Nitric Oxide (Inhalation-Local)


VA CLASSIFICATION
Primary: CV402

Commonly used brand name(s): INOmax.

Another commonly used name is:
Mononitrogen Monoxide{01} Nitrogen Monoxide{01} Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive (pulmonary) —

Indications

Accepted

Pulmonary hypertension (treatment)—Nitric oxide, together with ventilatory support or other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure due to pulmonary hypertension.{02}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Nitric oxide is a gas with the chemical formula of NO.{02}
Molecular weight—
    30.01{01}

Mechanism of action/Effect:

Nitric oxide is an endogenous compound that relaxes vascular smooth muscle by binding intracellularly to heme moieties of soluble guanylate cyclase; this activates guanylate synthase, resulting in increased synthesis of cyclic guanosine 3',5'-monophosphate (cGMP) and subsequent smooth muscle vasodilation. It increases the partial pressure of arterial oxygen (PaO2) by dilating the better ventilated areas of the lung and redistributing blood flow from areas with low ventilation/perfusion (V/Q) ratios to areas with normal ratios. {02}


Other actions/effects:

Nitric oxide reduces the pulmonary vascular resistance in neonates with persistent pulmonary hypertension of the newborn (PPHN) and improves oxygenation and reduces the right-to-left shunting of blood flow through the patent ductus arteriosus and foramen ovale. {02}

Absorption:

Nitric oxide is absorbed systemically after inhalation. {02}

Distribution:

After inhalation, nitric oxide distributes into the pulmonary capillary bed and rapidly inactivated by combining with hemoglobin. Systemic effects are clinically insignificant. {02}

Biotransformation:

Most nitric oxide combines with oxyhemoglobin in a 60–100% oxygen saturated environment to form methemoglobin and nitrate. In a low oxygen saturated environment, nitric oxide combines with deoxyhemoglobin to form nitrosylhemoglobin, which in the presence of oxygen forms nitrogen oxides and methemoglobin. In the lungs, nitric oxide combines with oxygen and water to form nitrogen dioxide and nitrite, which interacts with oxyhemoglobin to form methemoglobin and nitrate. The end products of nitric oxide that enter the systemic circulation are methemoglobin and nitrate.{02}

Half-life:

Elimination— 2–6 seconds{06}

Onset of action:

Pulmonary hypertension, inhalation: 1 to 3 minutes {07}.

Elimination:
    Renal, >70% of the nitric oxide dose is excreted as nitrate. Clearance of nitrate approaches the rate of glomerular filtration. {02}


Precautions to Consider

Carcinogenicity

Long-term studies in animals to evaluate the carcinogenic potential of nitric oxide have not been done. {02}

Mutagenicity

Nitric oxide has shown to be genotoxic in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. {02}

Pregnancy/Reproduction
Fertility—
Studies in animals and humans have not been done. {02}

Pregnancy—
Studies have not been done in animals and humans. {02}

FDA Pregnancy Category C {02}

Breast-feeding

It is not known whether nitric oxide is distributed into breast milk. Studies in the adult population have not been done. {02}

Pediatrics

Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of nitric oxide in children.


Geriatrics


No information is available on the relationship of age to the effects of nitric oxide in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Nitroglycerin or
Nitroprusside    (concurrent use of nitric oxide donor compounds may increase the risk of developing methemoglobinemia {02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Neonates who are dependent on right-to-left shunting of blood    (nitric oxide may worsen the condition of these patients)


Risk-benefit should be considered when the following medical problems exist


Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Methemoglobin, serum    (should be monitored periodically during therapy{02})


» Nitrogen dioxide    (concentrations of nitric oxide and nitrogen dioxide should be monitored continuously with properly calibrated analysis device with alarms)

{02}
» Partial pressure of arterial oxygen (PaO 2)    (should be monitored within 4 hours after initiation of therapy and periodically throughout treatment to evaluate whether oxygenation has improved and dosage can be reduced{02})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Atelectasis (coughing; difficult breathing)
    
cellulitis (swollen area that feels warm and tender)
    
hematuria (blood in urine; lower back pain; pain or burning while urinating )
    
hyperglycemia (drowsiness; fruit-like breath odor; increased urination; unusual thirst)
    
hypotension (blurred vision; confusion dizziness, faintness, or lightheadedness when getting up from a lying or sitting position sudden ; unusual sweating; tiredness or weakness )
    
