatment with Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension.

Drug Interactions

Zincoren ® ophthalmic suspension is incompatible with silver preparations. Local anesthetics related to p-aminobenzoic acid may antagonize the action of the sulfonamides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisolone has been reported to be noncarcinogenic. Long-term animal studies for carcinogenic potential have not been performed with Zincoren (Sulfacetamide Sodium).

One author detected chromosomal nondisjunction in the yeast Saccharomyces cerevisiae following application of Zincoren (Sulfacetamide Sodium) sodium. The significance of this finding to topical ophthalmic use of Zincoren (Sulfacetamide Sodium) sodium in the human is unknown.

Mutagenic studies with prednisolone have been negative. Studies on reproduction and fertility have not been performed with Zincoren (Sulfacetamide Sodium). A long-term chronic toxicity study in dogs showed that high oral doses of prednisolone prevented estrus. A decrease in fertility was seen in male and female rats that were mated following oral dosing with another glucocorticosteroid.

Pregnancy

Teratogenic Effects

Animal reproduction studies have not been conducted with Zincoren sodium. Prednisolone has been shown to be teratogenic in rabbits, hamsters, and mice. In mice, prednisolone has been shown to be teratogenic when given in doses 1 to 10 times the human ocular dose. Dexamethasone, hydrocortisone and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate well-controlled studies in pregnant women dosed with corticosteroids.

Kernicterus may be precipitated in infants by sulfonamides being given systemically during the third trimester of pregnancy. It is not known whether Zincoren (Sulfacetamide Sodium) sodium can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.

Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Systemically administered sulfonamides are capable of producing kernicterus in infants of lactating women. Because of the potential for serious adverse reactions in nursing infants from Zincoren (Sulfacetamide Sodium) sodium and prednisolone acetate ophthalmic suspensions, a decision should be made whether to discontinue nursing or to discontinue the medication.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

ADVERSE REACTIONS

The following adverse reactions have been identified during use of Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions have occurred with corticosteroid/antibacterial combination drugs which can be attributed to the corticosteroid component, the antibacterial component, or the combination.

Reactions occurring with Zincoren (Sulfacetamide Sodium) ® ophthalmic suspension include: cataract, dizziness, eye discharge, eyelid edema, eyelid erythema, eye irritation, eye pain, eye pruritus, and hypersensitivity including rash, skin pruritus, urticaria, ocular hyperemia, and visual disturbance (blurry vision).

Reactions occurring most often from the presence of the antibacterial ingredient are allergic sensitizations. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

The reactions due to the corticosteroid component in decreasing order of frequency are: delayed wound healing, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, and posterior subcapsular cataract formation.

Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical corticosteroids.

Corticosteroid-containing preparations can also cause acute anterior uveitis or perforation of the globe. Mydriasis, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids.

Secondary Infection

The development of secondary infection has occurred after use of combinations containing corticosteroids and antibacterials. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of corticosteroid. The possibility of fungal invasion must be considered in any persistent corneal ulceration where corticosteroid treatment has been used.

Secondary bacterial ocular infection following suppression of host responses also occurs.

DOSAGE AND ADMINISTRATION

SHAKE WELL BEFORE USING. Two drops should be instilled into the conjunctival sac every four hours during the day and at bedtime.

Not more than 20 milliliters should be prescribed initially, and the prescription should not be refilled without further evaluation as outlined in PRECAUTIONS above.

Zincoren (Sulfacetamide Sodium) ® dosage may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of application.

If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

HOW SUPPLIED

Zincoren (Sulfacetamide Sodium) ® (sulfacetamide sodium–prednisolone acetate ophthalmic suspension, USP) is supplied sterile in opaque white LDPE plastic bottles and white dropper tips with white high impact polystyrene (HIPS) caps as follows:

  • 5 mL in 10 mL bottle - NDC 11980-022-05
  • 10 mL in 15 mL bottle - NDC 11980-022-10

Note: Shake well before using.

Storage: Store at 8°-24°C (46°-75°F) in an upright position. PROTECT FROM LIGHT. Protect from freezing.

Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity.

KEEP OUT OF REACH OF CHILDREN.

Revised: 07/2017

© 2017 Allergan. All rights reserved.

All trademarks are the property of their respective owners.

Irvine, CA 92612

Made in the U.S.A.

72735US12

Allergan Logo

Zinc Sulfate:


INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) from a bolus injection. Administration of Zincoren (Zinc Sulfate) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Zincoren (Zinc Sulfate) are suggested as a guideline for subsequent Zincoren (Zinc Sulfate) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Zincoren 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 Zincoren (Zinc Sulfate) 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 Zincoren chloride. It is also not known whether Zincoren (Zinc Sulfate) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) was delivered intravenously over the course of 60 hours to a 72 year old patient.

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

Calcium supplements may confer a protective effect against Zincoren (Zinc Sulfate) toxicity.

DOSAGE AND ADMINISTRATION

Zincoren (Zinc Sulfate) 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 Zincoren (Zinc Sulfate) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Zincoren (Zinc Sulfate).

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

Zincoren (Zinc Sulfate) 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

Zincoren (Zinc Sulfate)

1 mg/mL

Zincoren (Zinc Sulfate) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

Zincoren 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.


Zincoren 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.


Zincoren 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.


Zincoren 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.


Zincoren 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.


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References

  1. Dailymed."NASAL SPA NATURAL SEA SALT (SODIUM CHLORIDE) SPRAY [NACUR HEALTHCARE LTD]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ZINC SULFATE TABLET [NATIONWIDE LABORATORIES, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."SULFACETAMIDE SODIUM SOLUTION/ DROPS [AKORN, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Zincoren?

Depending on the reaction of the Zincoren after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zincoren 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 Zincoren 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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Review

sdrugs.com conducted a study on Zincoren, 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 Zincoren 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.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

Visitor reported doses

No survey data has been collected yet

One visitor reported time for results

What is the time duration Zincoren drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 1 month to notice the result from using Zincoren drug. The time needed to show improvement in health condition after using the medicine Zincoren need not be same for all the users. It varies based on other factors.
Visitors%
1 month1
100.0%

Visitor reported administration

No survey data has been collected yet

Four visitors reported age

Visitors%
16-292
50.0%
46-601
25.0%
6-151
25.0%

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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