AHFS Class:

• Direct Vasodilators 24:08.16

Generic Name(s):

• Alprostadil

Alprostadil, the naturally occurring prostaglandin E₁, is a vasodilating agent and a platelet-aggregation inhibitor.1,  5,  20,  98

Erectile Dysfunction

Treatment

Alprostadil is used as an intracavernosal injection2,  6,  8,  9,  10,  11,  12,  13,  14,  17,  19,  20,  21,  22,  23,  25,  26,  27,  28,  30,  31,  32,  33,  34,  35,  36,  37,  38,  39,  40,  41,  45,  46,  62,  64,  66,  67,  68,  69,  71,  101,  102,  110 or a urethral suppository97,  98,  99,  104,  105,  106,  107 to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). Self-injection of alprostadil into a corpus cavernosum of the penis2,  9,  10,  16,  19,  24,  25,  27,  34,  36,  37,  38,  41,  46,  62,  67,  68 or administration of a urethral suppository (distributed into corpus spongiosum and corpus cavernosum of the penis)97,  98,  99,  100,  104,  105,  106,  107 has been effective in patients with organic (neurogenic, vasculogenic) or psychogenic erectile dysfunction and in those whose erectile dysfunction was of mixed etiology. Intracavernosal or intraurethral administration of alprostadil can increase tumescence (in both cavernosa because of cross circulation) and produce erection probably secondary to drug-induced relaxation of trabecular smooth muscle and by dilation of cavernosal arteries and branches.2,  11,  15,  19,  20,  21,  24,  27,  28,  34,  46,  64,  65,  71,  72,  98,  101,  102 Dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous outflow resistance resulting in penile blood engorgement and erection.15,  18,  85,  98 The goal of such therapy is to provide an erection of adequate rigidity and duration to be sexually functional and that is satisfying to the patient and his partner, while avoiding prolonged erection or priapism in the patient.2,  35,  39,  40,  41,  64

Erection, which can be potentiated by sexual arousal (e.g., genital stimulation), usually occurs within 2-25 or 5-10 minutes after injection or intraurethral administration of the drug, respectively, and may persist for approximately one (which is optimal) to several hours or 0.5-1 hour, respectively; tolerance to the beneficial vascular effects of the drug does not appear to occur during long-term use.2,  6,  8,  10,  12,  16,  17,  19,  21,  23,  24,  27,  28,  34,  35,  36,  37,  45,  46,  62,  65,  67,  69,  98,  101 Following intracavernosal injection of alprostadil, prolonged erection (persisting for 4-6 hours) or priapism (erection persisting for longer than 6 hours) may occur occasionally,2,  112 but alprostadil appears to cause a decreased incidence of priapism compared with combined phentolamine and papaverine or papaverine alone;8,  9,  12,  13,  18,  22,  24,  26,  28,  62 the manufacturers state that prolonged erection or priapism occurred in about 4 or 0.4%, respectively, of patients receiving intracavernosal alprostadil in clinical trials.2,  101 The manufacturer of alprostadil urethral suppositories states that although prolonged erection or priapism was reported very rarely in patients receiving the intraurethral preparation, occurring in 0.3 or less than 0.1% of patients, respectively, the possibility that overdosage of the intraurethral preparation may produce priapism should be considered.98 Patients should be instructed to contact their clinician immediately or, if unavailable, seek alternative immediate medical assistance for any erection persisting longer than 4 hours;2,  98,  102,  103 priapism or prolonged erection should be treated according to established medical practice.2,  6,  7,  8,  11,  12,  19,  20,  23,  46,  67,  83,  89,  98

Clinical Perspective

With the availability of orally active and convenient vasoactive (erectogenic) therapies (e.g., selective phosphodiesterase [PDE] type 5 inhibitors such as sildenafil, tadalafil, avanafil, and vardenafil), most experts (e.g., the American Urological Association [AUA]) now consider these drugs to be first-line therapies for a broad range of patients with ED unless contraindicated.161,  601 Because PDE type 5 inhibitors are administered orally, they are likely to be more acceptable to men with ED than other vasoactive therapies (e.g., intracavernosal injections, intraurethral suppositories) or mechanical or prosthetic devices.602 Alternative therapies (e.g., intracavernosal or intraurethral vasoactive agents, vacuum constriction devices) may be considered for patients who fail to respond to, or are not candidates for, first-line therapy (e.g., patients who require nitrate therapy).161,  189,  601 Ultimately, the choice of therapy for ED should be individualized, taking into account patient response, tolerability, and safety; administration considerations, cost and patient reimbursement factors; experience and judgment of the clinician; and individual patient and partner preference, expectations, and satisfaction.189,  601,  602

Although not as effective, intraurethral alprostadil generally is preferred over intracavernosal vasoactive therapy because it is less invasive.112 Intraurethral alprostadil may be considered for patients who are not candidates for or who have failed selective PDE type 5 therapy.112 Intracavernosal vasoactive therapy (e.g., alprostadil, papaverine, papaverine and phentolamine, other combinations) is the most effective nonsurgical treatment for erectile dysfunction;112 however, it is invasive and associated with the highest risk of priapism.112 Clinician preference and experience often guide the initial treatment choice when intracavernosal therapy is indicated.112

