EDEX

Alprostadil is a chemically-identical synthetic form of prostaglandin E1 (PGE1), a potent vasodilator produced endogenously.

In 1996, the FDA approved the use of alprostadil, administered either with an intracavernosal injection or an intraurethral suppository, for the treatment of erectile dysfunction, and it is used in men for whom oral treatment is either contraindicated or ineffective.

After administration, alprostadil promotes smooth muscle relaxation of the corpus cavernosal. 1, 3 Alprostadil is also used in neonatal patients with congenital heart defects that depend on a patent ductus for survival until corrective or palliative surgery can be performed.

This drug causes vasodilation by directly affecting vascular and ductus arteriosus (DA) smooth muscle, preventing or reversing the functional closure of the DA that occurs shortly after birth.

This results in increased pulmonary or systemic blood flow in infants. 4, 8, 10.

Alprostadil is indicated for palliative, not definitive, therapy 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 the patent ductus for survival.

It is also indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology, 6, 7 and as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.

E1 is produced endogenously to relax vascular smooth muscle and cause vasodilation.

As a synthetic form of prostaglandin

E1, alprostadil has the same pharmacodynamic effects.

Alprostadil inhibits platelet aggregation, has anti-inflammatory effects, interferes with immune responses, and stimulates factor X, a blood coagulation enzyme.

In adult males, the use of alprostadil may lead to prolonged erection and priapism, penile fibrosis, hypotension, and injection site bleeding.

In patients treated up to 24 months with alprostadil, the incidence of prolonged erections (>4 hours long) was 4% of all, and the incidence of priapism (erections greater than 6 hours in duration) was <1%.

Patients with preexisting cardiovascular disease treated with alprostadil may also have higher cardiac risk.

Neonates with congenital heart defects treated with alprostadil may experience apnea.

Apnea is experienced by 10-12% of neonates and is more common in those weighing less than 2 kg at birth.

The administration of alprostadil to neonates may also result in gastric outlet obstruction secondary to antral hyperplasia.

E2 receptor EP1 subtype Agonist Prostaglandin E2 receptor EP2 subtype Agonist Prostaglandin E2 receptor EP3 subtype Agonist + 1 more target.

In patients with erectile dysfunction given 20 μg of alprostadil intracavernously, the systemic plasma concentrations of prostaglandin E1 increased from a baseline of 0.8 pg/mL to a C max of 16.8 pg/mL (corrected for baseline).

The t max and

AUC for this group of patients were 4.8 min and 173 pg⋅min/mL, respectively.

In patients given 20 μg of alprostadil Intravenous, AUC was similar to the one detected in patients that received alprostadil intracavernously (174 pg⋅min/mL); however, they had a higher t max (25.5 min) and a lower C max (7.09 pg/mL).

Compared to the same dose given by a short-term intravenous infusion, the absolute bioavailability of alprostadil estimated from systemic exposure was about 98%.

The volume of distribution of alprostadil has yet to be determined.

Alprostadil is rapidly metabolized in the human body.

Following intracavernous administration, alprostadil is metabolized in the corpus cavernosum, and a smaller portion is absorbed from the penis into systemic circulation.

After intravenous or arterial administration, alprostadil is metabolized and distributed throughout the entire body except for the central nervous system.

As much as 60-90% of the circulating alprostadil may be metabolized in the lungs through first-pass pulmonary elimination, in a process known as beta.

• and omega-oxidation.

The enzymatic oxidation of the

C15-hydroxy group of alprostadil leads to the formation of 15-keto-PGE 1, while the reduction of the C13, 14-double bond produces 15-keto-PGE 0, and 13,14-dihydro-PGE 1 (PGE 0 ).

The 15-keto metabolites are inactive, but the PGE 0 metabolite has a similar potency to alprostadil in isolated animal organs.

The major metabolite of alprostadil is 15-keto-PGE 0.

Hover over products below to view reaction partners Alprostadil 15-keto-PGE1 15-keto-PGE0 13,14-dihydro-PGE1.

Following the degradation of alprostadil by beta.

• and omega-oxidation, metabolites are excreted primarily by the kidney, and excretion is essentially complete within 24 hours after administration (92%).

Approximately 88% and 12% of alprostadil metabolites are excreted through urine and feces, respectively, over 72 hours.

Alprostadil and its metabolites are not retained in tissues, and unchanged alprostadil has not been detected in urine. 7, 10.

In healthy adults and neonates given a single intravenous dose of alprostadil, half-life goes from 5-10 minutes.

In patients with erectile dysfunction given an intravenous infusion of alprostadil (20 μg), the total body clearance was 115 L/min.

