Alprostadil (Systemic)


VA CLASSIFICATION
Primary: HS200


Note: For information pertaining to use of alprostadil for diagnosis and treatment of impotence, see Alprostadil (Intracavernosal) .

Commonly used brand name(s): Prostin VR; Prostin VR Pediatric.

Other commonly used names are
PGE 1 {39} {55} and prostaglandin E 1 {03} {04} {05} {06} {07} {08} {09} {11} {12} {13} {14} {15} {17} {20} {21} {22} {23} {24} {25} {26} {38} {41} {42} {43} {44} {45} {46} {47} {48} {49} {50} {51} {52} {53} {54} {56} {57} {58} {59}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Ductus arteriosus patency adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Ductus arteriosus, patent (maintenance)—Alprostadil is indicated for palliative, not definitive, therapy in neonates born with various congenital heart defects, including pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, transposition of the great vessels with or without other defects {01} {02} {26} {27} {28} {36}, [hypoplastic left heart syndrome]1 , and [critical aortic valve stenosis]1 {69} {70}. The medication is used to maintain the patency of the ductus arteriosus (DA), thereby improving circulation and oxygenation until corrective or palliative surgery can be performed. {01} {02} {16} {26} {27} {28} {36} {59} Although alprostadil treatment is intended primarily as a short-term measure, long-term (up to several months) therapy may be needed, for example, when surgery must be delayed until a very small infant has grown sufficiently to undergo the procedure. {16} {59}
—In infants with cyanotic congenital heart disease (for example, pulmonary atresia or stenosis, tricuspid atresia, tetralogy of Fallot, or transposition of the great vessels) in which there is a severe or complete obstruction to right ventricular outflow, patency of the DA is necessary to provide adequate pulmonary blood flow (and, therefore, an adequate oxygen supply) and to prevent or reverse acidemia. {01} {03} {11} {12} {15} {16} {19} {24} {59} In infants with restricted pulmonary blood flow, the best results have generally been attained in patients with low pretreatment blood P O 2 who were 4 days old or less; little response was attained in patients with initial P O 2 values of 40 torr or more. {26} In infants with acyanotic congenital heart disease (for example, with aortic arch anomalies such as aortic arch interruption or severe coarctation of the aorta) in which there is obstructed systemic outflow {71}, partial or complete patency of the DA is necessary to provide adequate systemic blood flow and to prevent or reverse acidemia {03} {05} {09} {11} {15} {16} {19} {59}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Prostaglandins. {03} {04} {05} {06} {07} {08} {09} {11} {12} {13} {14} {15} {17} {20} {21} {22} {23} {24} {25} {26} {38} {41} {42} {43} {44} {45} {46} {47} {48} {49} {50} {51} {52} {53} {54} {56} {57} {58} {59}
Molecular weight—
    354.49 {60}

pKa—
    6.3

Mechanism of action/Effect:

Alprostadil is one of a family of naturally occurring prostaglandins. It causes vasodilation by means of a direct effect on vascular {16} {36} and ductus arteriosus (DA) {26} {29} {36} smooth muscle.


Ductus arteriosus (DA) patency maintenance:

By its effect on DA smooth muscle, alprostadil prevents or reverses the functional closure {71} of the DA that occurs shortly after birth, which results in increased pulmonary or systemic blood flow in infants with impairment of this blood flow. A reduction in pulmonary vascular resistance has also been postulated, which may improve pulmonary perfusion in neonates in whom congenital heart disease is associated with increased pulmonary vascular resistance. {04} {11} {16} {36} {71}

In cyanotic congenital heart disease, alprostadil's actions result in an increased oxygen supply to the tissues. {03} {04}

In infants with interrupted aortic arch or very severe aortic coarctation, {61} alprostadil maintains distal aortic perfusion by permitting blood flow through the DA from the pulmonary artery to the aorta. {09} {28} In infants with aortic coarctation, alprostadil reduces aortic obstruction either by relaxing ductus tissue in the aortic wall or by increasing effective aortic diameter by dilating the DA. In infants with these aortic arch anomalies, systemic blood flow to the lower body is increased, improving tissue oxygen supply and renal perfusion. {01} {03} {05} {09} {28}



Other actions/effects:

Alprostadil has been reported to inhibit macrophage activation, neutrophil chemotaxis, and release of oxygen radicals and lysosomal enzymes. {47} {50} Inhibition of neutrophil chemotaxis has the potential to impair defense mechanisms and increase the risk of bacterial infection. {73}