Although additional study of the long-term safety and efficacy of intracavernosal injection of vasoactive drugs for the treatment of erectile dysfunction is necessary and ongoing, particularly regarding the relative complications (e.g., penile scarring, penile fibrosis) and safety of each approach,19,  20,  26,  28,  69 some clinicians currently favor alprostadil, alone or combined with other agents, when intracavernosal treatment of erectile dysfunction is indicated because of possible improved efficacy and decreased adverse effects (e.g., priapism, fibrotic changes) compared with papaverine therapy.13,  14,  30,  31,  32,  61,  64,  65 However, all currently popular forms of therapy for erectile dysfunction, including intracavernosal or intraurethral vasoactive therapy, have been associated with high dropout rates, often early in treatment (e.g., secondary to adverse effects, compromised sexual spontaneity, loss of motivation or partner, spontaneous return of function).7,  19,  20,  34,  64,  65,  67,  68,  71,  97

Clinical Experience

Efficacy of alprostadil is variable in patients with erectile dysfunction, in part depending on the underlying etiology and dose employed.2,  34,  61,  64 The manufacturers of intracavernosal alprostadil state that about 70-90% of patients with erectile dysfunction of various etiologies experienced erections sufficient for sexual intercourse with alprostadil intracavernosal therapy at doses ranging up to 65 mcg in clinical trials.2,  64,  101,  110 In some reports involving erectile dysfunction of various etiologies, response rates ranged from about 40-85% for alprostadil doses ranging from 10-20 mcg.34,  41,  64

Results of a placebo-controlled multicenter study indicate that in the initial (dose titrating) phase about 66% of patients with erectile dysfunction of various etiologies experienced erections sufficient for sexual intercourse with alprostadil intraurethral therapy at doses ranging from 125-1000 mcg.97,  98,  99,  100,  104 In other studies in patients with erectile dysfunction, response rates ranged from 37-43% for intraurethral doses ranging from 125-1000 mcg.105,  106,  107

Alprostadil has been effective in patients with organic (neurogenic and/or mild to moderate vasculogenic) erectile dysfunction or with psychogenic erectile dysfunction, but efficacy in those with a vasculogenic component of their erectile dysfunction may vary depending on the extent and type of vascular dysfunction.19,  20,  24,  25,  27,  34,  36,  41,  45,  46,  64,  67,  71 Generally, vasculogenic erectile dysfunction of arteriogenic origin is more responsive (both in terms of dose and rate) to alprostadil than that of venogenic origin.36,  64 In addition, patients with neurogenic or psychogenic erectile dysfunction generally respond to lower doses than those with vasculogenic erectile dysfunction.2,  9,  19,  31,  64,  89 Overall response rate generally is less in patients with erectile dysfunction of mixed etiology than in those with neurogenic or psychogenic erectile dysfunction and those with vasculogenic erectile dysfunction.31,  64 In men with erectile dysfunction associated with diabetes mellitus, intracavernosal alprostadil was effective in producing satisfactory erections at doses ranging from 10-40 mcg; however, efficacy was less in men with long-standing diabetes (exceeding 10 years) and in those with long-standing erectile dysfunction (exceeding 5 years).67 In addition, lower response rates have been observed with intracavernosal alprostadil in older men, with or without diabetes, than in younger men, but dose escalation may increase efficacy in geriatric patients.27,  32,  40,  64,  67,  68 Limited data indicate that response rates in patients using intraurethral alprostadil are independent of the etiology of erectile dysfunction.97,  99

The dose of alprostadil is adjusted by the clinician according to the patient's response toward a therapeutic goal of achieving an erection satisfactory for intercourse of 1-hour duration; erections persisting longer than 1-hour increase the risk of priapism.2,  5,  12,  34,  69,  89,  97,  98 Most males with various etiologies of erectile dysfunction respond to initial single intracavernosal alprostadil doses of 5-20 mcg; some males, especially those with neurogenic or psychogenic erectile dysfunction, experience erections at doses as low as 0.5-5 mcg.2,  18,  22,  31,  34,  38,  36,  37,  45,  64 In addition, while intracavernosal doses as high as 140 mcg have been used, almost all patients who respond do so at doses of 60 mcg or less,2 and doses exceeding 60-65 mcg generally are not recommended.2,  26,  32,  35,  36,  41,  64 Results of a multicenter placebo-controlled study in patients with erectile dysfunction of various organic etiologies using intraurethral alprostadil in the initial (dose titrating) phase indicate that about 19% of the patients experienced erection with 125- or 250-mcg doses while about another 47% of patients experienced erection with 500- or 1000-mcg doses of the drug.97 In addition, a correlation appears to exist between dose of intraurethral alprostadil and mean duration of response.97,  35,  39,  40,  41,  64 In the home maintenance phase of the placebo-controlled multicenter study in patients receiving intraurethral alprostadil, at least one sexual intercourse occurred in about 65 or 19% of patients receiving alprostadil urethral suppositories or placebo, respectively, while orgasm (occurring at least once) was reported in about 64 or 24% of patients receiving the drug or placebo, respectively.97 In patients who responded to home maintenance therapy, 70% of administrations (7 out of 10) resulted in successful intercourse.97,  98 In studies that evaluated sexual intercourse during the home maintenance phase, 66-87% of the men using intracavernosal alprostadil reported satisfactory intercourse per injection. However, efficacy of the intracavernosal injection in the home during intercourse may be reduced relative to office-based titration to adequate erection,2,  32,  39,  40,  41,  64,  66 possibly secondary to problems with injection technique, anxiety associated with sexual performance, and/or problems in partner acceptance;32 as a result, some patients may require an increase in the office-titrated dose once maintenance therapy is under way at home.2,  39,  40,  41,  64,  66 In some cases, though, patients actually have a greater response to alprostadil in the home setting and may be able to decrease their dose.9,  11,  12,  18,  30,  32,  34,  41,  64,  66,  69

