Sodium nitroprusside-injection

Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity [see WARNINGS AND PRECAUTIONS] or as thiocyanate toxicity [see WARNINGS AND PRECAUTIONS]. Cyanide toxicity causes venous hyperoxemia with bright red venous blood. Cells become unable to extract the oxygen delivered to them, leading to air hunger, confusion and death. Lactic acidosis may occur, but its emergence may lag other life-threatening manifestations of cyanide toxicity.

Cyanide levels can be measured by many laboratories, and blood-gas studies that can detect venous hyperoxemia or acidosis are widely available. Acidosis may not appear until more than an hour after the appearance of dangerous cyanide levels. Suspicion of cyanide toxicity is adequate grounds for initiation of treatment.

Treatment of cyanide toxicity consists of:

• discontinuing sodium nitroprusside;
• administration of sodium nitrite to convert as much hemoglobin into methemoglobin as the patient can safely tolerate; and then
• infusing sodium thiosulfate to convert the cyanide into thiocyanate.

Hemodialysis is ineffective in removal of cyanide, but it will eliminate most thiocyanate.

Sodium nitrite is available in a 3% solution, and 4-6 mg/kg (about 0.2 mL/kg) should be injected over 2-4 minutes. This dose can be expected to convert about 10% of the patient’s hemoglobin into methemoglobin; this level of methemoglobinemia is not associated with any important hazard of its own.

Immediately after infusion of the sodium nitrite, sodium thiosulfate should be infused. This agent is available in 10% and 25% solutions, and the recommended dose is 150-200 mg/kg; a typical adult dose is 50 mL of the 25% solution. Thiosulfate treatment of an acutely cyanide-toxic patient will raise thiocyanate levels, but not to a dangerous degree.

The nitrite/thiosulfate regimen may be repeated, at half the original doses, after two hours.

Cyanide antidote kits are available.

Sodium nitroprusside is disodium pentacyanonitrosylferrate(2-) dihydrate, a hypotensive agent whose structural formula is

Sodium nitroprusside whose molecular formula is Na2[Fe(CN)5NO] • 2H2O, and whose molecular weight is 297.95. Dry sodium nitroprusside is a reddish-brown powder, soluble in water. In an aqueous solution infused intravenously, sodium nitroprusside is a rapid-acting vasodilator, active on both arteries and veins.

Sodium nitroprusside solution is rapidly degraded by trace contaminants, often with resulting color changes. (See DOSAGE AND ADMINISTRATION section.) The solution is also sensitive to certain wavelengths of light, and it must be protected from light in clinical use.

Sodium Nitroprusside Injection is available as:

50 mg Fliptop Vial - Each 2 mL vial contains the equivalent of 50 mg sodium nitroprusside dihydrate in sterile water for injection.

Sodium nitroprusside should not be used in the treatment of compensatory hypertension, where the primary hemodynamic lesion is aortic coarctation or arteriovenous shunting.

Sodium nitroprusside should not be used to produce hypotension during surgery in patients with known inadequate cerebral circulation, or in moribund patients (A.S.A. Class 5E) coming to emergency surgery.

Patients with congenital (Leber's) optic atrophy or with tobacco amblyopia have unusually high cyanide/thiocyanate ratios. These rare conditions are probably associated with defective or absent rhodanase, and sodium nitroprusside should be avoided in these patients.

Sodium nitroprusside should not be used for the treatment of acute congestive heart failure associated with reduced peripheral vascular resistance such as high-output heart failure that may be seen in endotoxic sepsis.

General: Like other vasodilators, sodium nitroprosside can cause increases in intracranial pressure. In patients whose intracranial pressure is already elevated, sodium nitroprusside should be used only with extreme caution.

Hepatic: Use caution when administering nitroprusside to patients with hepatic insufficiency.

Use in Anesthesia: When sodium nitroprusside (or any other vasodilator) is used for controlled hypotension during anesthesia, the patient's capacity to compensate for anemia and hypovolemia may be diminished. If possible, pre-existing anemia and hypovolemia should be corrected prior to administration of sodium nitroprusside.

