GES 45

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• GES 45 (Potassium Chloride) reviews

GES 45 (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of GES 45 (Potassium Chloride) containing 1500 mg of microencapsulated GES 45 (Potassium Chloride), USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of GES 45 (Potassium Chloride) within the gastrointestinal tract is reduced.

GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is GES 45 (Potassium Chloride), and the structural formula is KCl. GES 45 (Potassium Chloride), USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated GES 45 (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of GES 45 (Potassium Chloride).

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The potassium ion is the principal intracellular cation of most body tissues. Potassium ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or GES 45 (Potassium Chloride) may be able to restore normal potassium levels.

In rare circumstances (eg, patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE GES 45 (Potassium Chloride) PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

CONTRAINDICATIONS

Potassium supplements are contraindicated in patients with hyperkalemia since a further increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of GES 45 (Potassium Chloride) have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of GES 45 (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of GES 45 (Potassium Chloride) are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of GES 45 (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of GES 45 (Potassium Chloride) are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated GES 45 (Potassium Chloride) and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral GES 45 (Potassium Chloride) therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of GES 45 (Potassium Chloride) administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release GES 45 (Potassium Chloride) products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS

General

The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for potassium depletion. In interpreting the serum potassium level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body potassium while acute acidosis per se can increase the serum potassium concentration into the normal range even in the presence of a reduced total body potassium. The treatment of potassium depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of GES 45 (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma potassium it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Potassium is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with GES 45 Extended Release Tablets USP, 20 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of GES 45 (Potassium Chloride) supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of GES 45 (Potassium Chloride) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug 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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral potassium salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing potassium and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each GES 45 (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of GES 45 (Potassium Chloride).

GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of GES 45 (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

GES 45 (Potassium Chloride) Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

GES 45 (Potassium Chloride) 20 Meq

Sodium Bicarbonate:

• 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
• GES 45 (Sodium Bicarbonate) reviews

1 INDICATIONS AND USAGE

GES 45 nitrite is indicated for sequential use with GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) Nitrite Injection is indicated for sequential use with GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 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, GES 45 (Sodium Bicarbonate) Nitrite Injection and GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) thiosulfate, simultaneously with GES 45 (Sodium Bicarbonate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than GES 45 (Sodium Bicarbonate) thiosulfate, with GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite, followed by GES 45 (Sodium Bicarbonate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate.

GES 45 (Sodium Bicarbonate) nitrite injection and GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) nitrite should be administered first, followed immediately by GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of GES 45 (Sodium Bicarbonate) 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 GES 45 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 GES 45 (Sodium Bicarbonate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of GES 45 (Sodium Bicarbonate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to GES 45 (Sodium Bicarbonate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between GES 45 (Sodium Bicarbonate) thiosulfate and GES 45 (Sodium Bicarbonate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

GES 45 (Sodium Bicarbonate) Nitrite Injection consists of:

• One vial of GES 45 (Sodium Bicarbonate) 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: GES 45 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 GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with GES 45 (Sodium Bicarbonate) nitrite whenever possible. When GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite administered to an adult. GES 45 (Sodium Bicarbonate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

GES 45 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 GES 45 (Sodium Bicarbonate) 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 GES 45 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 GES 45 (Sodium Bicarbonate) nitrite.

5.7 Use with Other Drugs

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite.

The medical literature has reported the following adverse events in association with GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: GES 45 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. GES 45 (Sodium Bicarbonate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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, GES 45 (Sodium Bicarbonate) 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, GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to GES 45 (Sodium Bicarbonate) 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, GES 45 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 GES 45 (Sodium Bicarbonate) nitrite is excreted in human milk. Because GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of GES 45 (Sodium Bicarbonate) nitrite. In studies conducted with Long-Evans rats, GES 45 (Sodium Bicarbonate) 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 GES 45 nitrite in conjunction with GES 45 (Sodium Bicarbonate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of GES 45 (Sodium Bicarbonate) 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.