Occasionally, it may be possible to discontinue alprostadil therapy because normal erectile function returns.17,  19,  27,  34,  64,  66 In such cases, normal erectile functioning may result from decreased anxiety, improved self-confidence (e.g., in those with psychogenic erectile dysfunction), or improved penile circulation in those with vasculogenic erectile dysfunction.24,  34,  76

While most males with erectile dysfunction respond to alprostadil therapy, treatment failures occur in about 20% (and up to 33% of geriatric men) or 35% of patients receiving intracavernosal2,  19,  39,  62,  64,  89,  101 or intraurethral79 therapy, respectively, during home maintenance. In addition, other males may not be able to complete the dose titration phase of therapy,2,  19,  39,  62,  64,  89 and many patients, despite adequate response, eventually drop out from continued use for various reasons.7,  19,  20,  34,  64,  65,  67,  68 Corporeal veno-occlusive dysfunction may hamper the effectiveness of the drug in the treatment of erectile dysfunction, but men with arteriogenic, psychogenic, and neurogenic impotence also have reported failure with alprostadil.19,  24,  27,  31,  46

Several comparative studies have evaluated the efficacy of various formulations of alprostadil.107,  110 Limited data indicate that intracavernosal alprostadil may be more effective than intraurethral alprostadil in the treatment of erectile dysfunction.107 In one comparative study using intracavernosal alprostadil (up to 20 mcg) or intraurethral alprostadil (up to 1000 mcg), complete rigid erections occurred in 48 or 10% of patients, respectively, while total responses (complete rigid erection or full tumescence with partial rigidity) were reported in 70 or 43% of patients, respectively.107 Substantially higher alprostadil doses are needed for treatment of erectile dysfunction when the intraurethral route is used compared with intracavernosal therapy, since the drug contained in the urethral suppository is distributed from the mucosal cells of the urethra into the corpus spongiosum and corpus cavernosum.105 Alprostadil may undergo some metabolism in the urogenital tract and in addition, some alprostadil may be distributed from the corpus spongiosum directly into the pelvic venous circulation bypassing the corpus cavernosum.105 It has been suggested that a new technique involving an adjustable external penile band used in conjunction with the urethral suppositories possibly may improve delivery of the drug into the corpus cavernosum and thus achieve efficacy with lower doses of the intraurethral drug.105 Results of a crossover study evaluating intracavernosal alprostadil with (Caverject^® Impulse^®) or without alfadex (α-cyclodextrin) (Caverject^®) in a limited number of men with erectile dysfunction indicate that the safety and efficacy of the 2 formulations are comparable.110

Although the manufacturers state that safety and efficacy of combined vasoactive therapy for erectile dysfunction that includes alprostadil have not been established by systematic study and therefore currently is not recommended,2,  64,  101 intracavernosal alprostadil has been used in combination with phentolamine and papaverine; phentolamine, atropine, and papaverine; calcitonin gene-related peptide; or papaverine in an attempt to increase response, decrease dosage of individual agents, and decrease the incidence of local pain, penile corporal fibrosis, fibrotic nodules, hypotension, and priapism.9,  10,  11,  12,  14,  15,  17,  18,  21,  65,  71,  90,  91 Combined therapy with intraurethral alprostadil and a vacuum constriction device or an oral selective PDE type 5 inhibitor has exhibited increased efficacy relative to alprostadil alone;112 combined therapy with intracavernosal alprostadil and a selective PDE type 5 inhibitor has not been adequately evaluated.112 Additional study is needed to elucidate the long-term safety and benefits of such combined therapy.9,  10,  14,  18,  65,  90,  91

In a limited number of patients, intraurethral alprostadil has been used in combination with prazosin; increased response rates associated with the combination therapy were more pronounced in patients receiving the lower doses (i.e., 125 or 250 mcg) of alprostadil.105

Alprostadil should not be used in patients who might have conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia, thrombocythemia, polycythemia, propensity to develop venous thrombosis, hyperviscosity syndrome), in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease), or in men for whom sexual activity is inadvisable or contraindicated.2,  8,  19,  32,  64,  76,  89,  97,  98,  100 In addition, alprostadil should be discontinued in any patient who develops penile angulation, cavernosal fibrosis, or Peyronie's disease during therapy with the drug.2,  89 The manufacturers also state that patients with penile implants should not be treated with intracavernosal alprostadil.2,  101 Alprostadil urethral suppositories should not be used in patients with certain genitourinary tract disorders (e.g., urethral stricture or obstruction, balanitis, acute or chronic urethritis, severe hypospadias and curvature, anuria) or in those with an indwelling urethral catheter.97,  98,  99,  100,  105 Since alprostadil is embryotoxic in animals, patients using intraurethral alprostadil should not engage in sexual intercourse with a pregnant woman unless a condom is used.98,  100,  104

Diagnosis

Alprostadil also is used by intracavernosal injection as an adjunct in the differential diagnosis of erectile dysfunction and in evaluating the hemodynamic status of erectile tissue.2,  5,  15,  16,  17,  21,  24,  27,  28,  65,  66,  67,  110 The drug can be used alone (simply monitoring for erectile response after intracavernosal injection) or prior to other testing (e.g., penile angiography, duplex or Doppler ultrasonography, radioisotope penograms, cavernosography, radiolabeled-xenon penile clearance, cavernosometry) as an adjunct to facilitate visualization and assessment of the penile vasculature.2,  5,  15,  16,  17,  21,  24,  27,  28,  65,  66,  67,  86

