ALPROSTADIL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Dilution for Intravenous or Intra-arterial Infusion
-Dilute 1 mL (500 mcg) of the concentrate in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to an approximate concentration of 2 to 20 mcg/mL.
-When using a device with a volumetric infusion chamber, add the proper amount of diluent to the chamber first and then add the concentrate. Avoid direct contact of the concentrate with the wall of the plastic volumetric infusion chamber, which may change the appearance of the chamber and create a hazy solution. If this occurs, replace the solution and volumetric infusion chamber.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 5 mcg/mL or 10 mcg/mL.
-Maximum concentration should not exceed 20 mcg/mL.
-Storage: Store diluted solution at room temperature for up to 24 hours.
Intravenous Administration
Continuous Intravenous Infusion
-Infusion into a large vein is the preferred route of administration.
-The infusion rate depends on the concentration of the final solution and the desired dosage.
-Periodically monitor IV site; ensure reliable IV access because the duration of effect is short and a significant interruption in therapy could have serious adverse consequences.
-Closely monitor respiratory status, cardiovascular status, and temperature during alprostadil administration. Facilities and equipment for assisted ventilation should be readily available.

Other Injectable Administration
Intra-arterial Administration
Intra-arterial Infusion (i.e., umbilical artery catheter positioned at the ductal opening)
-The infusion rate depends on the concentration of the final solution and the desired dosage.
-Ensure reliable UAC access because the duration of alprostadil's effect is short and a significant interruption in therapy could have serious adverse consequences.
-Flushing may be the result of an incorrectly positioned intra-arterial catheter; assess catheter placement if flushing occurs.
-Closely monitor respiratory status, cardiovascular status, and temperature during alprostadil administration. Facilities and equipment for assisted ventilation should be readily available.

Apnea occurs in approximately 10% to 12% of neonates and infants with congenital heart defects treated with alprostadil and is most commonly seen in neonates weighing less than 2 kg at birth. Apnea usually occurs during the first hour of drug infusion. Monitor respiratory status closely in all patients receiving an alprostadil infusion and have ventilatory assistance and trained personnel immediately available. Other respiratory adverse reactions that occur in less than 1% of patients include bradypnea, bronchial wheezing, hypercapnia, respiratory depression, respiratory distress, and tachypnea.

Fever is one of the most common adverse effects associated with alprostadil infusions occurring in 14% of infants. Fever may also be a sign of toxicity; if fever occurs, reduce the infusion rate until it resolves. Monitor temperature in all patients. Seizures have also been reported in approximately 4% of infants. Other central nervous system adverse reactions that have been reported in less than 1% of patients receiving IV alprostadil include: cerebral bleeding, hyperextension of the neck, irritability, hypothermia, jitteriness, lethargy, and stiffness.

In neonates receiving infusions of alprostadil, sinus bradycardia (7%), hypotension (4%), sinus tachycardia (3%), cardiac arrest (1%), and edema (1%) were the most common cardiovascular adverse reactions. Hypotension and/or bradycardia may be a sign of excessive dosage. If hypotension occurs, reduce the infusion rate until it subsides. If bradycardia occurs, discontinue the infusion and provide appropriate supportive care. Use caution when restarting the infusion. Other cardiovascular adverse reactions reported in < 1% neonates receiving alprostadil infusions include congestive heart failure, hyperemia, second degree heart block (AV block), shock, spasm of the right ventricle infundibulum, supraventricular tachycardia (SVT), and ventricular fibrillation.

Flushing occurs in approximately 10% of neonates receiving alprostadil infusions and is more common with intra-arterial infusions. When flushing occurs in a patient receiving alprostadil via umbilical artery catheter (UAC), assess the catheter placement because flushing is often the result of incorrect catheter placement. Flushing may also be a symptom of excessive dosage.

Disseminated intravascular coagulation (DIC) has been reported in approximately 1% of patients receiving alprostadil infusions. In addition, anemia, bleeding, and thrombocytopenia have been reported in < 1%, of patients receiving infusions of alprostadil. Alprostadil is known to inhibit platelet aggregation; carefully monitor for signs of bleeding. Sepsis has been reported in about 2% of patients and peritonitis in < 1%. Leukocytosis is also associated with alprostadil infusions.

GI obstruction (gastric outlet obstruction) secondary to antral hyperplasia is the most serious GI adverse effect associated with parenteral alprostadil. The effect appears to be related to the duration of therapy and cumulative dose. Monitor patients who receive alprostadil for > 120 hours for evidence of antral hyperplasia and gastric outlet obstruction, and use the lowest effective dose. Diarrhea is the most common gastrointestinal adverse reaction (occurs in about 2% of patients); gastric regurgitation and hyperbilirubinemia were reported in < 1% of patients.

