General Information: Alprostadil (Prostglandin E1) is used to treat erectile dysfunction (ED) in adult males. The efficacy of alprostadil in treating ED varies with the cause; response rate is generally lower in patients with ED due to mixed etiologies compared to those with ED due to neurogenic, psychogenic, or vasculogenic causes. Two dosage forms are marketed for treating ED: a transurethral product (Muse) which uses a medicated pellet administered into the urethra and an injection (Caverject or Edex) that is directly injected into the corpus cavernosa. Other dosage forms such as a topical gel and a non-invasive liposomal delivery system are under investigation. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Second-line treatment options include intracavernous injection and intra-urethral therapy. Intracavernous injection therapy is the most effective nonsurgical treatment for ED, with predictable and sustained response. However, it is invasive and caries notable side-effects including priapism and penile fibrosis.1 FDA approvals are as follows: Caverject in July 1995, MUSE in October 1996, and Edex in June 1997.
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 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 less. 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.2 Intravenous alprostadil requires respiratory monitoring during administration because apnea develops in 10—12% of neonates.3 Alprostadil is FDA approved in pediatric patients as young as neonates. Prostin VR Pediatric was approved by the FDA in 1981.
Mechanism of Action: For the treatment of erectile dysfunction (ED), alprostadil relaxes the smooth muscles of the corpus cavernosum; however, the exact mechanism of action is unknown. It appears that the effects are due to increasing the intracellular concentrations of cyclic AMP. Alprostadil interacts with specific membrane-bound receptors that stimulate adenylate cyclase and elevate intracellular cyclic AMP, leading to activation of protein kinase and resultant smooth muscle relaxation. This action is in contrast to papaverine which inhibits oxidative phosphorylation mediated inactivation of cyclic AMP and interferes with calcium mobilization during muscle contraction. Alprostadil may also antagonize the vasoconstrictive actions of norepinephrine by preventing the neuronal release of norepinephrine and may enhance the actions of nonadrenergic, noncholinergic vasodilatory neurotransmitters. In treating ED, alprostadil induces erection by relaxing trabecular smooth muscle and dilating cavernosal arteries and their branches. Dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous outflow resistance. As a result, the lacunar spaces expand and blood becomes entrapped secondary to compression of venules against the tunica albuginea. To achieve adequate tumescence and rigidity, the tunica albuginea must be sufficiently stiff to compress the venules penetrating it and thus block venous outflow. This process is also referred to as the corporal veno-occlusive mechanism. Alprostadil does not directly affect ejaculation or orgasm.
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 (PaO2) 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 PaO2 (< 20 torr), narrowing ductus arteriosus, and who are 4 days old or younger. Neonates with PaO2 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 PaO2.
Pharmacokinetics: Alprostadil is administered by intravenous infusion, intracavernosal injection, or via an urethral suppository. Once in the systemic circulation, alprostadil is bound primarily to albumin (81%). No significant binding to erythrocytes or white blood cells occurs. Alprostadil is completely metabolized to several metabolites which are primarily excreted in the urine.
Intracavernosal Route: After intracavernosal administration, minimal systemic absorption occurs. Any alprostadil absorbed by this route is rapidly metabolized. Following intracavernosal administration, erection usually occurs within 2—25 minutes and may last for about 1 to several hours. Tolerance to the beneficial vascular effects does not appear to occur.
Intraurethral Route: After intraurethral administration, minimal systemic absorption occurs. Any alprostadil absorbed by this route is rapidly metabolized. Alprostadil given via the urethra is delivered directly to the urethral lining for transfer via the corpus spongiosum to the corpora cavernosa. The onset of effect is within 5—10 minutes after urethral administration and the duration of effect is approximately 30—60 minutes and will vary from patient to patient.
Indications: Prostglandin E1 is indicated for the teatment of erectile dysfunction. Studies that established benefit demosntrated improvements in success rates for sexual intercourse compared with similarly administered placebo. 4
Contraindications and Precautions: Any underlying and treatable medical cause for erectile dysfunction should be diagnosed and treated before therapy with alprostadil intracavernosal injection or urethral suppository is initiated.
Alprostadil intracavernosal injection is designed for one time use. After the one use, the injection devise and remaining solution should be discarded. Of note, the needle used for administration of alprostadil solution is a superfine (29 gauge) needle; with such a fine needle, breakage is possible. Patients should be carefully instructed on proper injection technique to minimize the risk of needle breakage. Needles or syringes should not be shared.
