Rheodextran

Dextran 40:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• References
• Im-3590
• Im-3591
• Rheodextran (Dextran 40) reviews

INDICATIONS AND USAGE

LMD (dextran 40) is indicated for use in the adjunctive treatment of shock or impending shock due to hemorrhage, burns, surgery or other trauma. It is not indicated as a replacement for whole blood or blood components if they are available. It should not replace other forms of therapy known to be of value in the treatment of shock.

LMD is also indicated for use as a priming fluid, either as a sole prime or as an additive, in pump oxygenators during extracorporeal circulation.

LMD is also indicated for use in prophylaxis of venous thrombosis and pulmonary embolism in patients undergoing procedures known to be associated with a high incidence of thromboembolic complications, such as hip surgery.

CONTRAINDICATIONS

LMD (dextran 40) is contraindicated in patients with known hypersensitivity to dextran, in those with marked hemostatic defects of all types (thrombocytopenia, hypofibrinogenemia, etc.) including those caused by drugs (heparin, warfarin, etc.), marked cardiac decompensation and in renal disease with severe oliguria or anuria.

WARNINGS

Although infrequent, severe and fatal anaphylactoid reactions consisting of marked hypotension or cardiac and respiratory arrest have been reported, most of these reactions have occurred in patients not previously exposed to intravenous dextran and early in the infusion period. It is strongly recommended, therefore, that patients not previously exposed to dextran be observed closely during the first minutes of the infusion period.

Anaphylactoid Reactions

There have been rare reports of serious and life-threatening dextran-induced anaphylactoid reactions (DIAR) associated with Rheodextran (Dextran 40) and Dextran 70 administration. To reduce the likelihood of DIAR, 20 mL dextran 1 should be administered prior to infusion of Rheodextran (Dextran 40) or Dextran 70 consistent with the dextran 1 package insert.^1-5 See DOSAGE AND ADMINISTRATION . Investigators have reported a 35-fold decrease (from 1:2000 to 1:70,000) in the incidence of DIAR following prophylactic use of dextran 1.⁶ However, serious and life-threatening reactions may still occur following initiation of an infusion of any clinical dextran (see ADVERSE REACTIONS ).

Because of the seriousness of anaphylactoid reactions, it is recommended that the infusion of intravenous dextran be stopped at the first sign of an allergic reaction provided that other means of sustaining the circulation are available. Resuscitative measures should be readily available for emergency administration in the event such a reaction occurs. In circulatory collapse due to anaphylaxis, rapid volume substitutions with an agent other than dextran should be instituted.

Because LMD (dextran 40) is a hypertonic colloid solution, it attracts water from the extravascular space. This shift of fluid should be considered if the drug is used for poorly hydrated patients where additional fluid therapy will be needed. If LMD is given in excess, vascular overload could occur. The latter possibility can be avoided with careful clinical monitoring preferably by central venous pressure.

Renal excretion of LMD causes elevations of the specific gravity of the urine. In the presence of adequate urine flow only minor elevation will occur, whereas in patients with reduced urine output, urine viscosity and specific gravity can be increased markedly. Since urine osmolarity is only slightly increased by the presence of dextran molecules, it is recommended that, when desired, a patient’s state of hydration be assessed by determination of urine or serum osmolarity. If signs of dehydration are present, additional fluid should be administered. An osmotic diuretic such as mannitol also can be used to maintain an adequate urine flow.

Although numerous studies attest to the “nephrotonic” effect of LMD, renal failure has been reported to occur after the use of LMD.

Evidence of tubular vacuolization (osmotic nephrosis) has been found following LMD administration in animals and man. While this appears to be reversible experimentally in animals and to be a consequence of high urine concentration of the drug, its exact clinical significance is presently unknown.

Occasional abnormal renal and hepatic function values have been reported following administration of LMD. However, the specific effect of LMD on renal and hepatic function could not be determined because most of the patients also had undergone surgery or cardiac catheterization. A comparative study of Rheodextran (Dextran 40) and 5% dextrose in water as pump-priming fluids in open-heart surgery has shown similar elevations of serum glutamic oxaloacetic transaminase (SGOT), aspartate aminotransferase and serum glutamic pyruvic transaminase (SGPT), alanine aminotransferase values in both groups.

Caution should be employed when LMD is administered to patients with active hemorrhage as the resulting increase in perfusion pressure and improved microcirculatory flow may result in additional blood loss.

Administering infusions of LMD that exceed the recommended dose should be avoided, since a dose-related increase in the incidence of wound hematoma, wound seroma, wound bleeding, distant bleeding (hematuria and melena) and pulmonary edema has been observed. Recommended doses should never be exceeded in patients with advanced renal disease, since excessive doses may precipitate renal failure.

