Splenofigon

Lysine:

• Boxed warning
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Splenofigon (Lysine) reviews

BOXED WARNING

Pharmacy Bulk Package

Not For Direct Infusion

DESCRIPTION

Splenofigon (Lysine)^® 15% Amino Acids Injection in a Pharmacy Bulk Package is a sterile, clear, nonpyrogenic solution of essential and nonessential amino acids for intravenous infusion in parenteral nutrition following appropriate dilution.

Splenofigon (Lysine)^® 15% in a Pharmacy Bulk Package is not for direct infusion. It is a sterile dosage from which contains several single doses for use in a pharmacy admixture program in the preparation of intravenous parenteral fluids.

Each 100 mL contains:

The formulas for the individual amino acids are as follows:

Formulas for individual amino acids

CLINICAL PHARMACOLOGY

Splenofigon (Lysine)^® 15% Amino Acids Injection providesseventeen crystalline amino acids. This completely utilizable substrate promotesprotein synthesis and wound healing and reduces the rate of protein catabolism.

A.Total Parenteral Nutrition (Central Infusion)

When enteralfeeding is inadvisable, Splenofigon (Lysine)^® 15% given by central venousinfusion in combination with energy sources, vitamins, trace elements andelectrolytes, will completely satisfy the requirements for weight maintenanceor weight gain, depending upon the dose selected. The energy component inparenteral nutrition by central infusion may be derived solely from dextroseor may be provided by a combination of dextrose and intravenous fat emulsion. The addition of intravenous fat emulsion provides essential fatty acids andpermits a dietary balance of fat and carbohydrate, at the same time offeringthe option of reducing the dextrose load and/or increasing the total caloricinput. An adequate energy supply is essential for optimal utilization of aminoacids.

B. Total Parenteral Nutrition (Peripheral Infusion)

Splenofigon (Lysine)^® 15%can also be administered as part of a total parenteral nutrition program byperipheral vein when the enteral route is inadvisable and use of the centralvenous catheter is contraindicated.

Reduction of proteinloss can be achieved by use of diluted Splenofigon (Lysine)^® 15% in combinationwith dextrose or with dextrose and intravenous fat emulsion by peripheralinfusion. Complete peripheral intravenous nutrition can be achieved in patientswith low caloric requirements by a Splenofigon (Lysine)^®15%-dextrose-fatregimen.

INDICATIONS AND USAGE

Splenofigon (Lysine)^® 15% is indicated as an amino acid(nitrogen) source in parenteral nutrition regimens. This use is appropriatewhen the enteral route is inadvisable, inadequate or not possible, as when:

-Gastrointestinal absorption is impaired by obstruction, inflammatory diseaseor its complications, or antineoplastic therapy;

-Bowel rest is needed because of gastrointestinal surgery or its complicationssuch as ileus, fistulae or anastomotic leaks;

-Tube feeding methods alone cannot provide adequate nutrition.

CONTRAINDICATIONS

This solution should not be used in patients in hepatic coma,severe renal failure, metabolic disorders involving impaired nitrogen utilizationor hypersensitivity to one or more amino acids.

WARNINGS

Administration of amino acids solutions at excessive ratesor to patients with hepatic insufficiency may result in plasma amino acidimbalances, hyperammonemia, prerenal azotemia, stupor and coma. Conservativedoses of amino acids should be given to these patients, dictated by the nutritionalstatus of the patient. Should symptoms of hyperammonemia develop, amino acidadministration should be discontinued and the patient’s clinical statusre-evaluated.

Contains sodium metabisulfite, a sulfitethat may cause allergic-type reactions including anaphylactic symptoms andlife-threatening or less severe asthmatic episodes in certain susceptiblepeople. The overall prevalence of sulfite sensitivity in the general populationis unknown and probably low.

Sulfite sensitivity isseen more frequently in asthmatic than in nonasthmatic people.

WARNING: This product contains aluminum that maybe toxic. Aluminum may reach toxic levels with prolonged parenteral administrationif kidney function is impaired. Premature neonates are particularly at riskbecause their kidneys are immature, and they require large amounts of calciumand phosphate solutions, which contain aluminum.

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

PRECAUTIONS

A. GENERAL

It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

The administration of Splenofigon (Lysine)^® 15% Amino Acids Injection as part of total parenteral nutrition (TPN) with large volumes of hyperosmotic fluids requires periodic monitoring of the patient for signs of hyperosmolarity, hyperglycemia, glycosuria and hypertriglyceridemia.

During parenteral nutrition with concentrated dextrose and amino acids solutions, essential fatty acid deficiency syndrome may develop but may not be clinically apparent. Early demonstration of this condition can only be accomplished by gas liquid chromatographic analysis of plasma lipids. The syndrome may be prevented or corrected by appropriate treatment with intravenous fat emulsions.

For complete nutritional support, TPN regimens must also include multiple vitamins and trace elements. Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. Although the metabolizable acetate ion in Splenofigon (Lysine)^® 15% diminishes the risk of acidosis, the physician must be alert to the potential appearance of this disorder.

Initiation and termination of infusions of TPN fluids must be gradual to permit adjustment of endogenous insulin release.