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) nitrite has the chemical name nitrous acid GES 45 (Sodium Bicarbonate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of GES 45 (Sodium Bicarbonate) Nitrite

GES 45 (Sodium Bicarbonate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of GES 45 (Sodium Bicarbonate) nitrite injection.

GES 45 (Sodium Bicarbonate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of GES 45 (Sodium Bicarbonate) nitrite in 10 mL solution (30 mg/mL). GES 45 (Sodium Bicarbonate) 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 GES 45 nitrite and GES 45 (Sodium Bicarbonate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

GES 45 (Sodium Bicarbonate) Nitrite

GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite. It has been suggested that GES 45 (Sodium Bicarbonate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, GES 45 (Sodium Bicarbonate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) Nitrite

When 4 mg/kg GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

GES 45 (Sodium Bicarbonate) Nitrite

GES 45 (Sodium Bicarbonate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free GES 45 (Sodium Bicarbonate) nitrite in humans have not been well studied. It has been reported that approximately 40% of GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) 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 GES 45 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to GES 45 (Sodium Bicarbonate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) 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. GES 45 (Sodium Bicarbonate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of GES 45 (Sodium Bicarbonate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) GES 45 (Sodium Bicarbonate) nitrite or 1 g/kg GES 45 (Sodium Bicarbonate) thiosulfate alone or in sequence immediately after subcutaneous injection of GES 45 (Sodium Bicarbonate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg GES 45 (Sodium Bicarbonate) nitrite and/or 0.5 g/kg GES 45 (Sodium Bicarbonate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of GES 45 (Sodium Bicarbonate) cyanide required to cause death, and when administered together, GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate resulted in a synergistic effect in raising the lethal dose of GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of GES 45 (Sodium Bicarbonate) nitrite and GES 45 (Sodium Bicarbonate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of GES 45 (Sodium Bicarbonate) nitrite, with or without GES 45 (Sodium Bicarbonate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) thiosulfate report its use in conjunction with GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) 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 GES 45 (Sodium Bicarbonate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of GES 45 (Sodium Bicarbonate) nitrite injection 30 mg/mL (containing 300 mg of GES 45 (Sodium Bicarbonate) 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: GES 45 (Sodium Bicarbonate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

GES 45 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

GES 45 (Sodium Bicarbonate) 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

GES 45 (Sodium Bicarbonate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Sodium Chloride:

• 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
• GES 45 (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

GES 45 nitrite is indicated for sequential use with GES 45 (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

GES 45 (Sodium Chloride) Nitrite Injection is indicated for sequential use with GES 45 (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 GES 45 (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 GES 45 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, GES 45 (Sodium Chloride) Nitrite Injection and GES 45 (Sodium Chloride) 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 GES 45 (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 GES 45 (Sodium Chloride) thiosulfate, simultaneously with GES 45 (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 GES 45 (Sodium Chloride) thiosulfate, with GES 45 (Sodium Chloride) 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 GES 45 (Sodium Chloride) nitrite and GES 45 (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 GES 45 (Sodium Chloride) nitrite, followed by GES 45 (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 GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate.

GES 45 (Sodium Chloride) nitrite injection and GES 45 (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. GES 45 (Sodium Chloride) nitrite should be administered first, followed immediately by GES 45 (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.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of GES 45 (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 GES 45 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 GES 45 (Sodium Chloride) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of GES 45 (Sodium Chloride) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to GES 45 (Sodium Chloride) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (Sodium Chloride) thiosulfate and GES 45 (Sodium Chloride) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

GES 45 (Sodium Chloride) Nitrite Injection consists of:

• One vial of GES 45 (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: GES 45 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 GES 45 (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. GES 45 (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 GES 45 (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 GES 45 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with GES 45 (Sodium Chloride) nitrite whenever possible. When GES 45 (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 GES 45 (Sodium Chloride) nitrite administered to an adult. GES 45 (Sodium Chloride) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. GES 45 (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 GES 45 (Sodium Chloride) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

GES 45 (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 GES 45 (Sodium Chloride) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

GES 45 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 GES 45 (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 GES 45 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 GES 45 (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

GES 45 (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.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of GES 45 (Sodium Chloride) nitrite.