Skeletal changes have been associated with alprostadil use in infants. Cortical proliferation of the long bones has been observed during long-term infusion of alprostadil; the cortical proliferation regressed after withdrawal of the drug.

Renal and metabolic adverse effects occasionally occur with alprostadil therapy and warrant monitoring. Hypokalemia has been reported in approximately 1% of patients, and < 1% of patients in clinical trials experienced anuria, hematuria, hypoglycemia, and hyperkalemia. In a case series of 9 neonates who received prolonged alprostadil therapy for > 14 days, hypokalemia was reported. After 3 neonates received 20 days of treatment with >= 0.05 mcg/kg/min, marked hypokalemia developed in all 3 neonates. Hyponatremia and hypercalciuria developed in 2 out of 3 neonates who received alprostadil for > 40 days.

Post-mortem tissue sections of the ductus and pulmonary arteries from infants treated with alprostadil infusions at the usual doses for 10 hours to 12 days and who died of causes unrelated to ductus structural weakness have shown intimal lacerations, a decrease in medial muscularity and disruption of the medial and internal elastic lamina. Localized and aneurysmal dilatations and vessel wall edema also were noted. The incidence and clinical implications of these structural alterations has not been defined.

Always select the proper product for administration of alprostadil to pediatric patients. Alprostadil injection formulations intended for intracavernosal injection (e.g., Caverject vials) contain benzyl alcohol and should not be used in patients with benzyl alcohol hypersensitivity or in neonates. Benzyl alcohol has been associated with reports of fatal 'gasping syndrome' in neonates; symptoms include a striking onset of gasping respiration, CNS depression, and metabolic acidosis. The minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic and renal capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. Intracavernosal injections of aloprostadil are not indicated for children or neonates and should not be substituted for intravenous alprostadil injection in these populations.

Apnea is experienced by approximately 10% to 12% of neonates and infants with congenital heart disease defects treated with intravenous alprostadil. Apnea is most often seen in premature neonates weighing less than 2 kg at birth and usually occurs during the first hour of drug infusion. Respiratory status should be monitored throughout treatment and neonatal use of alprostadil requires a specialized care setting and should only be undertaken where ventilatory assistance is immediately available. Alprostadil should be used cautiously in neonates and infants with respiratory depression.

The intravenous administration of alprostadil to neonates may result in GI obstruction (gastric outlet obstruction) secondary to antral hyperplasia. Duration of therapy and the accumulation of the drug appears to be related to this adverse effect. Careful monitoring is recommended in neonates receiving alprostadil for greater than 120 hours. Alprostadil should be administered at the lowest effective dose and for the shortest length of time. The risks of prolonged infusion should be weighed against the potential benefits to the infant.

Alprostadil intravenous infusions should not be used in neonates with neonatal respiratory distress syndrome. In these neonates, the ductus arteriosus must close in order to prevent overload of the pulmonary circulation. A differential diagnosis between neonatal respiratory distress syndrome and cyanotic heart disease (restricted pulmonary blood flow) should be made prior to initiating alprostadil therapy. If full diagnostic facilities are not immediately available, cyanosis (pO2 less than 40 torr) and restricted pulmonary blood flow apparent on an X-ray are appropriate indicators of congenital heart defects.

Alprostadil inhibits platelet aggregation and therefore can increase the risk of bleeding. Use intravenous alprostadil cautiously in patients with bleeding tendencies or receiving anticoagulant therapy. Additionally, caution should be used in patients at risk of coagulopathy.

Alprostadil injection can cause hypotension. Arterial pressure should be monitored periodically via umbilical artery catheter, auscultation, or Doppler transducer. If arterial pressure falls significantly, decrease the rate of the infusion immediately.

Description: Alprostadil is a naturally occurring prostaglandin E1. Alprostadil and other prostaglandins in the E series are naturally present in the placenta and ductus arteriosus of the fetus. The E-type prostaglandins vasodilate arterioles by direct relaxation of vascular smooth muscle. Other pharmacologic effects include an increase in cardiac output, dilation of both systemic and pulmonary vessels, dilation of the ductus arteriosus, inhibition of platelet aggregation, relaxation of bronchial muscle, increase in renal blood flow, and delay of gastric emptying time. Intravenous alprostadil is used in neonates with obstruction of right or left ventricular outflow to maintain the patency of the ductus arteriosus up until the time of corrective or palliative surgery. Alprostadil is generally more effective in those neonates with low pretreatment blood PO2 and who are 4 days old or younger. In neonates older than 4 days, there is a decrease in ductal smooth muscle reactivity due to postnatal involutional changes in the wall of the ductus arteriosus. Intravenous alprostadil requires respiratory monitoring during administration because apnea develops in 10% to 12% of neonates. Alprostadil is FDA approved in pediatric patients as young as neonates.

