NIPRIDE RTU (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on animal data and mechanism of action, sodium nitroprusside may lead to cyanide exposure and potential adverse effects in the fetus [see Clinical Pharmacology (12.3) and Clinical Considerations]. Published post-marketing reports with sodium nitroprusside use in pregnant women are insufficient to inform a drug-associated risk of adverse pregnancy related outcomes [see Data]. There were no animal reproduction studies conducted with sodium nitroprusside during pregnancy. However, there are published studies in pregnant sheep that demonstrate that nitroprusside crosses the placenta and that fetal cyanide levels were dose-related to maternal levels of sodium nitroprusside [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use and large doses of sodium nitroprusside during pregnancy may result in cyanide toxicity that may be fatal to the fetus. In the unusual case that there is no appropriate alternative to therapy with sodium nitroprusside for a particular patient, apprise the mother of the potential risk to the fetus [see Warnings and Precautions (5.2)].

Data

Human Data

A small number of cases have reported adverse events, including stillbirths, in pregnant women with severe pregnancy-induced hypertension who were treated with sodium nitroprusside. However, methodological limitations, including small sample size and limited information on sodium nitroprusside dosage and duration of treatment, as well as the cyanide concentration in maternal blood or fetal tissue, preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of sodium nitroprusside during pregnancy.

Animal Data

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.

8.2 Lactation

Risk Summary

There is no information about the presence of sodium nitroprusside in human milk, the effects on the breastfed infant, or the effects on milk production. Thiocyanate, one of sodium nitroprusside’s metabolites, is present in human milk. It is unclear how long, if ever, levels of thiocyanate in milk are clinically relevant.

8.4 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 Studies (14)].

10 OVERDOSAGE

Overdosage of nitroprusside can be manifested as excessive hypotension or cyanide toxicity [see Warnings and Precaution (5.1, 5.2)] or as thiocyanate toxicity [see Warnings and Precautions (5.3)]. 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.

11 DESCRIPTION

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

structure
(click image for full-size original)

Sodium Nitroprusside has molecular formula Na2 [Fe(CN)5 NO] • 2H2 O and molecular weight of 297.95. Dry sodium nitroprusside is a reddish-brown powder, soluble in water.

Sodium nitroprusside solution is rapidly degraded by trace contaminants, often with resulting color changes [see Dosage and Administration (2.1)].

NIPRIDE ® RTU is supplied as a sterile, unpreserved, colorless to red-brown solution packaged in a single-use 100-mL vial. Each 100 mL of solution in vial contains 50 mg of sodium nitroprusside (0.5 mg/mL), 900 mg of sodium chloride, USP (9 mg/mL), in sterile water for injection, USP.

NIPRIDE ® RTU is also supplied as a sterile, unpreserved, colorless to red-brown solution packaged in a single-use 100-mL vial. Each 100 mL of solution in vial contains 20 mg of sodium nitroprusside (0.2 mg/mL), 900 mg of sodium chloride, USP (9 mg/mL), in sterile water for injection, USP.

NIPRIDE ® RTU is also supplied as a sterile, unpreserved, colorless to red-brown solution packaged in a single-use 50-mL vial. Each 50 mL of solution in vial contains 10 mg of sodium nitroprusside (0.2 mg/mL), 450 mg of sodium chloride, USP (9 mg/mL), in sterile water for injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sodium nitroprusside interacts with oxyhemoglobin to produce methemoglobin, cyanide, and nitric oxide (NO). NO then reacts with guanylate cyclase in vascular smooth muscle to produce cGMP that reduces intracellular calcium concentrations resulting in relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins. Other smooth muscle (e.g., uterus, duodenum) is not affected. Sodium nitroprusside is more active on veins than on arteries, but this selectivity is much less marked than that of nitroglycerin. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs.

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