Pharmacologic test doses of intracavernosal alprostadil generally are used alone when simply assessing the adequacy of penile arterial and veno-occlusive function.2,  28,  34,  45,  65,  67 The induction of a rigid or nearly rigid erection after intracavernosal alprostadil generally indicates that arterial inflow is adequate to occlude venous outflow drainage, and patients with such response generally are suitable candidates for intracavernosal vasoactive therapy.28,  34,  45,  65,  67 Genital stimulation may be used to increase the erectile response in such testing.16,  17,  65,  89 Intracavernosal alprostadil testing also may be used as an aid in differentiating erectile dysfunction that is of vasculogenic versus neurogenic or psychogenic origin; a positive response, especially at low doses, may be indicative of neurogenic or psychogenic erectile dysfunction.28,  34,  45,  65,  67 If partial tumescence occurs, mild to moderate arterial or venous disease may be present,34 and an erection after alprostadil injection that is not sustained may be indicative of venous dysfunction.16,  17,  92

Patients with an inadequate or negative response to intracavernosal alprostadil may benefit from further vascular testing; such additional testing may aid in differentiating between arteriogenic or venogenic erectile dysfunction.16,  21,  27,  28,  65,  67,  76,  85,  92,  93 However, it should be recognized that failure to respond adequately may not indicate vascular insufficiency but rather could simply be secondary to patient anxiety or discomfort.15,  65,  76,  78,  82,  85,  86,  88,  89,  92 In addition, the number of patients who may benefit from additional vascular testing is small but includes patients who are candidates for vascular surgery, such as young men with a history of perineal or pelvic trauma and resultant arterial blockage with or without neurologic deficit.15,  16,  65,  76,  78,  85,  86 Studies to further define vasculogenic disorders include duplex ultrasonography, dynamic infusion cavernosometry/cavernosography, radioisotope penogram, and pelvic-penile angiography; such testing can be performed alone or in conjunction with intracavernosal vasoactive agents such as alprostadil.15,  16,  17,  18,  24,  33,  34,  65,  67,  80,  85,  88,  92,  93 Specialized references should be consulted for additional information on the performance and interpretation of tests of erectile function involving intracavernosal alprostadil, and consideration should be given to referral to clinicians with expertise and interest in evaluating the vascular aspects of erectile dysfunction, particularly when specialized tests such as ultrasonography, cavernosometry/cavernosography, or angiography are performed.7,  12,  23,  65,  80,  71,  85,  87

Ductus Arteriosus-dependent Congenital Heart Disease

Alprostadil is used IV for palliative, not definitive, therapy in maintaining patency of the ductus arteriosus in neonates born with various ductal-dependent congenital heart defects such as pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, and/or transposition of the great vessels with or without other defects.1,  3,  29,  42,  43,  44,  47,  51,  56,  57,  60 The drug is used to provide adequate circulation and oxygenation and prevent or correct resultant acidemia until corrective or palliative surgery can be performed.1,  3,  42,  43,  44,  47,  49,  51,  52,  53,  54,  55,  56,  60 Alprostadil is only effective if initiated prior to complete anatomic closure of the ductus.29,  42,  43,  44,  57 Although alprostadil therapy is indicated principally as a short-term measure, more prolonged therapy (e.g., up to several months) with the drug occasionally may be indicated (e.g., when surgical risk to the neonate dictates delay of the procedure), but the possible risks of prolonged therapy with the drug (e.g., gastric outlet obstruction secondary to antral hyperplasia, cortical hyperostosis of long bones, morphologic changes in pulmonary arteries) should be weighed carefully against the potential benefits.1,  3,  44,  47,  49,  50,  52,  54,  55,  58,  59,  95

Because of the risk of respiratory depression and apnea, which is greatest during the first hour of drug infusion particularly in neonates weighing less than 2 kg at birth, the manufacturer of Prostin VR Pediatric^® states that alprostadil therapy for maintaining ductal patency should be performed only by trained personnel in facilities providing pediatric intensive care where respiratory status can be monitored throughout treatment and facilities and equipment for assisted ventilation are readily available.1,  3,  44,  50,  53,  60 However, some clinicians suggest that an alprostadil IV infusion can be initiated at the local neonatal unit prior to transport to a tertiary care center, provided adequate monitoring can be undertaken and respiratory support initiated if necessary.44,  53,  54,  55,  57,  60

Alprostadil should not be used in patients with neonatal respiratory distress syndrome.1,  4,  42,  49,  64 In such neonates, closure of the ductus arteriosus is necessary to prevent overload of the pulmonary circulation.4,  42,  49,  55 Therefore, a differential diagnosis between neonatal respiratory distress syndrome (hyaline membrane disease) and cyanotic heart disease (restricted pulmonary blood flow) should be made prior to initiating alprostadil therapy.1 The manufacturer of Prostin VR Pediatric^® states that if full diagnostic facilities are not readily available, cyanosis (evidenced by a PO₂ less than 40 mm Hg) and radiographic evidence of restricted pulmonary blood flow are appropriate indicators of congenital heart defects.1 Alprostadil also should not be used in premature neonates with patent ductus arteriosus since cardiopulmonary management of such neonates also depends on closure of the ductus.4,  42,  49,  55,  64 In addition, the risk to benefit of alprostadil therapy should be weighed carefully in neonates with bleeding disorders (because of the drug's platelet-aggregation inhibiting effects)1,  42,  44,  50,  64 and in those with conditions in which alprostadil-induced increases in pulmonary blood flow may precipitate pulmonary edema and/or congestive heart failure.3,  29,  52,  54,  60,  70