Alprostadil inhibits coagulation by inhibiting platelet aggregation {26} {50} and possibly by inhibiting activation of factor X (by increasing the concentration of cyclic adenosine monophosphate [cAMP]) {58}. Alprostadil may also promote fibrinolysis by stimulating production of tissue plasminogen activator, which converts plasminogen to the fibrinolytic enzyme plasmin. {50} {57} Stimulation of cellular adenylate cyclase may initiate this effect. {57}

Other effects of prostaglandins include stimulation of intestinal and uterine smooth muscle. {26}

Protein binding:

High to very high (81 to 99%), depending on the method of measurement, to albumin. {25} {74}

Biotransformation:

Pulmonary. {26} {50} {56} In patients with normal respiratory function, up to 80% of a dose may be metabolized in one pass through the lungs. {26}

Half-life:

5 to 10 minutes (after a single dose), in healthy adults. Although the half-life in premature neonates has not been determined, a short half-life would be expected in these patients also. {75}

Time to peak effect


Acyanotic congenital heart disease:

Coarctation of the aorta: Usually about 3 hours (range, 15 minutes to 11 hours). {76} {77}

Interruption of aortic arch: Usually about 1.5 hours (range, 15 minutes to 4 hours). {76} {77}



Cyanotic congenital heart disease:

Approximately 30 minutes. {76} {77}


Duration of action:

Ductus arteriosus (DA) patency maintenance—As long as the infusion is continued; closure of the DA usually begins within 1 to 2 hours after the infusion is discontinued.

Elimination:
    Renal (as metabolites); elimination is virtually complete within 24 hours after administration. {26}


Precautions to Consider

Carcinogenicity

Studies have not been done {26}.

Mutagenicity

According to results of Ames and Alkaline Elution assays, alprostadil has no potential for mutagenicity. {26}

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: In addition to the interactions listed below, the possibility should be considered that multiple effects leading to further impairment of blood clotting and/or increased risk of bleeding may occur if alprostadil is administered to a patient receiving any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage. {79}

Anticoagulants, coumarin-derivative, or
Cefamandole or
Cefoperazone or
Cefotetan or
Heparin or
Moxalactam or
Platelet aggregation inhibitors, other (See Appendix II ), or
Thrombolytic agents    (these medications may cause one or more interferences with blood clotting; concurrent use with alprostadil may increase the risk of bleeding)


Sympathomimetics, alpha-adrenergic, especially metaraminol, epinephrine, and phenylephrine    (these medications reverse the vasodilating effect of alprostadil {68})


Vasodilators, other    (concurrent use with alprostadil may increase the risk of vasodilation-associated side effects such as hypotension {80})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Bilirubin concentrations    (may be increased—incidence less than 1% {26})


Calcium concentrations, serum    (may be decreased—incidence about 15% {29})


Glucose concentrations, blood    (may be decreased—incidence less than 1% {26})


Potassium concentrations, serum    (may be decreased or increased—incidence 1% or less {26})


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:
» Respiratory distress syndrome, neonatal    (closure of the ductus arteriosus [DA] is necessary to prevent overload of pulmonary circulation; a differential diagnosis between cyanotic heart disease [restricted pulmonary blood flow] and neonatal respiratory distress syndrome [hyaline membrane disease] is essential prior to administration {26})


Risk-benefit should be considered when the following medical problems exist
Bleeding disorders    (increased risk of bleeding because alprostadil inhibits platelet aggregation and may promote fibrinolysis)


Conditions in which increased pulmonary blood flow may result in pulmonary edema{81}
Sensitivity to alprostadil, history of

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):


For all infants with congenital heart defects
Blood gases (P O 2, P CO 2), arterial, measurement of{01}{03}{09}{12}{15}    (recommended at intermittent intervals throughout the infusion)


Blood pH, arterial, measurement of{11}{15}    (recommended at frequent intervals during infusion)


Blood pressure, arterial, measurement of by umbilical artery catheter, auscultation, or Doppler transducer, and{01}{03}{09}{12}{15}{19}
Electrocardiogram (ECG) and{03}{09}{15}
Heart rate, measurement of, and{03}{09}{12}{15}
Respiratory rate, measurement of, and{01}{03}{09}{15}
Temperature, rectal, measurement of, and{03}{12}{15}
Respiratory status{01}{03}{09}{15}{26}    (monitoring is recommended throughout therapy for maintaining neonatal ductus arteriosus patency; continuous monitoring is recommended initially, and may be continued throughout short-term therapy, but intermittent monitoring is usually sufficient when treatment is to be continued for an extended period after the patient's condition has stabilized)


Note: In infants with restricted pulmonary blood flow, efficacy of alprostadil may be determined by monitoring improvement in blood oxygenation. In infants with restricted systemic blood flow, improvement of systemic blood pressure and blood pH confirms efficacy {26}.