General dosing information:
-Alprostadil is indicated for palliative therapy to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenial heart defects such as pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, or transposition of the great vessels, and who depend upon the patent ductus for survival.
-Monitor hemodynamic status, respiratory status, and temperature in all patients receiving alprostadil. If pyrexia or hypotension occur, reduce the infusion rate until these symptoms subside.
-In neonates with restricted pulmonary blood flow (cyanotic lesions), measure efficacy by monitoring improvement in blood oxygenation. In neonates with restricted systemic blood flow (acyanotic lesions), measure efficacy by improvement in systemic blood pressure and blood pH.

For ductus arteriosis maintenance to maintain patency in neonates with patent ductus-dependent congential heart defects until palliative or corrective surgery can be performed:
Intravenous or Intra-Arterial dosage:
Neonates: 0.05 to 0.1 mcg/kg/minute continuous IV or intra-arterial (umbilical) infusion, initially. After a therapeutic response is achieved (i.e., increased pO2 in infants with restricted pulmonary blood flow or increased systemic blood pressure and blood pH in infants with restricted blood flow), reduce the dose to the lowest possible dose that maintains the response. Dose may be decreased from 0.1 to 0.05 to 0.025 to 0.01 mcg/kg/minute; if response to 0.05 mcg/kg/minute is inadequate, dosage may be increased. Usual dose: 0.01 to 0.1 mcg/kg/minute. 0.01 to 0.02 mcg/kg/minute may effectively maintain patency while minimizing the risk of apnea. Max: 0.4 mcg/kg/minute; however, high infusion rates do not usually produce greater effects and have a higher incidence of adverse effects.
Infants: 0.05 to 0.1 mcg/kg/minute continuous IV or intra-arterial (umbilical) infusion, initially. After a therapeutic response is achieved (i.e., increased pO2 in infants with restricted pulmonary blood flow or increased systemic blood pressure and blood pH in infants with restricted blood flow), reduce the dose to the lowest possible dose that maintains the response. Dose may be decreased from 0.1 to 0.05 to 0.025 to 0.01 mcg/kg/minute; if response to 0.05 mcg/kg/minute is inadequate, dosage may be increased. Usual dose: 0.01 to 0.1 mcg/kg/minute. 0.01 to 0.02 mcg/kg/minute may effectively maintain patency while minimizing the risk of apnea. Max: 0.4 mcg/kg/minute; however, high infusion rates do not usually produce greater effects and have a higher incidence of adverse effects.

Maximum Dosage Limits:
-Neonates
0.4 mcg/kg/minute IV.
-Infants
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Alprostadil (prostaglandin E1) is one of a family of naturally occurring acidic lipids with various pharmacologic effects. Vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle are among the most notable of these effects. In the treatment of ductus arteriosus-dependent congenital heart defects, alprostadil maintains ductal patency by relaxing the smooth muscles of the ductus arteriosus. Alprostadil is only effective if given prior to complete anatomic closure of the ductus arteriosus. Administration of alprostadil to neonates with cyanotic congenital heart defects (restricted pulmonary blood flow) results in an increase in pulmonary blood flow and/or increase in mixing between the systemic and pulmonary circulation which leads to a temporary increase in arterial oxygen partial pressure (PO2) and oxygen saturation. The response of the cyanotic neonate to alprostadil therapy is also inversely related to pretreatment PO2. The greatest response appears to be in those neonates with low pretreatment PO2 (less than 20 torr), narrowing ductus arteriosus, and who are 4 days old or younger. Neonates with PO2 values of 40 torr or more usually have little response to alprostadil. In neonates with restricted systemic blood flow, administration of alprostadil can result in prevention or correction of acidemia, increased cardiac output with increased systemic blood pressure, increased femoral pulse volume, increased renal blood flow and function, decreased gradient of descending to ascending aortic blood pressures (in neonates with coarctation of the aorta), and/or decreased ratio of pulmonary artery pressure to descending aortic pressure (in neonates with interruption of the aortic arch). Unlike in cyanotic neonates, the efficacy of alprostadil in acyanotic neonates does not depend on age or pretreatment PO2.

Pharmacokinetics: Alprostadil is administered by continuous intravenous infusion. Alprostadil is bound primarily to albumin (81%) and no significant binding to erythrocytes or white blood cells occurs. Alprostadil is rapidly metabolized; up to 80% of circulating alprostadil may be metabolized in one pass through the lungs primarily by beta and omega oxidation. It is completely metabolized to several metabolites that are primarily excreted in the urine. Twenty-four hours after administration, excretion is complete; no unchanged alprostadil has been found in the urine and there is no evidence of tissue retention of alprostadil.

Affected cytochrome P450 isoenzymes: none