The ductus arteriosus is present during fetal life, connecting the pulmonary artery to the descending aorta and thus diverting from the lungs to the placenta (for gas exchange) most blood passing through this artery.3,  4,  42,  51,  54,  55,  57 The ductus arteriosus apparently is maintained in a dilated state by a low partial pressure of oxygen and by effects of prostaglandins, presumably of the E series, which are produced by the placenta and in the ductus itself.3,  4,  42,  44,  55 The ductus usually closes within 24-96 hours after birth, partly as a result of a loss of circulating prostaglandins, a decrease in sensitivity to prostaglandins, and an increase in pulmonary blood flow.42,  44,  47,  55,  58 In neonates with congenital heart defects that result in cyanosis either by restricting pulmonary blood flow (pulmonary atresia, pulmonary stenosis, tetralogy of Fallot, tricuspid atresia) or systemic arteriovenous mixing (transposition of the great arteries) or that result in restriction of systemic blood flow (interruption of the aortic arch, coarctation of the aorta), the ductus arteriosus functions to preserve blood oxygenation and lower body perfusion.1,  3,  4,  29,  42,  43,  44 The spontaneous closure of the ductus arteriosus after birth is associated with hypoxemia and metabolic acidosis in neonates with restricted pulmonary blood flow and with metabolic acidosis, poor systemic perfusion, oliguria, and severe heart failure in those with restricted systemic blood flow.1,  3,  4,  44,  51

Dilation of the constricted ductus arteriosus with alprostadil in neonates with cyanotic congenital heart disease results in a temporary increase in arterial oxygen partial pressure (PaO₂) and oxygen saturation secondary to the increase in pulmonary blood flow and/or increased mixing between the systemic and pulmonary circulation.1,  3,  43,  56,  58 Efficacy of alprostadil in increasing PaO₂ or oxygen saturation has been established relative to pretreatment values in the same neonates; data from placebo-controlled or comparative trials are not available.1,  3,  43,  56,  58,  64 The increase in pulmonary blood flow may result from combined maintenance of the patency of the ductus arteriosus and dilation of the pulmonary vascular bed induced by the drug.43,  44,  55,  56,  58,  60,  70

Response to alprostadil therapy in cyanotic neonates is inversely related to pretreatment PO₂.1,  29,  43,  57 Thus, while about half of cyanotic neonates respond to the drug with at least a 10- mm Hg (mm Hg) increase in blood PO₂, neonates having pretreatment values of 40 mm Hg or greater (e.g., those with a widely patent ductus) usually exhibit little response,1,  29,  43,  57 and response increases to 77% in those with low pretreatment blood PO₂ (less than 20 mm Hg), with a narrowing of the ductus arteriosus, and who are 4 days old or younger.1,  29,  42,  43,  44 The age-dependent efficacy of alprostadil Prostin VR Pediatric^® administration in cyanotic neonates suggests that anatomic closure progresses irreversibly or that permanent functional closure occurs secondary to decreased responsiveness of ductal tissue to prostaglandins.29,  42,  43,  44,  57,  60

Alprostadil has been used to increase arteriovenous mixing and pulmonary blood flow in neonates with transposition of the great arteries.1,  3,  43,  47,  54,  55,  56,  60,  63,  70 However, the optimal timing of administration of the drug and the duration of therapy in conjunction with atrial septostomy or septectomy and arterial switching have not been established.3,  43,  47,  54,  55,  56,  60,  63,  70

In neonates with restricted systemic blood flow, dilation of the ductus arteriosus with alprostadil can result in prevention or correction of acidemia, increased cardiac output accompanied by increased systemic blood pressure, increased femoral pulse volume, increased renal blood flow and function (urine production), decreased gradient of descending to ascending aortic blood pressures (in neonates with coarctation of the aorta), and/or decreased gradient of pulmonary artery to descending aortic pressures (in neonates with interruption of the aortic arch).1,  3,  29,  43,  44,  51,  56,  57,  60 Unlike cyanotic neonates, acyanotic neonates do not display as pronounced an age dependence for a positive effect, and efficacy does not depend on low pretreatment arterial partial pressure (PaO₂); acyanotic neonates may have normal or slightly reduced PaO₂.43,  57 Alprostadil reportedly has increased arterial pH from pretreatment values of 6.8-7.22 to posttreatment values of 7.22-7.45 in acyanotic neonates; efficacy in reversing metabolic acidosis does not appear to be dose related.51,  60 In addition, the need for alkalinizing agents generally is reduced or eliminated.43 Mean systolic and diastolic blood pressures in the descending aorta increased 48-52% and 21-25%, respectively, in neonates with coarctation of the aorta receiving alprostadil infusion.43,  57 The mean pressure difference between the main pulmonary artery and the descending aorta decreased from 13-14 mm Hg to 2-3 mm Hg in neonates with interruption of the aorta receiving alprostadil therapy.43,  57

Administration

Alprostadil is administered by intracavernosal injection for the treatment and diagnosis of erectile dysfunction, by urethral suppository for the treatment of erectile dysfunction, or by continuous IV or intra-arterial infusion to maintain the patency of the ductus arteriosus in neonates.1,  2,  97,  98,  100,  101,  102