Dextran may interfere to some extent with platelet function and should be used with caution in cases with thrombocytopenia. Transient prolongation of bleeding time and/or slightly increased bleeding tendency may occur with the administration of doses greater than 1,000 mL. Care should be taken to prevent a depression of hematocrit below 30% by volume. When large volumes of dextran are administered, plasma protein levels will be decreased.

Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.

The intravenous administration of this solution can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of administered parenteral solutions.

The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of such solutions.

In patients with diminished renal function, administration of solutions containing sodium ions may result in sodium retention.

PRECAUTIONS

The possibility of circulatory overload should be kept in mind. Special care should be exercised in patients with impaired renal clearance of dextran. When the risk of pulmonary edema and/or congestive heart failure may be increased, dextran should be used with caution.

In patients with normal hemostasis, dosage of LMD (dextran 40) approximating 15 mL/kg of body weight may prolong bleeding time and depress platelet function. Dosages in this range also markedly decrease factor VIII, and decrease factors V and IX to a greater degree than would be expected to occur from hemodilution alone. Since these changes tend to be more pronounced following trauma or major surgery, patients should be observed for early signs of bleeding complications.

Since increased rouleaux formation may occur in the presence of dextran, it is recommended that blood samples be drawn for typing and cross-matching prior to the infusion of dextran and reserved for subsequent use if necessary. If blood is drawn after infusion of dextran, the saline agglutination and indirect antiglobulin methods may be used for typing and cross-matching. Difficulty may be encountered when proteolytic enzyme techniques are used to match blood.

Consideration should be given to withdrawal of blood for chemical laboratory tests prior to initiating therapy with dextran because of the following:

• Blood sugar determinations that employ high concentrations of acid may result in hydrolysis of dextran, yielding falsely elevated glucose assay results. This has been observed both with sulfuric acid and with acetic acid.
• In other laboratory tests, the presence of dextran in the blood may result in the development of turbidity, which can interfere with the assay. This has been observed in bilirubin assays in which alcohol is employed and in total protein assays employing biuret reagent.

Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus.

Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotropin.

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Drug Interactions. Additive medications should not be delivered via plasma volume expanders.

Pregnancy Category C. Animal reproduction studies have not been conducted with Rheodextran (Dextran 40) in dextrose or sodium chloride. It is also not known whether Rheodextran (Dextran 40) in dextrose or sodium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 10% LMD (dextran 40) in dextrose or sodium chloride should be given to a pregnant woman only if clearly needed.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 10% LMD (dextran 40) in dextrose or sodium chloride is administered to a nursing woman.

Pediatric Use. The safety and effectiveness of Rheodextran (Dextran 40) have not been established in neonates. Its limited use in neonates has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Antigenicity of dextrans is directly related to their degree of branching. Since LMD (dextran 40) has a low degree of branching, it is relatively free of antigenic effect. However, a few individuals have experienced mild urticarial reactions. More severe reactions, consisting of severe anaphylactoid reaction, generalized urticaria, tightness of the chest, wheezing, hypotension, nausea and vomiting may occur in rare instances. Symptoms and signs of adverse systemic reaction may be relieved by parenteral administration of antihistamines, ephedrine or epinephrine, while other means of shock therapy are instituted. The route of administration and dosages of the therapeutic agent selected will depend upon the severity and rapidity of progression of the reaction.

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary (see WARNINGS for treatment of anaphylactic shock).

Post Marketing

Severe reactions have been observed with Rheodextran (Dextran 40) and Dextran 70. Reported reactions include: generalized urticaria, nausea and vomiting, wheezing, hypotension, shock and cardiac arrest (dextran-induced anaphylactoid reactions, DIAR). FDA has received 94 reports of severe DIAR since 1964. Because these reactions are reported voluntarily and the treated population is of indeterminate size, the frequency of reactions cannot be estimated reliably.

DOSAGE AND ADMINISTRATION

LMD (dextran 40) is administered by I.V. infusion only.

Dextran 1 should be administered prior to administration of clinical dextran solutions.

• In shock, it is suggested that total dosage not exceed 20 mL/kg for adults and adolescents, during the first 24 hours. The first 10 mL/kg may be infused as rapidly as necessary to effect improvement. It is strongly recommended that central venous pressure be monitored frequently during the initial infusion of the drug. Should therapy continue beyond 24 hours, subsequent dosage should not exceed 10 mL/kg per day and therapy should not continue beyond five days.
• In extracorporeal perfusion, the dosage of LMD used will vary with the volume of the pump oxygenator. LMD can serve as a sole primer or as an additive to other priming fluids. For adults and adolescents, generally 10 to 20 mL of a 10% solution (1 to 2 g) of LMD per kilogram of body weight are added to the perfusion circuit. Usually total dosage should not exceed 2 g/kg of body weight.
• In prophylaxis of venous thrombosis and thromboembolism, the dosage of LMD for adults and adolescents, should be chosen according to the risk of thromboembolic complications, e.g., type of surgery and duration of immobilization. In general, treatment should be initiated during surgery; 500 to 1,000 mL (approximately 10 mL/kg of body weight) should be administered on the day of operation. Treatment should be continued at a dose of 500 mL daily for an additional two to three days; then, according to the risk of complications, 500 mL may be given every second or third day during the period of risk, for up to two weeks.
• Infants may be given 5 mL per kg body weight and children 10 mL per kg.

