NIPRIDE RTU Solution for injection Ref.[10893] Active ingredients: Nitroprusside

5.1 Excessive Hypotension

Sodium nitroprusside, can cause excessive hypotension leading to hypoperfusion of vital organs. Hypotension should resolve within 1-10 minutes after discontinuation of the nitroprusside infusion; during these few minutes, it may be helpful to put the patient into a head-down (Trendelenburg) position to maximize venous return. If hypotension persists more than a few minutes after discontinuation, consider other causes. Elderly patients may be more sensitive to the hypotensive effects of the drug.

5.2 Cyanide Toxicity

Sodium nitroprusside infusions above 2 mcg/kg/min generate cyanide ion (CN¯) faster than the body can normally dispose of it. At the maximum recommended infusion rate of 10 mcg/kg/min, the patient’s ability to buffer CN¯ will be exceeded in less than one hour [see Overdose (10)].

Patients with hepatic dysfunction are more susceptible to cyanide toxicity.

An early manifestation of cyanide toxicity is increasing dosage requirements to maintain blood pressure control. Metabolic acidosis may not be evident for more than an hour after toxic cyanide levels accumulate.

If cyanide toxicity develops, discontinue sodium nitroprusside, and consider specific treatment of cyanide toxicity [see Overdosage (10)].

5.3 Thiocyanate Toxicity

Most of the cyanide produced during metabolism of sodium nitroprusside is eliminated in the form of thiocyanate. Thiocyanate is mildly neurotoxic (tinnitus, miosis, hyperreflexia) at serum levels of 1 mmol/L (60 mg/L). Thiocyanate is life-threatening when levels reach ~200 mg/L. Therefore, routine monitoring of plasma thiocyanate levels is recommended in patients with normal renal function when cumulative sodium nitroprusside doses exceed 7 mg/kg/day. In patients with eGFR <30 mL/min/1.73 m², limit the mean infusion rate to less than 3 mcg/kg/min. In anuric patients, limit the mean infusion rate to 1 mcg/kg/min.

Renal hemodialysis may be used to eliminate thiocyanate in cases of severe toxicity.

5.4 Methemoglobinemia

Sodium nitroprusside infusions cause conversion of hemoglobin to methemoglobin in a dose-dependent manner. Methemoglobin binds oxygen more strongly than does hemoglobin, and when methemoglobin levels are elevated, oxygen release from red blood cells in tissue capillaries may be impaired. However, conversion of methemoglobin back to hemoglobin is normally rapid, and clinically significant methemoglobinemia is infrequent.

Suspect methemoglobinemia 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. Methemoglobinemic blood is chocolate brown, without the expected color change on exposure to air. Methemoglobin levels >10% are considered clinically significant.

When methemoglobinemia is diagnosed, the treatment of choice is 1-2 mg/kg of methylene blue, administered intravenously over several minutes.

5.5 Increased Intracranial Pressure

Like other vasodilators, sodium nitroprusside can cause increases in intracranial pressure.

5.6 Anemia and Hypovolemia with 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, correct pre-existing anemia and hypovolemia prior to administration.

The following adverse reactions are described, or described in greater detail, in other sections:

• Hypotension [see Warnings and Precautions (5.1)]
• Cyanide Toxicity [see Warnings and Precautions (5.2)]
• Thiocyanate Toxicity [see Warnings and Precautions (5.3)]
• Methemoglobinemia [see Warnings and Precautions (5.4)]
• Increased Intracranial Pressure [see Warnings and Precautions (5.5)]
• Anemia and Hypovolemia [see Warnings and Precautions (5.6)]

Less common adverse reactions include:

Cardiovascular: Bradycardia, electrocardiographic changes, tachycardia, palpitations, retrosternal discomfort

Dermatologic: Rash

Endocrine: Hypothyroidism

Gastrointestinal: Ileus, nausea, abdominal pain

Hematologic: Decreased platelet aggregation

Musculoskelatal: Muscle twitching

Neurologic: Increased intracranial pressure, dizziness, headache

Miscellaneous: Flushing, diaphoresis, venous streaking, irritation at the infusion site

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.

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.

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)].