Intracavernosal Administration

Intracavernosal alprostadil therapy should be initiated in a medical setting (e.g., physician's office), with the initial injections being administered by medically trained personnel.2,  7,  23,  34,  65,  101,  102,  110,  112 Patients can begin intracavernosal self-injection of alprostadil only after they have received and reviewed a copy of the patient instructions provided by the manufacturer and have been instructed carefully and trained well about proper administration techniques, including aseptic techniques and precautions.2,  5,  22,  34,  67,  69,  71,  83,  101,  102,  112 Careful instruction about administration technique can minimize the likelihood of local adverse effects associated with faulty technique (e.g., hematoma, ecchymosis) and also can minimize patient frustration and treatment failure.2,  5,  7,  22,  25,  71,  83,  101,  102,  112

To improve compliance and potentially decrease treatment dropout, patients should be highly motivated and properly educated about intracavernosal therapy, and they and their partners should be provided long-term follow-up support to assist them in adjusting to this therapeutic intervention.23,  65,  83 Careful and continuous follow-up should include ongoing education and support in therapy, careful determination of reasons for discontinuing therapy if this occurs, and discussion of therapeutic options if alprostadil therapy is not tolerated or is unsuccessful.2,  7,  19,  20,  34,  65,  67,  89 Adequate assessment of the motivations and expectations of the patient and partner prior to intracavernosal therapy also can aid in optimizing outcome.65,  79,  83 Follow-up is particularly important during the initial period of self-injections since dosage adjustment often is necessary during this period.2,  8,  9,  11,  12,  18,  30,  32,  34,  39,  40,  41,  64,  66,  69,  101,  102

Patients also should be instructed that unreconstituted alprostadil sterile powder (Caverject^®) may be stored for up to 3 months at 25°C or colder, while avoiding freezing.2 During travel, care should be taken to avoid exposure to freezing or temperatures exceeding 25°C; therefore, the powder should not be stored in checked airline baggage (storage in the passenger compartment is permitted) or in a closed automobile.2,  64 The sterile lyophilized powder in an alfadex (α-cyclodextrin) inclusion complex (Edex^®) should be stored at room temperature at 15-30°C.101 The sterile lyophilized powder with alfadex (Caverject^® Impulse^®) should be stored at 25°C but may be exposed to temperatures ranging from 15-30°C.110

Prior to reconstitution, alprostadil sterile powder (Caverject^®) should be warmed to room temperature under ambient conditions;2,  5,  64 use of a water bath to facilitate warming is not recommended.64 Commercially available alprostadil sterile powder (Caverject^®) for intracavernosal use should be reconstituted just prior to administration by adding 1 mL of bacteriostatic water for injection or sterile water to a vial labeled as containing 11.9, 23.2, or 46.4 mcg of the drug to provide a solution containing 10.5, 20.5, or 41.1 mcg/mL, respectively.2 Although the resultant diluted solutions contain 10.5, 20.5, or 41.1 mcg/mL, the deliverable amount of alprostadil in these dilutions is 10, 20, or 40 mcg/mL, respectively, bacause approximately 0.5, 0.5, or 1.1 mcg, respectively, of the drug is adsorbed onto the vial and syringe.2

Alternatively, the commercially available lyophilized powder of alprostadil in an alfadex inclusion complex (Edex^®) for intracavernosal use should be reconstituted just prior to administration by adding 1.2 mL of bacteriostatic 0.9% sodium chloride injection (which is supplied by the manufacturer in a separate vial when the drug is contained in a kit) to a vial labeled as containing 12.45, 24.9, or 49.8 mcg of the drug, to deliver a solution containing 10, 20, or 40 mcg/mL, respectively.101 After adding the diluent but before removing the syringe from the vial, the contents of the vial may be swirled gently until a clear solution is obtained.2 The desired dose (determined by careful titration) of the reconstituted solution can then be withdrawn into the same syringe.2 If the reusable injection device containing alprostadil powder in an alfadex inclusion complex is used, the drug should be reconstituted immediately by placing the commercially available dual-chambered cartridge into the injection device and then turning the threaded plunger of the device to force the diluent (1.075 mL of 0.9% sodium chloride injection) into the lower chamber containing alprostadil powder and mixing the contents of the cartridge gently to dissolve the solid.101 The reconstituted solution of alprostadil in an alfadex inclusion complex may initially appear cloudy as a result of introduction of small air bubbles.101 The vial or cartridge containing alprostadil in an alfadex inclusion complex contains the drug in a cake approximately three-sixteenths or (3/8) inch in thickness, respectively.101 If the vial or cartridge is damaged or the cake is substantially smaller than the manufacturer's specifications, the vial or cartridge should not be used.101

If the single-use, disposable dual-chambered syringe system containing alprostadil powder and alfadex (Caverject^® Impulse^®) is used,110 the drug should be reconstituted by turning the plunger rod clockwise until the rod meets resistance to force the diluent (sterile bacteriostatic water for injection) into the chamber containing alprostadil powder.111 The contents of the syringe should then be mixed thoroughly by turning the device upside down several times.111 The reconstituted solution of alprostadil should be clear.110 The dose to be delivered is set by slowly turning the end of the plunger rod clockwise until the number visible in the dose window matches the appropriate dose of the drug (in mcg).111 The delivery device labeled as containing 10 mcg of alprostadil can be set to deliver a dose of 2.5, 5, 7.5, or 10 mcg of the drug (solution volume of 0.125, 0.25, 0.375, or 0.5 mL, respectively), and the delivery device labeled as containing 20 mcg of alprostadil can be set to deliver a dose of 5, 10, 15, or 20 mcg (solution volume of 0.125, 0.25, 0.375, or 0.5 mL, respectively).110 The single-use delivery device and any remaining solution should be disposed of properly following use.110,  111