infection and
sepsis (chills; fever; fast heartbeat)
    
stridor ( harsh, high-pitched sound during breathing)
    
withdrawal (chest pain; difficulty in breathing )
{02}
Incidence rare
    
Gastrointestinal bleeding (black or tarry stools; blood in stools)
    
intracranial hemorrhage, periventricular leukomalacia, or cerebral infarction (headache ; numbness; sensation that you or surroundings are spinning; aphasia or dysarthria (speech disorder affecting pronunciation, reading, and writing skills)
    
pulmonary hemorrhage (coughing up blood or bloody mucus)
    
seizures ( convulsions)
{02}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Acute lung injury (coughing; shortness of breath )—due to exposure to increased level of nitrogen dioxide
    
methemoglobinemia (bluish-colored lips, fingernails, palms; dark urine; difficulty breathing; dizziness or lightheadedness; fatigue; fever; headache; pale skin; rapid heart rate; shortness of breath; sore throat; unusual bleeding or bruising; unusual tiredness or weakness)

{02}
Treatment of overdose
Nitric oxide dose should be reduced or discontinued when nitrogen dioxide levels are >3 parts per million or methemoglobin levels are >7%.{02}


Specific treatment:
Administer intravenous ascorbic acid, intravenous methylene blue, or blood transfusion if methemoglobinemia does not resolve after reduction or discontinuation of nitric oxide therapy. {02}

See Methylene Blue (Systemic) monograph for specific dosing guidelines.



Monitoring:
May include monitoring of serum methemoglobin and nitric oxide levels in the Y-piece proximal to the patient.{02}



General Dosing Information

For inhalation dosing forms:
Additional therapies, such as surfactant, high-frequency oscillatory, or mechanical ventilation, vasodilators, intravenous fluids, and bicarbonate therapy, should be used with nitric oxide to maximize blood oxygenation (PaO2). {02}

The nitric oxide delivery system must provide a constant predetermined concentrations of nitric oxide throughout the respiratory cycle.{02}

Nitric oxide therapy should not be stopped abruptly as it may result in an increase in pulmonary artery pressure and/or worsening of PaO 2. Treatment should be discontinued and weaned cautiously.{02}

A backup battery power supply and a reserve nitric oxide delivery system should be available in the event of a power failure. {02}


Inhalation Dosage Forms

NITRIC OXIDE GAS

Usual Pediatric Dose
Pulmonary hypertension
Term and near-term neonates (>34 weeks): inhalation, 20 parts per million (ppm) for 14 days or until the oxygen desaturation has been resolved.{02}

In clinical trial, dose was reduced to 5 ppm as tolerated in patients whose oxygenation improved after 4 hours of treatment.{02}


Usual pediatric prescribing limits
20 ppm.

Doses up to 80 ppm has been used but usually ineffective in those patients who did not improve at the 20 ppm dose. The risk of methemoglobinemia and elevated nitrogen dioxide levels increased significantly at doses >20 ppm.{02}

Strength(s) usually available
U.S.—


100 ppm in nitrogen (Rx) [INOmax ( Size D, portable aluminum cylinders)]


800 ppm in nitrogen (Rx) [INOmax ( Size D, portable aluminum cylinders)]


100 ppm in nitrogen (Rx) [INOmax ( Size 88, aluminum cylinders)]


800 ppm in nitrogen (Rx) [INOmax ( Size 88, aluminum cylinders)]

Canada—
Not commercially available.

Packaging and storage:
Store at 25 °C (77 °F) with excursion permitted between 15 and 30 °C (59 and 86 °F).{02}


Caution:
The Occupational Safety and Health Administration (OSHA) exposure limit for nitric oxide is 25 ppm, and for nitrogen dioxide is 5 ppm.{02}



Developed: 03/08/2000



References
  1. Parfitt, K (ed): Martindale, The Complete Drug Reference, 32nd ed. Pharmaceutical Press, London, UK, 1999:p.923.
  1. Product Information: INOmax™, nitric oxide, INO Therapeutics, Clinton, NJ, rev. 12/99, reviewed 2/2000.
  1. Not used.
  1. Not used.
  1. Not used.
  1. Higenbottam T: Inhaled nitric oxide: a magic bullet? Q J Med 1993; 86:555-558.
  1. Roberts JD, Lang P, Bigatello LM et al: Inhaled nitric oxide in congenital heart disease. Circulation 1993; 87:447-453.
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