Sodium Nitroprusside

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Sodium Nitroprusside Prescribing Information

Sodium Nitroprusside Injection is not suitable for direct injection. The solution must be further diluted in sterile 5% dextrose injection before infusion.

Sodium Nitroprusside Injection can cause precipitous decreases in blood pressure (see

DOSAGE AND ADMINISTRATION

). In patients not properly monitored, these decreases can lead to irreversible ischemic injuries or death. Sodium nitroprusside should be used only when available equipment and personnel allow blood pressure to be continuously monitored.

Except when used briefly or at low (< 2 mcg/kg/min) infusion rates, sodium nitroprusside gives rise to important quantities of cyanide ion, which can reach toxic, potentially lethal levels (see

WARNINGS

). The usual dose rate is 0.5-10 mcg/kg/min, but infusion at the maximum dose rate should never last more than 10 minutes. If blood pressure has not been adequately controlled after 10 minutes of infusion at the maximum rate, administration of sodium nitroprusside should be terminated immediately.

Although acid-base balance and venous oxygen concentration should be monitored and may indicate cyanide toxicity, these laboratory tests provide imperfect guidance.

Sodium nitroprusside is indicated for the immediate reduction of blood pressure of adult and pediatric patients in hypertensive crises. Concomitant longer-acting antihypertensive medication should be administered so that the duration of treatment with sodium nitroprusside can be minimized.

Sodium nitroprusside is also indicated for producing controlled hypotension in order to reduce bleeding during surgery.

Sodium nitroprusside is also indicated for the treatment of acute congestive heart failure.

Dilution to proper strength for infusion:

Depending on the desired concentration, the solution containing 50 mg of sodium nitroprusside must be further diluted in 250-1000 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 injection. 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 injection 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.

Table 2: Infusion Rates (mL/hour) to Achieve Initial (0.3 mcg/kg/min) and Maximal (10 mcg/kg/min) Dosing of sodium nitroprusside injection

Volume sodium nitroprusside injection concentration		250 mL 50 mg 200 mcg/mL		500 mL 50 mg 100 mcg/mL		1000 mL 50 mg 50 mcg/mL
pt	weight
kg	lbs	init	max	init	max	init	max
10	22	1	30	2	60	4	120
20	44	2	60	4	120	7	240
30	66	3	90	5	180	11	360
40	88	4	120	7	240	14	480
50	110	5	150	9	300	18	600
60	132	5	180	11	360	22	720
70	154	6	210	13	420	25	840
80	176	7	240	14	480	29	960
90	198	8	270	16	540	32	1080
100	220	9	300	18	600	36	1200

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 5-10 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 toxicities.

WARNING:

Do not use flexible container in series connections.

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.

The most important adverse reactions to sodium nitroprusside are the avoidable ones of excessive hypotension and cyanide toxicity, described above under

WARNINGS.

The adverse reactions described in this section develop less rapidly and, as it happens, less commonly.

Methemoglobinemia:

As described in

CLINICAL PHARMACOLOGY

above, sodium nitroprusside infusions can cause sequestration of hemoglobin as methemoglobin. The back-conversion process is normally rapid, and clinically significant methemoglobinemia (>10%) is seen only rarely in patients receiving sodium nitroprusside injection. Even patients congenitally incapable of back-converting methemoglobin should demonstrate 10% methemoglobinemia only after they have received about 10 mg/kg of sodium nitroprusside, and a patient receiving sodium nitroprusside at the maximum recommended rate (10 mcg/kg/min) would take over 16 hours to reach this total accumulated dose.

Methemoglobin levels can be measured by most clinical laboratories. The diagnosis should be suspected in patients who have received >10 mg/kg of sodium nitroprusside and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is 1-2 mg/kg of methylene blue, administered intravenously over several minutes. In patients likely to have substantial amounts of cyanide bound to methemoglobin as cyanmethemoglobin, treatment of methemoglobinemia with methylene blue must be undertaken with extreme caution.

Thiocyanate Toxicity:

As described in

CLINICAL PHARMACOLOGY

above, most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. When cyanide elimination is accelerated by the co-infusion of thiosulfate, thiocyanate production is increased.

Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 mmol/L (60 mg/L). Thiocyanate toxicity is life-threatening when levels are 3 or 4 times higher (200 mg/L).

The steady-state thiocyanate level after prolonged infusions of sodium nitroprusside is increased with increased infusion rate, and the half-time of accumulation is 3-4 days. To keep the steady-state thiocyanate level below 1 mmol/L, a prolonged infusion of sodium nitroprusside should not be more rapid than 3 mcg/kg/min; in anuric patients, the corresponding limit is just 1 mcg/kg/min. When prolonged infusions are more rapid than these, thiocyanate levels should be measured daily.

Physiologic maneuvers (e.g., those that alter the pH of the urine) are not known to increase the elimination of thiocyanate. Thiocyanate clearance rates during dialysis, on the other hand, can approach the blood flow rate of the dialyzer.

Thiocyanate interferes with iodine uptake by the thyroid.

Abdominal pain, apprehension, diaphoresis, "dizziness," headache, muscle twitching, nausea, palpitations, restlessness, retching, and retrosternal discomfort have been noted when the blood

pressure was too rapidly reduced. These symptoms quickly disappeared when the infusion was slowed or discontinued, and they did not reappear with a continued (or resumed) slower infusion.

Other adverse reactions reported are:

Cardiovascular:

Bradycardia, electrocardiographic changes, tachycardia.

Dermatologic:

Rash.

Endocrine:

Hypothyroidism.

Gastrointestinal:

Ileus.

Hematologic:

Decreased platelet aggregation.

Neurologic:

Increased intracranial pressure.

Miscellaneous:

Flushing, venous streaking, irritation at the infusion site.

To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1- 800-417-9175 or FDA at 1-800 -FDA-1088 or www.fda.gov/medwatch

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, 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.

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Sodium Nitroprusside

Sodium Nitroprusside Prescribing Information

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