Apnea is experienced by approximately 10—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.3 Respiratory status should be monitored throughout treatment and neonatal use of alprostadil 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 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.
Alprostadil inhibits platelet aggregation and therefore can increase the risk of bleeding. Use intravenous alprostadil cautiously in neonates with bleeding tendencies.
Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with administration of drugs for the treatment of erectile dysfunction. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. The use of alprostadil intracavernosal injection or urethral suppository is contraindicated in patients who are prone to venous thrombosis or who have a hyperviscosity syndrome and are therefore at increased risk of priapism. This includes patients with sickle cell disease or trait, thrombocytosis,polycythemia, leukemia, or multiple myeloma. In clinical trials of alprostadil urethral suppository, priapism (rigid erection lasting >= 6 hours) and prolonged erection (rigid erection lasting 4 hours and < 6 hours) were reported in < 0.1% and 0.3% of patients, respectively. Patients receiving intracavernosal alprostadil also reported prolonged erection (4%) and priapism (0.4%). Lower dosages or discontinuation of treatment should be considered in patients who develop priapism or prolonged erection.5
The use of alprostadil intracavernosal injection or urethral suppository is contraindicated in men with penile structural abnormality. The intracavernosal injection is specifically contraindicated in patients with penile angulation, cavernosal fibrosis, or Peyronie's disease. The urethral suppository is contraindicated in men with urethral stricture, balanitis,Peyronie's disease, severe hypospadia and curvature, or acute or chronic urethritis. The use of alprostadil intracavernosal injection in patients with penile implants is contraindicated; the use of alprostadil urethral suppository in this population has not been studied. Both of these products are contraindicated in patients for whom sexual intercourse is inadvisable or contraindicated. In addition, there is no experience of using alprostadil in homosexual men and no experience with non-vaginal intercourse.
Alprostadil urethral suppository should be used cautiously in patients with a coagulopathy or in those receiving anticoagulant therapy. Improper administration of the alprostadil urethral suppository may cause urethral abrasion resulting in minor bleeding or spotting. Patients on anticoagulant therapy or with bleeding disorders may be at increased risk of bleeding. Although patients on anticoagulant therapy have been treated safely with the urethral suppository, the manufacturer recommends that the risk/benefit ratio in these patients be considered prior to prescribing. In addition, the intracavernosal injection of alprostadil may cause a small amount of bleeding at the site of administration. This can increase the transmission of a blood-borne diseases to a sexual partner.
Alprostadil for the management of erectile dysfunction should be used cautiously in patients with cardiovascular disease. Symptomatic hypotension and syncope occurred in 3% and 0.4%, respectively, of patients during in-clinic dosing of alprostadil urethral suppository. Titration of the alprostadil urethral suppository dose should be carried out under medical supervision. Patients should be monitored for symptoms of hypotension during dosing and the lowest effective dose of the alprostadil urethral suppository should be prescribed. Patients should also be cautioned to avoid activities, such as driving or hazardous tasks, where injury could result if hypotension or syncope were to occur after alprostadil administration. Alprostadil injection for the maintenance of patency of the ductus arteriosus also causes hypotension; neonates receiving an alprostadil infusion should be carefully monitored for a drop in blood pressure.