The medical literature has reported the following adverse events in association with GES 45 (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 GES 45 (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.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with GES 45 (Sodium Chloride) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: GES 45 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. GES 45 (Sodium Chloride) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

GES 45 (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 GES 45 (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 GES 45 (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, GES 45 (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, GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (Sodium Chloride) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

GES 45 (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 GES 45 (Sodium Chloride) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to GES 45 (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, GES 45 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 GES 45 (Sodium Chloride) nitrite is excreted in human milk. Because GES 45 (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 GES 45 (Sodium Chloride) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of GES 45 (Sodium Chloride) nitrite. In studies conducted with Long-Evans rats, GES 45 (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 GES 45 nitrite in conjunction with GES 45 (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 GES 45 (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.

GES 45 (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 GES 45 (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

GES 45 (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

GES 45 (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 GES 45 (Sodium Chloride) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

GES 45 (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 GES 45 (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 GES 45 (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

GES 45 (Sodium Chloride) nitrite has the chemical name nitrous acid GES 45 (Sodium Chloride) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of GES 45 (Sodium Chloride) Nitrite

GES 45 (Sodium Chloride) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of GES 45 (Sodium Chloride) nitrite injection.

GES 45 (Sodium Chloride) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of GES 45 (Sodium Chloride) nitrite in 10 mL solution (30 mg/mL). GES 45 (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 GES 45 nitrite and GES 45 (Sodium Chloride) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

GES 45 (Sodium Chloride) Nitrite

GES 45 (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 GES 45 (Sodium Chloride) nitrite. It has been suggested that GES 45 (Sodium Chloride) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, GES 45 (Sodium Chloride) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

GES 45 (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. GES 45 (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

GES 45 (Sodium Chloride) Nitrite

When 4 mg/kg GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (Sodium Chloride) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

GES 45 (Sodium Chloride) Nitrite

GES 45 (Sodium Chloride) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free GES 45 (Sodium Chloride) nitrite in humans have not been well studied. It has been reported that approximately 40% of GES 45 (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 GES 45 (Sodium Chloride) nitrite and GES 45 (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 GES 45 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. GES 45 (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. GES 45 (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 GES 45 (Sodium Chloride) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to GES 45 (Sodium Chloride) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

GES 45 (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. GES 45 (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. GES 45 (Sodium Chloride) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of GES 45 (Sodium Chloride) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (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 GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) GES 45 (Sodium Chloride) nitrite or 1 g/kg GES 45 (Sodium Chloride) thiosulfate alone or in sequence immediately after subcutaneous injection of GES 45 (Sodium Chloride) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg GES 45 (Sodium Chloride) nitrite and/or 0.5 g/kg GES 45 (Sodium Chloride) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of GES 45 (Sodium Chloride) cyanide required to cause death, and when administered together, GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate resulted in a synergistic effect in raising the lethal dose of GES 45 (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 GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of GES 45 (Sodium Chloride) nitrite and GES 45 (Sodium Chloride) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of GES 45 (Sodium Chloride) nitrite, with or without GES 45 (Sodium Chloride) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of GES 45 (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 GES 45 (Sodium Chloride) thiosulfate report its use in conjunction with GES 45 (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 GES 45 (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 GES 45 (Sodium Chloride) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of GES 45 (Sodium Chloride) nitrite injection 30 mg/mL (containing 300 mg of GES 45 (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: GES 45 (Sodium Chloride) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

GES 45 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

GES 45 (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

GES 45 (Sodium Chloride) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Sodium Citrate:

• 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
• GES 45 (Sodium Citrate) reviews

1 INDICATIONS AND USAGE

GES 45 nitrite is indicated for sequential use with GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) Nitrite Injection is indicated for sequential use with GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 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, GES 45 (Sodium Citrate) Nitrite Injection and GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) thiosulfate, simultaneously with GES 45 (Sodium Citrate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than GES 45 (Sodium Citrate) thiosulfate, with GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite, followed by GES 45 (Sodium Citrate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate.

