Pharmacia & Upjohn
Action And Clinical Pharmacology: Alprostadil (also known as prostaglandin E1) relaxes the ductus arteriosus in early postnatal life and supports its patency when continuously infused i.v. or intra-arterially in neonates with congenital heart defects who depend on a patent ductus for survival. The desired pharmacological effects are obtained with an initial dosage of 0.1 µg/kg/minute. Higher doses do not offer added benefit. Postnatally the ductus arteriosus rapidly loses its responsiveness to alprostadil and consequently alprostadil appears to be most effective within 96 hours after birth, particularly when the pre-infusion arterial p02 is less than 40 mm Hg.
The estimated half-life of alprostadil is 5 to 10 minutes. I.V. administered alprostadil is rapidly distributed and metabolized and the pulmonary vascular bed removes about 68% of the drug in a single pass. Alprostadil is weakly bound to serum albumin. The major route of elimination of alprostadil and its metabolites is via the kidneys. In laboratory animals and humans, alprostadil can lower blood pressure, probably by relaxing the smooth muscle of the cardiovascular system. Alprostadil can elevate body temperature and this effect has been observed in some neonates receiving the drug.
Indications And Clinical Uses: To temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenital heart defects and who depend upon a patent ductus arteriosus for survival.
Alprostadil should be administered only by medically trained personnel in facilities in which pediatric patients can receive or have access to pediatric intensive care.
Contra-Indications: In the following patients: Cyanotic neonates with persistent fetal circulation. Neonates with total anomalous pulmonary venous return below the diaphragm, neonates with polysplenia or asplenia in whom pulmonary atresia is combined with anomalous pulmonary venous return which may be obstructed.
In such patients alprostadil may precipitate pulmonary edema because of increased pulmonary blood flow.
Manufacturers’ Warnings In Clinical States: Approximately 10 to 12% of neonates treated with alprostadil experienced apnea. Apnea is seen most often in neonates weighing less than 2 kg at birth and usually appears during the first hour of drug infusion. Therefore alprostadil should be used in facilities with immediately available intensive care for intubation and assisted ventilation.
Pathologic studies of the ductus arteriosus and pulmonary arteries of infants with prostaglandin E1 have disclosed histologic changes compatible with a weakening effect upon these structures. The specificity or clinical relevance of these findings is not known.
Cortical proliferation of the long bones has followed long-term infusions of alprostadil in infants. The proliferation appeared to regress after withdrawal of the drug.
The administration of alprostadil to neonates may result in gastric outlet obstruction secondary to antral hyperplasia. This effect appears to be related to duration of therapy and cumulative dose of the drug. Neonates receiving alprostadil at recommended doses for more than 120 hours should be closely monitored for evidence of antral hyperplasia and gastric outlet obstruction.
Alprostadil should be infused for the shortest period of time at the lowest dose which will produce the desired effects. Risk of long-term treatment infusion of alprostadil should be weighed against the possible benefits that critically ill infants may derive from its administration.
Precautions: Alprostadil should be used with caution in infants with suspected bleeding tendencies.
Care should be taken to avoid the use of alprostadil in neonates with respiratory distress syndrome (hyaline membrane disease), which sometimes can be confused with cyanotic heart disease. If full diagnostic facilities are not immediately available, cyanosis (p02 less than 40 mm Hg) and restricted pulmonary blood flow apparent on an x-ray are good indicators of congenital heart defects.
In all neonates, blood pressure should be monitored by appropriate methods such as an umbilical artery catheter, or by a Doppler transducer. Should arterial pressure fall significantly, reduce the rate of infusion immediately.
Since alprostadil appears most effective within 96 hours after birth due to a decreasing responsiveness of the ductus arteriosus with time after birth, every effort should be made to start infusion of the drug during this period.
Long-term carcinogenicity and fertility studies have not been done.
The Ames and Alkaline Elution assays reveal no potential for mutagenesis.
In infants with restricted pulmonary blood flow, the increase in blood oxygenation is inversely proportional to pre-treatment pO2 values; that is, patients with low pO2 values (less than 40 torr) respond best, and patients with high pO2 values (greater than 40 torr) usually have little response.
In infants with restricted pulmonary blood flow, measure efficacy of alprostadil by monitoring an improvement in blood oxygenation. In infants with restricted systemic blood flow, measure efficacy by monitoring improvement of systemic blood pressure and blood pH.
Drug Interactions: No drug interactions have been reported to occur between alprostadil and the standard therapy employed in neonates with congenital heart defects. Standard therapy includes antibiotics, such as penicillin or gentamicin; vasopressors, such as dopamine or isoproterenol; cardiac glycosides; and diuretics, such as furosemide.
Adverse Reactions: In infants whose ductus arterious must be kept patent, the most frequent adverse reactions observed with alprostadil infusion are related to its known pharmacological effects. The following incidences are based on experience in 436 patients.
Cardiovascular System: The most common adverse reactions reported in these patients were flushing 10.1%, bradycardia 6.7%, hypotension 3.9%, tachycardia 2.8%, cardiac arrest 1.1% and edema 1.1%. The following reactions were reported in less than 1% of patients: congestive heart failure, hyperemia, pneumo-pericardium, second degree heart block, shock, spasm of the right infundibulum (conus arteriosus), supraventricular tachycardia, ventricular fibrillation, ventricular hypertrophy, tachyphylaxis.