For infants with aortic arch anomalies (in addition to those listed above)
Blood pressure, measured in descending aorta or lower extremity, and{11}{15}
Femoral pulse, palpation for, and{05}
Renal output, measurement of{12}    (recommended at periodic intervals during infusion to confirm efficacy)




Side/Adverse Effects

Note: Cardiovascular side effects (especially cutaneous vasodilation) have been reported more frequently in infants with cyanotic lesions than in those with aortic lesions (possibly because the intra-aortic route [no longer recommended] {59} {62} was used more often in these patients). {03}
Cardiovascular {16} {59} side effects are more frequent in infants weighing less than 2 kg or with infusions of greater than 48 hours' duration. Respiratory depression occurs more commonly in patients weighing less than 2 kg at birth {16} {26} {59} and in cyanotic infants. {16} {59} Central nervous system (CNS) side effects are more frequent in neonates with preinfusion pH of 7.1 or less and with infusions of greater than 48 hours' duration. {16} {59}
Damage to the ductus, pulmonary artery, and aorta (weakening of the wall, leading to edema, laceration, and possible aneurysm) has been reported with long-term use. {07} {13} {16} {19} {22}

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
    
Apnea —incidence 10 to 12%;{26} generally occurs within the first hour of infusion;{26} the incidence is greatest in neonates weighing less than 2 kg at birth{26} and is also increased if a rapid or large infusion is given initially (e.g., to purge the intravenous line){31}
    
fever —incidence 14%,{26} primarily a CNS effect,{01}{03}{11}{12}{13}{20}{26} infection occurs in about 2% of patients{26}
    
flushing of face or arm —incidence about 10%, especially with intra-arterial{26} or intra-aortic administration, which is no longer recommended, may indicate misplacement of the catheter{63} and introduction of alprostadil into the subclavian or carotid artery{01}{12}{21}{26}
    
hypocalcemia{03}

Incidence less frequent {26}
    
Bradycardia —incidence 7%
    
diarrhea —incidence 2%
    
hypotension —incidence 4%
    
seizures —incidence 4%
    
tachycardia —incidence 3%

Incidence rare
—1% or less{26}    
Anemia
    
anuria
    
bleeding
    
bradypnea, tachypnea, or bronchial wheezing
    
cardiac arrest
    
cerebral bleeding
    
congestive heart failure
    
cortical hyperostosis —with long-term therapy,{01}{13}{14}{26} regresses after discontinuation of therapy{01}{26}{48}
    
disseminated intravascular coagulation
    
edema
    
gastric regurgitation
    
second degree heart block
    
hematuria
    
hypercapnia
    
hyperemia
    
hyperextension of the neck
    
ketotic hyperglycemia —when given to an infant born to an insulin-dependent diabetic patient{52}
    
hyperirritability
    
hyperkalemia or hypokalemia
    
hypoglycemia
    
hypothermia
    
jitteriness
    
lethargy
    
peritonitis
    
respiratory distress, including respiratory depression
    
shock
    
spasm of right ventricle infundibulum
    
stiffness
    
supraventricular tachycardia
    
thrombocytopenia
    
ventricular fibrillation





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:

Apnea

bradycardia

fever

flushing of skin{05}

hypotension


General Dosing Information
Because of the risk of apnea {32}, it is recommended that alprostadil be administered in an area with trained personnel and facilities necessary to provide pediatric intensive care. Respiratory support should be immediately available. {26} {27}

In patients with cyanotic heart defects, alprostadil is effective only if it is administered before permanent closure of the ductus arteriosus (DA) occurs. In normal-term infants, functional closure of the DA is usually complete within 10 to 15 hours after birth, and the DA is usually completely sealed off within 2 to 3 weeks. {06} {12} {18} In clinical studies, the greatest response to alprostadil in patients with cyanotic heart defects was achieved in infants 4 days old or less. {26} In infants with acyanotic heart defects, DA closure may be delayed, or the age of the patient and/or the extent of DA closure may be less critical. Beneficial responses to alprostadil may be achieved in infants up to 2 weeks of age, and occasionally in even older patients. {77}

Because of its rapid metabolism, alprostadil must be diluted and administered by infusion. {01} {26} Use of a constant-rate infusion pump is recommended to avoid inadvertent rapid administration, because of the risk of apnea. {32}

Alprostadil may be administered by intravenous infusion (peripheral or central) or intra-arterial infusion (through the pulmonary artery or an umbilical arterial catheter positioned at the level of the DA). The medication has also been administered via intra-aortic infusion, into the descending aorta adjacent to the DA. Theoretically, intra-aortic or intra-arterial administration should provide the greatest concentration to the DA and allow for rapid deactivation in the lungs, thereby reducing the risk of side effects. However, intra-arterial or intra-aortic administration has not proved more efficacious than intravenous administration {03} {04} {09} {12} {15} {17} {19} {20} {21} {24}, nor has it decreased the occurrence of side effects. {71} Intravenous administration is now preferred for maintaining DA patency. {34} {59}