Of the approximately 1065 patients who entered the in-office dose-titration period in clinical studies for erectile dysfunction, 25% were geriatric (>= 65 years). In clinical studies, elderly patients required, on average, higher minimally effective doses and had a higher rate of lack of effect (optimum dose not determined). Overall differences in safety were not observed between these elderly patients and younger patients. Elderly patients should be dosed and titrated according to the same dosage and administration recommendations as younger patients, and the lowest possible effective dose should always be used. Alprostadil is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Given the indications for use for adult male erectile dysfunction, alprostadil intracavernosal injection and urethral suppository are contraindicated for use in adult females, and inchildren, infants, and neonates.6 5 Alprostadil intracavernosal injection (e.g., Caverject and Caverject Impulse) contains the preservative benzyl alcohol, which can cause adverse effects in neonates or in other patients with a benzyl alcohol hypersensitivity. The preservative has been associated with reports of fatal 'gasping syndrome' in neonates; symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse. 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 capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.5
Alprostadil is classified in FDA pregnancy risk category C. Given the indications for use, alprostadil would not be expected to be used in a female during pregnancy. However, the alprostadil urethral suppository should not be used by a male for sexual intercourse with a pregnant woman unless a condom barrier is used.6 It is recommended that all couples using alprostadil for erectile dysfunction employ adequate contraception if the female partner is of childbearing potential. There is no information on the effects on early pregnancy of PGE1 at the levels received by female partners. Prostaglandins generally promote uterine contractions, and exposure to prostaglandins during pregnancy may induce labor. Animal data report embryotoxic effects when alprostadil was given as a subcutaneous bolus, however, no harm to the fetus was reported when the drug was given intravaginally.5
Pregnancy: Alprostadil is classified in FDA pregnancy risk category C. Given the indications for use, alprostadil would not be expected to be used in a female during pregnancy. However, the alprostadil urethral suppository should not be used by a male for sexual intercourse with a pregnant woman unless a condom barrier is used.6 It is recommended that all couples using alprostadil for erectile dysfunction employ adequate contraception if the female partner is of childbearing potential. There is no information on the effects on early pregnancy of PGE1 at the levels received by female partners. Prostaglandins generally promote uterine contractions, and exposure to prostaglandins during pregnancy may induce labor. Animal data report embryotoxic effects when alprostadil was given as a subcutaneous bolus, however, no harm to the fetus was reported when the drug was given intravaginally.5
Interactions: There have been no drug interactions reported with any formulation of alprostadil, however, the concomitant use of MUSE® (alprostadil) and antihypertensive agents may increase the risk of hypotension.6 Systemic drug interactions with MUSE® urethral suppository are unlikely because low or undetectable amounts of the drug are found in the peripheral venous circulation following MUSE® administration.6 Drugs which affect erectile function may influence the response to MUSE®. The potential for pharmacokinetic drug-drug interactions with alprostadil administered via Caverject® and other agents has not been formally studied.7
As ibuprofen lysine is used for the pharmacologic closure of patent ductus arteriosus (PDA) 8, do not administer to patients who require alprostadil dilation of ductus arteriosus for oxygenation and perfusion.9 Prostin VR Pediatric® has been used with the standard therapy for neonates with restricted pulmonary or systemic blood flow which includes antibiotics (e.g., penicillin and gentamicin), vasopressors (e.g., dopamine, isoproterenol), cardiac glycosides, and diuretics (e.g., furosemide).9
Adverse Reactions: Central nervous system adverse reactions of alprostadil are reported more frequently following intravenous administration (i.e., when used for ductus arteriosus maintenance). Apnea has been reported in approximately 10—12% of neonates and infants with congenital heart defects treated with alprostadil and was most seen in neonates weighing < 2 kg at birth. Apnea usually occurred during the first hour of drug infusion. Other respiratory adverse reactions occurring in < 1% of patients include bradypnea, bronchial wheezing, hypercapnia, respiratory depression, respiratory distress, and tachypnea. Other common adverse reactions include fever (14%) and seizures (4%). The following adverse reactions have been reported in less than 1% of patients receiving IV alprostadil: cerebral bleeding, hyperextension of the neck, irritability (reported as hyperirritability), hypothermia, jitteriness, lethargy, and stiffness.3