CNS: The most common adverse reactions reported were fever in 13.8% and seizures in 4.1% of patients. The following reactions were reported in less than 1% of patients: intracranial bleeding, hyper-extension of neck, hyperirritability, hypothermia, jitteriness, lethargy, stiffness.
Respiratory System: The most common adverse reaction reported was apnea in 11.5% of patients. The following reactions were reported in less than 1% of patients: bradypnea, bronchial wheezing, hypercapnia, pneumothorax, respiratory depression, respiratory distress, tachypnea.
Gastrointestinal System: The most common adverse reaction reported was diarrhea in 2.6% of patients. The following reactions were reported in less than 1% of patients: gastric regurgitation, hyperbilirubinemia, peritonitis.
Hematologic: The most common adverse reaction reported was disseminated intravascular coagulation in 1.1% of patients. The following reactions were reported in less than 1% of patients: anemia, bleeding, thrombocytopenia, hypochromic anemia.
Urinary tract: The following reactions were reported in less than 1% of patients: anuria, hematuria, renal failure.
Metabolic: The most common adverse reaction reported was hypokalemia in 1.1% of patients. The following reactions were reported in less than 1% of patients: hypoglycemia, hyperkalemia.
Infection: Sepsis was reported in 1.6% and peritonsillitis in less than 1% of patients.
Ductus arteriosus histological changes: One group of investigators reported edema of the media, separation of the medial components by clear spaces, pathological interruption of the internal elastic lamina, and intimal lacerations some of which extended into the media in the ductus arteriosus of 4 patients.
Cortical proliferation of long bones: Following long term infusion of alprostadil, cortical proliferation of long bones has been reported.
This hypertrophic osteoarthropathy appeared to be reversible on discontinuation of the drug.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Apnea, bradycardia, pyrexia, hypotension and flushing may be signs of drug overdose. If apnea or bradycardia occur, the infusion should be discontinued and the appropriate medical treatment initiated. Caution should be used if the infusion is restarted. If pyrexia or hypotension occur, the infusion rate should be reduced until these symptoms subside. Flushing is usually attributed to incorrect intra-arterial catheter placement and is usually alleviated by repositioning the tip of the catheter.
Dosage And Administration: The initial infusion rate of alprostadil should be 0.1 µg/kg of body weight/minute. When the desired effect on the ductus arteriosus is achieved, decrease infusion to the lowest possible dose while maintaining the desired effect. This may be accomplished by reducing the dosage from 0.1 to 0.05 to 0.025 to 0.01 µg/kilogram of body weight/minute. Although doses up to 0.4 µg/kilogram of body weight/minute have been used, doses above 0.1µg/kilogram of body weight/minute generally do not offer additional benefits.
The preferred route of administration of alprostadil is by continuous i.v. infusion into a large vein. Alternatively, alprostadil may be administered through an umbilical artery catheter placed at the ductal opening. Adverse effects have occurred with both routes of administration, but higher incidence of flushing has been associated with intra-arterial than with i.v. administration.
If undiluted alprostadil comes in direct contact with a plastic container, plasticizers are leached from the sidewalls. The solution may turn hazy and the appearance of the container may change. Should this occur, the solution should be discarded and the plastic container replaced. This appears to be a concentration-dependent phenomenon. To minimize the possibility of haze formation, alprostadil should be added directly to the i.v. infusion solution avoiding contact with the walls of plastic containers.
Dilution Instructions: To prepare infusion solutions, dilute 1 mL of Prostin VR with sterile Sodium Chloride Injection or sterile Dextrose Injection. Dilute to volumes appropriate for the pump delivery system available. Prepare fresh infusion solution every 24 hours. Discard any solution more than 24 hours old.
For administration using a pump capable of delivering small volume constant infusions (i.e., not limited to discrete infusion rates) dissolve 1 mL Prostin VR (500 µg alprostadil) in 25 to 100 mL sterile 0.9% Sodium Chloride injection USP or sterile 5% Dextrose Injection USP to provide a solution containing 500 µg alprostadil. The infusion rate to deliver 0.1 µg/kg of body weight/minute can be calculated as follows:
Infusion rate (mL/hr) = Volume containing 500ug alprostadil x body weight (kg) / 83.3
For administration using an infusion pump limited to discrete infusion rates, infuse 2 to 4 mL/hour. The volume of saline or glucose to be added to the 1 mL Prostin VR is to be calculated as follows:
Volume of saline or glucose needed (mL) = [Pump rate (mL/hr) x 83.3 / Body weight (kg)] – 1
The infusion solution may be mixed conveniently in a graduated mixing chamber inserted between the i.v. bottle and the pump.
Change the dosage from 0.1 µg/kg of body weight/minute to 0.05 µg/kg of body weight/minute by reducing the pump rate to one-half the original rate.
Availability And Storage: Each 1 mL ampul contains: alprostadil 500 µg in anhydrous ethanol. Ampuls of 1 mL. Store in a refrigerator at 2 to 8°C. Prepare fresh dilutions every 24 hours. Discard any dilution more than 24 hours old.
PROSTIN® VR Pharmacia & Upjohn Alprostadil Prostaglandin