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In neonatal patients given alprostadil

Intravenous, apnea, bradycardia, pyrexia, hypotension, and flushing may be signs of drug overdosage.

In patients with apnea or bradycardia, discontinue the infusion, and provide appropriate medical treatment.

Caution should be used in restarting the infusion.

In patients with pyrexia or hypotension, reduce the infusion rate until these symptoms subside.

Flushing is usually a result of incorrect intraarterial catheter placement, and the catheter should be repositioned.

For patients given alprostadil intracavernosally for the treatment of erectile dysfunction, there is limited data on overdosage.

Systemic reactions are uncommon with the intracavernous use of alprostadil, and hypotension occurrs in less than 1% of patients treated with this drug.

A prolonged erection or priapism is the main symptom of an alprostadil overdose in this group of patients.

Erections lasting more than 6 hours should be treated due to the potential for tissue hypoxia and possible necrosis.

In the event of an intracavernous overdose, the patient is strongly encouraged to go to the nearest emergency room if his personal physician is not available.

Supportive therapy according to the presence of other symptoms is recommended. 6, 7 The oral LD of alprostadil in mice and rats is 186 mg/kg and 228 mg/kg, respectively. 9, 12.

WARNING box.

Alprostadil injection must be diluted before it is administered.

See dilution instructions in DOSAGE AND

ADMINISTRATION section.

The administration of alprostadil injection 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 injection at recommended doses for more than 120 hours should be closely monitored for evidence of antral hyperplasia and gastric outlet obstruction.

Alprostadil injection should be infused for the shortest time and at the lowest dose that will produce the desired effects.

The risks of long-term infusion of alprostadil injection should be weighed against the possible benefits that critically ill infants may derive from its administration.

The preferred route of administration for alprostadil injection is continuous intravenous infusion into a large vein.

Alternatively, alprostadil injection may be administered through an umbilical artery catheter placed at the ductal opening.

Increases in blood pO 2 (torr) have been the same in neonates who received the drug by either route of administration.

Begin infusion with 0.05 to 0.1 micrograms alprostadil per kilogram of body weight per minute.

A starting dose of 0.1 micrograms per kilogram of body weight per minute is the recommended starting dose based on clinical studies; however, adequate clinical response has been reported using a starting dose of 0.05 micrograms per kilogram of body weight per minute.

After a therapeutic response is achieved (increased pO in infants with restricted pulmonary blood flow or increased systemic blood pressure and blood pH in infants with restricted systemic blood flow), reduce the infusion rate to provide the lowest possible dosage that maintains the response.

This may be accomplished by reducing the dosage from 0.1 to 0.05 to 0.025 to 0.01 micrograms per kilogram of body weight per minute.

If response to 0.05 micrograms per kilogram of body weight per minute is inadequate, dosage can be increased up to 0.4 micrograms per kilogram of body weight per minute although, in general, higher infusion rates do not produce greater effects.

To prepare infusion solutions, dilute 1 mL of alprostadil injection with sodium chloride injection, USP or dextrose injection, USP.

Undiluted alprostadil injection may interact with the plastic sidewalls of volumetric infusion chambers causing a change in the appearance of the chamber and creating a hazy solution.

Should this occur, the solution and the volumetric infusion chamber should be replaced.

When using a volumetric infusion chamber, the appropriate amount of intravenous infusion solution should be added to the chamber first.

The undiluted alprostadil injection should then be added to the intravenous infusion solution, avoiding direct contact of the undiluted solution with the walls of the volumetric infusion chamber.

Dilute to volumes appropriate for the pump delivery system available.

Prepare fresh infusion solutions every 24 hours.

Discard any solution more than 24 hours old.

Sample Dilutions and Infusion Rates to Provide a Dosage of 0.1 Micrograms per Kilogram of Body Weight per Minute Add 1 vial (500 micrograms) alprostadil to: Approximate Concentration of resulting solution (micrograms/mL) lnfusion rate (mL/min per kg) (of body weight) 250 mL 2 0.05 100 mL 5 0.02 50 mL 10 0.01 25 mL 20 0.005 Example: To provide 0.1 micrograms/kilogram of body weight per minute to an infant weighing 2.8 kilograms using a solution of 1 vial alprostadil injection in 100 mL of saline or dextrose: INFUSION RATE = 0.02 mL/min per kg × 2.8 kg = 0.056 mL/min or 3.36 mL/hr. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Each mL contains 500 micrograms alprostadil in dehydrated alcohol.

Injection, USP (500 mcg per mL) Package Factor NDC 71288.

• 206 -02 500 mcg per mL Single-Dose Vial 10 vials per carton Store alprostadil injection, USP in a refrigerator at 2° to 8°C (36° to 46°F).

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