Hypotensive anesthetic techniques may also cause abnormalities of the pulmonary ventilation/perfusion ratio. Patients intolerant of these abnormalities may require a higher fraction of inspired oxygen.

Extreme caution should be exercised in patients who are especially poor surgical risks (A.S.A. Class 4 and 4E).

Laboratory Tests: The cyanide-level assay is technically difficult, and cyanide levels in body fluids other than packed red blood cells are difficult to interpret. Cyanide toxicity will lead to lactic acidosis and venous hyperoxemia, but these findings may not be present until an hour or more after the cyanide capacity of the body's red-cell mass has been exhausted.

Drug Interactions: The hypotensive effect of sodium nitroprusside is augmented by that of most other hypotensive drugs, including ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Animal studies assessing sodium nitroprusside's carcinogenicity and mutagenicity have not been conducted. Similarly, sodium nitroprusside has not been tested for effects on fertility.

Pregnancy: Teratogenic effects: Pregnancy Category C.

There are no adequate, well-controlled studies of sodium nitroprusside in either laboratory animals or pregnant women. It is not known whether sodium nitroprusside can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Sodium nitroprusside should be given to a pregnant woman only if clearly needed.

Nonteratogenic effects: In three studies in pregnant ewes, nitroprusside was shown to cross the placental barrier. Fetal cyanide levels were shown to be dose-related to maternal levels of nitroprusside. The metabolic transformation of sodium nitroprusside given to pregnant ewes led to fatal levels of cyanide in the fetuses. The infusion of 25 mcg/kg/min of sodium nitroprusside for one hour in pregnant ewes resulted in the death of all fetuses. Pregnant ewes infused with 1 mcg/kg/min of sodium nitroprusside for one hour delivered normal lambs.

According to one investigator, a pregnant woman at 24 weeks gestation was given sodium nitroprusside to control gestational hypertension secondary to mitral valve disease. Sodium nitroprusside was infused at 3.9 mcg/kg/min for a total of 3.5 mg/kg over 15 hours prior to delivery of a 478 gram stillborn infant without any obvious anomalies. Cyanide levels in the fetal liver were less than 10 mcg/mL. Toxic levels have been reported to be more than 30 to 40 mcg/mL. The mother demonstrated no cyanide toxicity.

The effects of administering sodium thiosulfate in pregnancy, either by itself or as a co-infusion with sodium nitroprusside, are completely unknown.

Nursing Mothers: It is not known whether sodium nitroprusside and its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sodium nitroprusside, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Efficacy in the pediatric population was established based on adult trials and supported by the dose-ranging trial (Study 1) and an open label trial of at least 12 hour infusion at a rate that achieved adequate MAP control (Study 2) with pediatric patients on sodium nitroprusside. No novel safety issues were seen in these studies in pediatric patients. See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

Dilution to proper strength for infusion: Depending on the desired concentration, the solution containing 50 mg of sodium nitroprusside must be further diluted in 250 to 1000 mL of sterile 5% dextrose injection. The diluted solution should be protected from light, using the supplied opaque sleeve, aluminum foil, or other opaque material. It is not necessary to cover the infusion drip chamber or the tubing.

Verification of the chemical integrity of the product Sodium nitroprusside solution can be inactivated by reactions with trace contaminants. The products of these reactions are often blue, green, or red, much brighter than the faint brownish color of unreacted sodium nitroprusside. Discolored solutions, or solutions in which particulate matter is visible, should not be used. If properly protected from light, the freshly diluted solution is stable for 24 hours.

No other drugs should be administered in the same solution with sodium nitroprusside.

Avoidance of excessive hypotension: While the average effective rate in adult and pediatric patients is about 3 mcg/kg/min, some patients will become dangerously hypotensive when they receive sodium nitroprusside at this rate. Infusion of sodium nitroprusside should therefore be started at a very low rate (0.3 mcg/kg/min), with upward titration every few minutes until the desired effect is achieved or the maximum recommended infusion rate (10 mcg/kg/min) has been reached.