If fever or hypotension occurs, the rate of alprostadil infusion should be reduced {01} {12} {15}

If a significant reduction of arterial blood pressure occurs, alprostadil should be discontinued immediately and appropriate treatment measures (e.g., volume replacement, administration of vasopressors) {66} instituted. After the patient's blood pressure has stabilized, therapy may be reinstituted cautiously. {26}

If apnea occurs, alprostadil should be discontinued {01} {26} or respiratory support instituted if continued use of alprostadil may be life saving. {32} {33}

If bradycardia occurs, alprostadil should be discontinued and appropriate medical treatment provided. {01} {26}

Flushing (peripheral arterial vasodilation) is usually the result of incorrect intra-arterial catheter placement and {26} usually responds to repositioning of the catheter. {01} {12} {19} {26}

Alprostadil infusion may be continued during cardiac catheterization and may even facilitate the procedure. {12} {15}

Alprostadil infusion is usually continued until surgical repair is completed, usually within 24 to 48 hours after initiation of therapy, although it is sometimes continued postoperatively. {03} {05} {09} {15} {59} Alprostadil should be administered for the shortest time and in the lowest dose that will produce the desired effect. {26} However, long-term treatment may be required for some patients, especially very small infants who cannot undergo surgery until sufficient growth has taken place. {16} {59} The risks of long-term use (e.g., vascular damage, cortical proliferation of the long bones) {01} {07} {12} {13} {14} {15} {17} {19} {21} must be weighed against the possible benefits. {26} However, infants with severe cyanotic congenital heart disease have been treated for up to 3 months without adverse effects occurring. {65}


Parenteral Dosage Forms

ALPROSTADIL INJECTION USP

Usual pediatric dose
Ductus arteriosus patency adjunct
Initial: Intravenous, into a large vein (preferred) or intra-arterial (via umbilical arterial catheter placed at the ductal opening), {66} 0.05 to 0.1 mcg per kg of body weight per minute. However, if the ductus arteriosus is nonrestrictive at the time of diagnosis, an initial dose as low as 0.01 mcg per kg of body weight per minute may be effective. The rate of infusion may gradually be increased to up to 0.4 mcg per kg of body weight per minute, if necessary, although doses higher than 0.1 mcg per kg of body weight per minute have not been shown to produce greater effects. {26} {67} After a satisfactory response is obtained, the rate of infusion may be reduced {26} to the minimum level that will maintain the response. Dosage reduction is usually accomplished by progressively halving the previous dose, {16} e.g., from 0.1 to 0.05 to 0.025 to 0.01 mcg per kg of body weight per minute. {16} {26}

Maintenance: Intravenous, into a large vein (preferred) or intra-arterial (via umbilical arterial catheter placed at the ductal opening), {66} infused at the minimum rate that will maintain the desired response. Doses as low as 0.002 mcg per kg of body weight per minute have been effective in some infants. {16} However, maintenance dosage requirements may vary, and the infusion rate should be adjusted (increased or decreased) as necessary.


Strength(s) usually available
U.S.—


500 mcg (0.5 mg) per mL (Rx) [Prostin VR Pediatric (in dehydrated alcohol)]

Canada—


500 mcg (0.5 mg) per mL (Rx) [Prostin VR (in dehydrated alcohol)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), {26} unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Alprostadil infusions are prepared by diluting 1 mL of the injection with a volume of 0.9% sodium chloride injection or 5% dextrose injection suitable for the pump delivery system available. For example, to provide 0.1 mcg per kg of body weight per minute, the following dilutions and infusion rates could be used:

Amount of Diluent
(mL) for each
mL (500 mcg)
of Alprostadil
Approximate
Concentration
of Resulting
Solution
(mcg/mL)
Infusion Rate
(mL/min per kg
of body weight)
250
2
0.05
100
5
0.02
50
10
0.01
25
20
0.005


Caution: Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:
Alprostadil infusions should be discarded 24 hours after they are prepared. {26}



Revised: 04/09/1992



References
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  1. Panel comment.
  1. Panel consensus.
  1. Freed MD, Heymann MA, Lewis AB, Roehl SL, Kensey RC. Prostaglandin E 1 in ductus arteriosus-dependent congenital heart disease. Circulation 1981; 65: 899-905.
  1. Panelist comment.
  1. Panel consensus.
  1. Panel comment.
  1. Bhatt V, Nahata MC. Pharmacologic management of patent ductus arteriosus. Clin Pharm 1989; 8: 17-33.
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