Reconstituted solutions of certain formulations of alprostadil for intracavernosal injection (Caverject^®, Edex^®) are intended for single-use only and should be used immediately.2,  28,  101 Reconstituted solutions of alprostadil (Caverject^® Impulse^®) prepared from the powder for injection are intended for single-use only and should be used within 24 hours when stored at or below 25°C.110 Reconstituted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.2,  101,  110

For intracavernosal injection, the head (glans) of the penis (if uncircumcised, the foreskin should pulled back initially) is held between the thumb and forefinger and stretched lengthwise along the thigh while sitting upright or slightly reclined, and the needle of the syringe or injection device is then positioned so that the drug will be injected into a corpus cavernosum underneath the tunica albuginea along the dorsolateral aspect of the proximal third of the penis.2,  22,  24,  27,  67,  69,  71,  83,  89,  101 Once positioned, the needle of the syringe or injection device provided by the manufacturer (a fixed-hub, ½-inch, 27-, 29- or 30-gauge needle) should be pushed straight into the site using a steady motion until the metal portion of the needle is almost entirely in the penis; the dose should then be injected slowly (over 5-10 seconds) into the chosen corpus cavernosum.2,  22,  27,  64,  71,  83,  101,  110,  111 If a syringe other than the one provided by the manufacturer is used, it is recommended that it be a ½-inch, 27- to 30-gauge needle.2,  64 If the needle becomes severely bent at anytime during reconstitution or injection of alprostadil, the needle should be discarded and a new unused needle should be used for these procedures.2 Blood vessels, corpus spongiosum, subcutaneous tissue, urethra, and dorsal neural vascular structures should be avoided as injection sites.2,  5,  7,  8,  28,  34,  83 The syringe or injection device then should be withdrawn and pressure applied to the injection site with an alcohol swab for 5 minutes (or until bleeding stops) to avoid hematologic complications (e.g., intracorporeal hematoma, ecchymosis, hemorrhage at the site of injection), especially in patients receiving concomitant anticoagulant therapy.2,  7,  22,  25,  67,  71,  83,  89,  101,  111 To minimize adverse effects related to repeated local injection, the side of the penis and the site of injection should be varied.2,  8,  89,  111 Patients should be cautioned against reuse of syringes and needles and should be given instructions on the proper disposal in puncture-resistant containers.2 Unused reconstituted solutions of alprostadil should be discarded.2,  10,  28,  110

Patients should be advised of the potential for prolonged erections (priapism), particularly with intracavernosal therapy, and informed of the steps to take in the event that this potentially serious adverse effect occurs.112,  113

Patients should be advised that use of intracavernosal alprostadil provides no protection against sexually transmitted diseases, and they should be counseled regarding protective measures to guard against such transmission.2,  110 In addition, they should be counseled about the potential increased risk of transmitting blood-borne diseases secondary to possible exposure of the sexual partner to the small amount of blood at the injection site.2,  110

IV and Intra-arterial Infusion

To maintain patency of the ductus arteriosus, alprostadil (Prostin VR Pediatric^®) preferably is administered by continuous IV infusion into a large vein (peripheral or central)1,  44 via a controlled-infusion device (e.g., an electronic volumetric controller, volumetric IV infusion pump) or other apparatus to ensure precise control of the flow rate during infusion since inadvertent rapid administration could result in toxicity (e.g., apnea).1,  50,  60,  70 Alternatively, alprostadil may be administered through an umbilical artery catheter placed at the ductal opening.1 However, the IV route has been better tolerated (e.g., flushing is more common with intra-arterial injection) and is currently the preferred route of alprostadil administration for maintaining patency of the ductus arteriosus.1,  3,  44,  50,  53,  57,  60 If flushing occurs during intra-arterial infusion, the catheter should be repositioned.1 Because systemically administered alprostadil is metabolized rapidly with a substantial portion undergoing β- and ω-oxidation on first pass through the lungs, the drug must be infused continuously to maintain ductal patency.1,  20,  22,  24,  26,  27,  28,  34,  44,  54,  55,  67,  94

Alprostadil for injection concentrate containing 500 mcg/mL must be diluted prior to infusion. 1 For infusion, 1 mL of the concentrate labeled as containing 500 mcg of alprostadil is diluted in 0.9% sodium chloride or dextrose 5% injection to provide a solution containing 2-20 mcg/mL, depending on the controlled-infusion device employed and the needs of the neonate.1,  64 When using a device with a volumetric infusion chamber, the appropriate volume of diluent should be added to the chamber first and then 1 mL of alprostadil concentrate for infusion should be added to the diluent.1 The following table lists sample alprostadil dilutions and infusion rates when a dosage of 0.1 mcg/kg of body weight per minute is employed.1 This dosage is commonly used for initiation of alprostadil therapy to maintain patency of the ductus arteriosus.1

For example, to provide an alprostadil dosage of 0.1 mcg/kg of body weight per minute to an infant weighing 2.8 kg using 500 mcg of alprostadil concentrate in 100 mL of compatible diluent, the resultant infusion rate for this solution would be 0.056 mL/minute (i.e., 0.02 mL/minute per kg × 2.8 kg) or 3.36 mL/hour.1

During dilution, care should be taken to avoid direct contact of the concentrate with the wall of the plastic volumetric infusion chamber since the appearance of the chamber may change and a hazy solution may develop; if this occurs, the chamber and solution should be discarded.1