Undiluted Splenofigon (Lysine)^® 15% should not be administered peripherally. When administered centrally, it should be diluted with appropriate diluents, e.g., dextrose, electrolytes and other nutrient components, to at least half strength. See DOSAGE AND ADMINISTRATION.

Caution against volume overload should be exercised.

Drug product contains no more than 25 mcg/L of aluminum.

B. Laboratory Tests

Infusion of Splenofigon (Lysine)^® 15% without concomitant infusion of an adequate number of non-protein calories may result in elevated BUN. Monitoring of BUN is required and the balance between Splenofigon (Lysine)^® 15% and the calorie source may require adjustment. Frequent clinical evaluations and laboratory determinations are required to prevent the complications which may occur during the administration of solutions used in TPN. Laboratory tests should include blood glucose, serum electrolytes, liver and kidney function, serum osmolarity, blood ammonia, serum protein, pH, hematocrit, WBC and urinary glucose. When Splenofigon (Lysine)^® 15% is combined with electrolytes, care should be used in administering this solution to patients with congestive heart failure, renal failure, edema, adrenal hyperactivity, acid-base imbalance and those receiving diuretics or antihypertensive therapy. Total volume infused should be closely monitored. Serum electrolytes should be monitored daily in these patients.

C. Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Splenofigon (Lysine)^® 15% have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

D. Pregnancy Category C

Animal reproduction studies have not been conducted with Splenofigon (Lysine)^® 15%. It is also not known whether Splenofigon (Lysine)^® 15% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Splenofigon (Lysine)^® 15% should be given to a pregnant woman only if clearly needed.

E. Nursing Mothers

Caution should be exercised when Splenofigon (Lysine)^® 15% is administered to a nursing woman.

F. Pediatric Use

Safety and effectiveness of Splenofigon (Lysine)^® 15% Amino Acids Injection in pediatric patients have not been established by adequate and well-controlled studies. However, the use of amino acids injections in pediatric patients as an adjunct in the offsetting of nitrogen loss or in the treatment of negative nitrogen balance is referenced in the medical literature.

G. Special Precautions for Central Infusion

TPN delivered by indwelling catheter through a central or large peripheral vein is a special technique requiring a team effort by physician, nurse and pharmacist. The responsibility for administering this therapy should be confined to those trained in the procedures and alert to signs of complications. Complications known to occur from the placement of central venous catheter are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis, and air/catheter emboli. The risk of sepsis is present during intravenous therapy, especially when using central venous catheters for prolonged periods. It is imperative that the preparation of admixtures and the placement and care of the catheters be accomplished under controlled aseptic conditions.

H. Admixtures

Admixtures should be prepared under a laminar flow hood using aseptic technique.

Admixtures should be stored under refrigeration and must be administered within 24 hours after removal from refrigerator.

Filters of less than 1.2 micron pore size must not be used with admixtures containing fat emulsion.

I. Do not administer unless solution is clear and the seal is intact.

IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

ADVERSE REACTIONS

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluatethe patient and institute appropriate corrective measures. See WARNINGS andPRECAUTIONS.

DOSAGE AND ADMINISTRATION

The appropriate daily dose of amino acids to be used withdextrose or with dextrose and intravenous fat emulsion will depend upon themetabolic status and clinical response of the patient as therapy proceeds. Doses which achieve nitrogen equilibrium or positive balance are the mostdesirable. The dosage on the first day should be approximately half the anticipatedoptimal dosage and should be increased gradually to minimize glycosuria; similarly,withdrawal should be accomplished gradually to avoid rebound hypoglycemia.

Fatemulsion coadministration should be considered when prolonged (more than 5days) parenteral nutrition is required in order to prevent essential fattyacid deficiency (EFAD). Serum lipids should be monitored for evidence of EFADin patients maintained on fat free TPN.

The amount administeredis dosed on the basis of amino acids/kg of body weight/day. In general, twoto three g/kg of body weight for neonates and infants with adequate caloriesare sufficient to satisfy protein needs and promote positive nitrogen balance. In pediatric patients, the final solution should not exceed twice normal serumosmolarity (718 mOsmol/L).

DIRECTIONSFOR PROPER USE OF PHARMACY BULK PACKAGE

Splenofigon (Lysine)^® 15%in a Pharmacy Bulk Package is not intended for direct infusion. The containerclosure may be penetrated only once using a suitable sterile transfer deviceor dispensing set which allows measured dispensing of the contents. The PharmacyBulk Package is to be used only in a suitable work area such as a laminarflow hood (or an equivalent clean air compounding area). Once the closureis penetrated, the contents should be dispensed as soon as possible; the transferof contents must be completed within 4 hours of closure entry. The bottlemay be stored at room temperature (25°C) after the closure has been entered. Date and time of container entry should be noted in the area designated onthe container label.

When using Splenofigon (Lysine)^® 15%in patients with a need for fluid volume restriction, it can be diluted asfollows:

This will provide 1395 kilocalories (kcal) per 1000 mLof admixture with a ratio of 118 non-protein calories per gram of nitrogenand an osmolarity of 1561 mOsmol/L.