Because sodium nitroprusside's hypotensive effect is very rapid in onset and in dissipation, small variations in infusion rate can lead to wide, undesirable variations in blood pressure. Since there is inherent variation in blood pressure measurement, confirm the drug effect at any infusion rate after an additional 5 minutes before titrating to a higher dose to achieve the desired blood pressure. Sodium nitroprusside should not be infused through ordinary I.V. apparatus, regulated only by gravity and mechanical clamps. Only an infusion pump, preferably a volumetric pump, should be used.

Because sodium nitroprusside can induce essentially unlimited blood-pressure reduction, the blood pressure of a patient receiving this drug must be continuously monitored, using either a continually reinflated sphygmomanometer or (preferably) an intra-arterial pressure sensor. Special caution should be used in elderly patients, since they may be more sensitive to the hypotensive effects of the drug.

When sodium nitroprusside is used in the treatment of acute congestive heart failure, titration of the infusion rate must be guided by the results of invasive hemodynamic monitoring with simultaneous monitoring of urine output. Sodium nitroprusside can be titrated by increasing the infusion rate until:

• measured cardiac output is no longer increasing,
• systemic blood pressure cannot be further reduced without compromising the perfusion of vital organs, or
• the maximum recommended infusion rate has been reached, whichever comes earliest. Specific hemodynamic goals must be tailored to the clinical situation, but improvements in cardiac output and left ventricular filling pressure must not be purchased at the price of undue hypotension and consequent hypoperfusion.

Table 2 below shows the infusion rates corresponding to the recommended initial and maximal doses (0.3 mcg/kg/min and 10 mcg/kg/min, respectively) for both adult and pediatric patients of various weights. This infusion rate may be lower than indicated in the table for patients less than 10 kg. Note that when the concentration used in a given patient is changed, the tubing is still filled with a solution at the previous concentration.

Avoidance of cyanide toxicity: As described in CLINICAL PHARMACOLOGY above, when more than 500 mcg/kg of sodium nitroprusside is administered faster than 2 mcg/kg/min, cyanide is generated faster than the unaided patient can eliminate it. Administration of sodium thiosulfate has been shown to increase the rate of cyanide processing, reducing the hazard of cyanide toxicity. Although toxic reactions to sodium thiosulfate have not been reported, the co-infusion regimen has not been extensively studied, and it cannot be recommended without reservation. In one study, sodium thiosulfate appeared to potentiate the hypotensive effects of sodium nitroprusside.

Co-infusions of sodium thiosulfate have been administered at rates of 5 to 10 times that of sodium nitroprusside. Care must be taken to avoid the indiscriminate use of prolonged or high doses of sodium nitroprusside with sodium thiosulfate as this may result in thiocyanate toxicity and hypovolemia. Incautious administration of sodium nitroprusside must still be avoided, and all of the precautions concerning sodium nitroprusside administration must still be observed.

Consideration of methemoglobinemia and thiocyanate toxicity: Rare patients receiving more than 10 mg/kg of sodium nitroprusside will develop methemoglobinemia other patients, especially those with impaired renal function, will predictably develop thiocyanate toxicity after prolonged, rapid infusions. In accordance with the descriptions in ADVERSE REACTIONS above, patients with suggestive findings should be tested for these toxicides.

WARNING: Do not use flexible container in series connections.

Sodium Nitroprusside Injection is supplied in amber-colored, single-dose 50 mg/2 mL Fliptop Vials

NDC 17478-014-02 2 mL Single-dose vial

Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

To protect Sodium Nitroprusside Injection from light, it should be stored in its carton until it is used.

Akorn
Manufactured for: Akorn, Inc.
Lake Forest, IL 60045
PC4952B         Rev. 11/16

NDC 17478-014-02

Sodium

Nitroprusside

Injection

50 mg/2 mL Vial

(25 mg/mL)

FOR I.V. INFUSION ONLY

2 mL Single-dose Vial

NDC 17478-014-02

Sodium

Nitroprusside

Injection

50 mg/2 mL Vial

(25 mg/mL)

FOR INTRAVENOUS INFUSION ONLY.

Must be diluted.

Potent drug: Monitor blood

pressure before and during

administration.

2 mL Single-dose Vial

Rx only Akorn Logo