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

Note: When infusing concentrated LMD, the administration set should include a filter.

Instructions for use

To Open

Tear outer wrap at notch and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect solution quality or safety. The opacity will diminish gradually.

Preparation for Administration

(Use aseptic technique)

• Close flow control clamp of administration set.
• Remove cover from outlet port at bottom of container.
• Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated. Note: See full directions on administration set carton.
• Suspend container from hanger.
• Squeeze and release drip chamber to establish proper fluid level in drip chamber.
• Open flow control clamp and clear air from set. Close clamp.
• Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
• Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

HOW SUPPLIED

10% LMD in 5% Dextrose Injection (Dextran 40 in Dextrose Injection, USP) is supplied as follows:

10% LMD in 0.9% Sodium Chloride Injection (Dextran 40 in Sodium Chloride Injection, USP) is supplied as follows:

• Do not use if crystallization has occurred.
• Store at 20 to 25°C (68 to 77°F). Protect from freezing.

REFERENCES

• Richter W. Build-in hapten inhibition of anaphylaxis by the low molecular weight fractions of a B 512 dextran fraction of MW 3400. Int Arch Allergy 1973;45:930
• Lungstrom K-G, Renck H, Hedin H, et al. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. I. A Scandinavian multicenter study on the effects of 10 mL dextran 1, 15%, administered before Dextran 70 or Rheodextran (Dextran 40). Acta Chir Scand 1983;149:341-348
• Renck H, Ljungstrom K-G, Rosberg B, et al. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. II. A comparison of the effects of 20 mL dextran 1, 15%, administered either admixed to or before Dextran 70 or Rheodextran (Dextran 40). Acta Chir Scand 1983;149:349-353
• Renck H, Ljungstrom K-G, Hedin H, et al. Prevention of dextran-induced anaphylactic reactions by hapten inhibition. III. A Scandinavian multicenter study on the effects of 20 mL dextran 1, 15%, administered before Dextran 70 or Rheodextran (Dextran 40). Acta Chir Scand 1983;149:355-360
• Ljungstrom K-G, Renck H, Strandberg K, et al. Adverse reactions to dextran in Sweden 1970-1979. Acta Chir Scand 1983;149:253-262
• Hedin H, Ljungstrom K-G. Prevention of dextran anaphylaxis. Ten years experience with hapten dextran. Int Arch Allergy Immunol 1997;113:358-359

Revised: 11/2014

EN-3695

Hospira, Inc., Lake Forest, IL 60045 USA

Hospira logo

IM-3590

IM-3591

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
• Rheodextran (Sodium Chloride) reviews

1 INDICATIONS AND USAGE

Rheodextran nitrite is indicated for sequential use with Rheodextran (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

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

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

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

3 DOSAGE FORMS AND STRENGTHS

Rheodextran (Sodium Chloride) Nitrite Injection consists of:

• One vial of Rheodextran (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: Rheodextran 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 Rheodextran (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. Rheodextran (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 Rheodextran (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 Rheodextran nitrite.

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

5.3 Anemia

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

5.4 Smoke Inhalation Injury

Rheodextran 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 Rheodextran (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 Rheodextran 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 Rheodextran (Sodium Chloride) nitrite.

5.7 Use with Other Drugs

Rheodextran (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 Rheodextran (Sodium Chloride) nitrite.

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

8 USE IN SPECIFIC POPULATIONS

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

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

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

Rheodextran (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 Rheodextran (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

Rheodextran (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

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

Rheodextran (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 Rheodextran (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 Rheodextran (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

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

Structure of Rheodextran (Sodium Chloride) Nitrite

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

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

Rheodextran (Sodium Chloride) Nitrite

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

Rheodextran (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. Rheodextran (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

Rheodextran (Sodium Chloride) Nitrite

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

12.3 Pharmacokinetics

Rheodextran (Sodium Chloride) Nitrite

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

Mutagenesis

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

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

14 CLINICAL STUDIES

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

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

17 PATIENT COUNSELING INFORMATION

Rheodextran 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

Rheodextran (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

Rheodextran (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