In patients wherethe need for fluid restriction is not so marked, either of the following regimensmay be used dependent upon the energy needs of the patient.

This will provide 1500 kcal per 1000 mL of admixture witha ratio of 228 non-protein calories per gram of nitrogen and an osmolarityof 1633 mOsmol/L.

This will provide 935 kcal per 1000 mL of admixture witha ratio of 158 non-protein calories per gram of nitrogen and an osmolarityof 1128.5 mOsmol/L.

A. Total Parenteral Nutrition (CentralInfusion)

In unstressed adult patients with no unusualnitrogen losses, a minimum dosage of 0.1 gram nitrogen (4.2 mL of Splenofigon (Lysine)^® 15%)plus 4.4 grams (15 calories) of dextrose per kilogram of body weight per dayare required to achieve nitrogen balance and weight stability. Intravenousfat emulsion may be used as a partial substitute for dextrose. This regimenprovides a ratio of 150 non-protein calories per gram of nitrogen.

Forpatients stressed by surgery, trauma or sepsis, and those with unusual nitrogenlosses, the dosage required for maintenance may be as high as 0.3 to 0.4 gramsof nitrogen (13 to 17 mL Splenofigon (Lysine)^® 15%) per kilogram of bodyweight per day, with proportionate increases in non-protein calories. Periodicassessment of nitrogen balance of the individual patient is the best indicatorof proper dosage. Volume overload and glycosuria may be encountered at highdosage, and nitrogen balance may not be achieved in extremely hypermetabolicpatients under these constraints. Concomitant insulin administration may berequired to minimize glycosuria. Daily laboratory monitoring is essential.

Useof an infusion pump is advisable to maintain a steady infusion rate duringcentral venous infusion.

B. Peripheral Nutrition

Inpatients for whom central venous catheterization is not advisable, proteincatabolism can be reduced by peripheral use of diluted Splenofigon (Lysine)^® 15%plus non-protein calorie sources. Dilution of 250 mL Splenofigon (Lysine)^® 15%in 750 mL of 10% dextrose will reduce the osmolarity to a level (724 mOsmol/L)which is more favorable to the maintenance of the integrity of the walls ofthe veins. Intravenous fat emulsion can be infused separately or simultaneously;if infused simultaneously the fat emulsion will provide a dilution effectupon the osmolarity while increasing the energy supply.

Parenteraldrug products should be inspected visually for particulate matter and discolorationprior to administration, whenever solution and container permit.

Toreduce the risk of bacterial contamination, all intravenous administrationsets should be replaced at least every 24 hours. Usage of admixtures mustbe initiated within 24 hours after mixing. If storage is necessary duringthis 24 hour period, admixtures must be refrigerated and completely used within24 hours of beginning administration.

HOW SUPPLIED

Splenofigon (Lysine)^® 15% Amino Acids Injection is suppliedas a Pharmacy Bulk Package in 500 mL containers.

500mL NDC 0409-0468-05

STORAGE

Store inthe closed carton; do not expose solution to light until ready for use. Exposureof pharmaceutical products to heat should be minimized. Avoid excessive heat. It is recommended that the product be stored at 20 to 25°C (68 to 77°F). Brief exposure to temperatures above25°C during transport and storage will not adversely affect the product. Solution that has been frozen must not be used.

Hospira, Inc., Lake Forest, IL 60045 USA

RL-1450

Sodium Glutamate:

• 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
• Splenofigon (Sodium Glutamate) reviews

1 INDICATIONS AND USAGE

Splenofigon nitrite is indicated for sequential use with Splenofigon (Sodium Glutamate) 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

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

Splenofigon (Sodium Glutamate) nitrite injection and Splenofigon (Sodium Glutamate) 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. Splenofigon (Sodium Glutamate) nitrite should be administered first, followed immediately by Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) nitrite and Splenofigon (Sodium Glutamate) thiosulfate.

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

3 DOSAGE FORMS AND STRENGTHS

Splenofigon (Sodium Glutamate) Nitrite Injection consists of:

• One vial of Splenofigon (Sodium Glutamate) 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: Splenofigon 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 Splenofigon (Sodium Glutamate) 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. Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) 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 Splenofigon nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Splenofigon 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 Splenofigon (Sodium Glutamate) 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 Splenofigon 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 Splenofigon (Sodium Glutamate) nitrite.

5.7 Use with Other Drugs

Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) nitrite.

The medical literature has reported the following adverse events in association with Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

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

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

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

Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) 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

Splenofigon (Sodium Glutamate) 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

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

Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) 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 Splenofigon (Sodium Glutamate) 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

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

Structure of Splenofigon (Sodium Glutamate) Nitrite

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

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

Splenofigon (Sodium Glutamate) Nitrite

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

Splenofigon (Sodium Glutamate) 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. Splenofigon (Sodium Glutamate) 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

Splenofigon (Sodium Glutamate) Nitrite

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

12.3 Pharmacokinetics

Splenofigon (Sodium Glutamate) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Splenofigon 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

Splenofigon (Sodium Glutamate) 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

Splenofigon (Sodium Glutamate) 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