GES 45 (Sodium Citrate) nitrite injection and GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) nitrite should be administered first, followed immediately by GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of GES 45 (Sodium Citrate) 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 GES 45 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 GES 45 (Sodium Citrate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of GES 45 (Sodium Citrate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to GES 45 (Sodium Citrate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between GES 45 (Sodium Citrate) thiosulfate and GES 45 (Sodium Citrate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

GES 45 (Sodium Citrate) Nitrite Injection consists of:

• One vial of GES 45 (Sodium Citrate) 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: GES 45 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 GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with GES 45 (Sodium Citrate) nitrite whenever possible. When GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite administered to an adult. GES 45 (Sodium Citrate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

GES 45 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 GES 45 (Sodium Citrate) 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 GES 45 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 GES 45 (Sodium Citrate) nitrite.

5.7 Use with Other Drugs

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite.

The medical literature has reported the following adverse events in association with GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: GES 45 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. GES 45 (Sodium Citrate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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, GES 45 (Sodium Citrate) 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, GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to GES 45 (Sodium Citrate) 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, GES 45 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 GES 45 (Sodium Citrate) nitrite is excreted in human milk. Because GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of GES 45 (Sodium Citrate) nitrite. In studies conducted with Long-Evans rats, GES 45 (Sodium Citrate) 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 GES 45 nitrite in conjunction with GES 45 (Sodium Citrate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of GES 45 (Sodium Citrate) 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.

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) nitrite has the chemical name nitrous acid GES 45 (Sodium Citrate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of GES 45 (Sodium Citrate) Nitrite

GES 45 (Sodium Citrate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of GES 45 (Sodium Citrate) nitrite injection.

GES 45 (Sodium Citrate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of GES 45 (Sodium Citrate) nitrite in 10 mL solution (30 mg/mL). GES 45 (Sodium Citrate) 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 GES 45 nitrite and GES 45 (Sodium Citrate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

GES 45 (Sodium Citrate) Nitrite

GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite. It has been suggested that GES 45 (Sodium Citrate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, GES 45 (Sodium Citrate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) Nitrite

When 4 mg/kg GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

GES 45 (Sodium Citrate) Nitrite

GES 45 (Sodium Citrate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free GES 45 (Sodium Citrate) nitrite in humans have not been well studied. It has been reported that approximately 40% of GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) 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 GES 45 nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to GES 45 (Sodium Citrate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) 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. GES 45 (Sodium Citrate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of GES 45 (Sodium Citrate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) GES 45 (Sodium Citrate) nitrite or 1 g/kg GES 45 (Sodium Citrate) thiosulfate alone or in sequence immediately after subcutaneous injection of GES 45 (Sodium Citrate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg GES 45 (Sodium Citrate) nitrite and/or 0.5 g/kg GES 45 (Sodium Citrate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of GES 45 (Sodium Citrate) cyanide required to cause death, and when administered together, GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate resulted in a synergistic effect in raising the lethal dose of GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of GES 45 (Sodium Citrate) nitrite and GES 45 (Sodium Citrate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of GES 45 (Sodium Citrate) nitrite, with or without GES 45 (Sodium Citrate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) thiosulfate report its use in conjunction with GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) 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 GES 45 (Sodium Citrate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of GES 45 (Sodium Citrate) nitrite injection 30 mg/mL (containing 300 mg of GES 45 (Sodium Citrate) 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: GES 45 (Sodium Citrate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

GES 45 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

GES 45 (Sodium Citrate) 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

GES 45 (Sodium Citrate) 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