Cardiovascular adverse effects have been reported with alprostadil. Alprostadil associated hypotension has been reported following intravenous infusion (i.e., when used for ductus arteriosus maintenance), transurethral administration (i.e., when used for erectile dysfunction), and intracavernosal injection (i.e., when used for erectile dysfunction). Specifically, transurethral administration causes approximately 3% (45 of 1511) of patients to develop symptomatic hypotension, clinically insignificant hypotension may also occur; intracavernosal injection causes hypotension in < 1% of patients and is considered clinically insignificant. In contrast to intravenous and transurethral administration, intracavernosal alprostadil can also result in hypertension in 2% of patients. In neonates receiving intravenous infusions of alprostadil (i.e., for ductus arteriosus maintenance), flushing (10%), sinus bradycardia (7%), hypotension (4%), sinus tachycardia (3%), cardiac arrest (1%), and edema (1%) were the most common cardiovascular adverse reactions. Other cardiovascular adverse reactions reported in <1% neonates receiving intravenous infusions of alprostadil include congestive heart failure, hyperemia, second degree heart block, shock, spasm of the right ventricle infundibulum, supraventricular tachycardia (SVT), and ventricular fibrillation. In patients (n=1511) receiving alprostadil urethral suppositories (i.e., when used for erectile dysfunction), approximately 4% reported dizziness and 0.4% had syncope. During post-marketing surveillance, syncope occurring within one hour of administration has been reported.5 6 3
Local adverse reactions associated with alprostadil used for treating erectile dysfunction were usually mild and transient; however, approximately 7% of patients withdrew from therapy because of adverse reactions. The most frequent local adverse reactions reported with the use of alprostadil urethral suppository include penile pain (36%), urethral pain (13%), and testicular pain (5%). Urethral bleeding/spotting and other minor abrasions to the urethra were reported in approximately 3% of patients. In clinical trials of alprostadil urethral suppository, priapism (rigid erection lasting >= 6 hours) and prolonged erection (rigid erection lasting 4 hours and < 6 hours) were reported in < 0.1% and 0.3% of patients, respectively. Patients receiving intracavernosal alprostadil injection also reported prolonged erection (4%) and priapism (0.4%). The most common local adverse reactions reported with alprostadil administered by intracavernosal injection include penile pain (37%), penile fibrosis (3%), injection site reaction (hematoma (3%), ecchymosis (2%)), penis disorder (numbness, yeast infection, phimosis, irritation, sensitivity, pruritus, erythema, discoloration of penile head, penile skin tear, abnormal feeling of penis) (3%), penile rash (1%), and penile edema (1%). Prolonged erection and priapism were reported in 4% and 0.4% of patients, respectively, following intracavernosal injection. This incidence of priapism is reportedly less than that of combined phentolamine and papaverine or papaverine alone. The patient should be instructed to immediately report to his physician or, if unavailable, to seek immediate medical assistance for any erection that persists for longer than 4 hours. During post-marketing surveillance, needle breakage with alprostadil intracavernosal injection (Edex) has been reported. In addition, device malfunction/failure (Caverject) and decreased drug effect or no effect have been reported.5 Systemic adverse reactions associated with intracavernosal or transurethral administration (i.e., when used for erectile dysfunction) include headache, back pain, flu-like symptoms, pelvic pain, peripheral edema, perineal pain, prostatic disorder (prostatitis, pain, hypertrophy, enlargement), respiratory disorder (i.e., rhinitis, sinusitis, nasal congestion, upper respiratory infection, or cough).36 5
Disseminated intravascular coagulation (DIC) has been reported in approximately 1% of patients receiving intravenous administration of alprostadil (i.e., for ductus arteriosus maintenance). In addition, anemia, bleeding, and thrombocytopenia have been reported in < 1%, and sepsis reported in about 2%, of patients receiving intravenous administration of alprostadil.3
Female partners of men using alprostadil urethral suppository (i.e., when used for erectile dysfunction) have reported adverse reactions. Vaginal irritation (vaginal burning/itching) was reported by 5.8% of female partners of patients on active vs 0.8% of partners of patients on placebo. It is unknown if these adverse reactions in female partners were a result of the medication or a result of resuming sexual intercourse.6
Gastrointestinal adverse reactions have been reported following intravenous administration of alprostadil (i.e., when used for ductus arteriosus maintenance). Diarrhea occurred in about 2% of patients and gastric regurgitation and hyperbilirubinemia were reported in < 1% of patients. Other adverse reactions reported following intravenous alprostadil and occurring in < 1% of patients include anuria, hematuria, peritonitis, hypoglycemia, and hyperkalemia.3
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.
- 1. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005;174:230-9.
- 2. American Academy of Pediatrics. Prostaglandin E and the Ductus Arteriosus. Pediatrics in Review 1985; 7(3): 75 -76.
- 3. Prostin VR Pediatric® (alprostadil injection) package insert. Kalamazoo, MI: Pharmacia and Upjohn Company.; 2006 Apr.
- 4. Alprostadil Package Insert. MEDA Pharmaceuticals. Somerset, New Jersey. 2014
- 5. Caverject (alprostadil for injection) package insert. New York, NY: Pharmacia and Upjohn Company; 2014 Mar.
- 6. MUSE® (alprostadil) urethral suppository package insert. Mountain View, CA: Vivus, Inc.; 2003 Aug.
- 7. averject® (alprostadil for injection) package insert. Kalamazoo, MI: Pharmacia & Upjohn Co.; 2002 Oct.
- 8. NeoProfen® (ibuprofen lysine) package insert. Deerfield, IL: Ovation Pharmaceuticals; 2006 Apr.
- 9. Prostin VR Pediatric® (alprostadil injection) package insert. Kalamazoo, MI: Pharmacia & Upjohn Co.; 2002 Aug.