Alprostadil for injection concentrate should be stored at 2-8°C.1 The manufacturer of Prostin VR Pediatric^® recommends that diluted solutions of the drug be prepared freshly every 24 hours and that any remaining solution should be discarded.1,  44

Because of the risk of respiratory depression and apnea, respiratory status of the neonate should be monitored throughout alprostadil Prostin VR Pediatric^® administration, and facilities and equipment for assisted ventilation should be readily available.1,  50 Apnea is most likely to develop during the first hour of infusion, particularly in neonates weighing less than 2 kg at birth.1,  3,  50 In addition during infusion, arterial pressure should be monitored periodically via umbilical artery catheter, auscultation, or Doppler transducer and the rate of infusion decreased immediately if a clinically important decrease in arterial pressure occurs.1,  50 The infusion rate also should be slowed if fever or hypotension (appropriate therapy also may be necessary) occurs since these may be signs of overdosa once they subside, the rate can be increased cautiously if necessary.1,  3,  50 If apnea or bradycardia occurs, the infusion should be discontinued and appropriate treatment initiated;1,  50 in some cases, the infusion can be reinitiated cautiously if continued therapy is considered necessary.1,  3,  42,  50,  64

Standardize 4 Safety

Standardized concentrations for IV alprostadil have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249 For additional information on S4S (including updates that may be available), see [Web].249

Intraurethral Administration

Alprostadil is administered intraurethrally as a suppository.97,  98,  99,  100,  104,  105,  106 Therapy with intraurethral alprostadil should be initiated in a medical setting (e.g., physician's office).98,  100 Patients should begin intraurethral self-administration of alprostadil only after they have received and reviewed a copy of the patient instructions (including a video) provided by the manufacturer and have been instructed carefully about proper administration techniques and precautions.98,  100

Patients should urinate immediately prior to insertion of the alprostadil urethral suppository and they should gently shake the penis to remove excess urine.97,  100,  105,  106 The micro suppository (medicated pellet) is designed to dissolve in the small quantity of urine remaining in the urethra after urination.99,  100 Alprostadil urethral suppository should be inserted with a urethral applicator according to the manufacturer's instructions.97,  100 After the suppository has been inserted, the removed applicator should be visually inspected to confirm that the urethral suppository is no longer in the applicator tip.100 If some residual medication is left in the applicator, the insertion procedure should be repeated.100 Urination or dribbling immediately following intraurethral alprostadil may result in loss of drug from the urethral area.100

After application of the medicated pellet (suppository), the penis should be held upright, stretched to its full length and rolled firmly between the hands for at least 10 seconds to ensure that the drug is adequately distributed along the walls of the urethra.100 If a burning sensation occurs, the penis may be rolled for an additional 30-60 seconds or until burning subsides.100 After administration, sitting, standing, or walking for 10 minutes will increase blood flow to the penis and enhance erection; lying down (especially on the back) immediately after administration of the suppository may reduce blood flow to the penis and reduce the development of erection.100,  106 During sexual activity, erection may be better maintained in positions that favor blood flow into the penis.100

Patients should be advised that use of intraurethral alprostadil provides no protection against sexually transmitted diseases, and they should be counseled regarding protective measures to guard against such transmission.98,  100

Dosage

Initiation and Titration in Patients with Erectile Dysfunction

Intracavernosal Dosage

Dosage of intracavernosal alprostadil must be individualized carefully according to the patient's erectile response.2,  5,  8,  12,  19,  32,  34,  89,  101 Initiation and titration of dosage should be undertaken in a medical setting, and the patient must remain in this setting during titration of each dose until complete detumescence occurs.2,  5,  19,  32,  64 If no response occurs with a given dose, upward titration should be attempted after about 1 hour; no more than 2 injections should be administered initially within a 24-hour period.2,  64,  101,  110 If a response is observed, at least 24 hours should elapse before administering the next dose.2,  101 Dosage should be titrated slowly to the lowest possible effective level in order to avoid priapism.2,  5,  12,  19,  32,  101

For the treatment of neurogenic impotence secondary to spinal cord injury, the usual adult intracavernosal dose of alprostadil ranges from 1.25-60 mcg.2 Generally, therapy is started with the smaller dosage and increased until the optimum dose (as determined by maintenance of an erection that is satisfactory for intercourse but persists no longer than 1 hour) is attained.2,  5,  19,  30,  41,  89 For the treatment of pure neurogenic impotence (i.e., spinal cord injury), the manufacturers recommend an initial intracavernosal dose of 1.25 mcg of alprostadil administered in a medical setting.2,  5,  89,  101,  110 If no response is observed with the initial dose of alprostadil, the dose may be doubled to 2.5 mcg after about 1 hour; no more than 2 doses should be administered within a 24-hour period.2,  64,  101,  110 If additional dosage titration is required, a dose of 5 mcg may be administered during the next 24 hours, followed by subsequent increases in 5-mcg increments, with each incremental increase separated by at least 24 hours, until optimum response is achieved.110 If the duration of the erection achieved exceeds 1 hour, the subsequent dose of alprostadil should be reduced.2

For the treatment of vasculogenic erectile dysfunction, psychogenic erectile dysfunction, or erectile dysfunction of mixed etiology, the manufacturers recommend an initial intracavernosal test dose of alprostadil of 2.5 mcg.2,  8,  101,  110 If a partial response is observed, the dose may be doubled to 5 mcg after about 1 hour.2,  101,  110 If no response to the initial test dose is observed, then the second dose may be increased to 7.5 mcg after about 1 hour.2,  101,  110 No more than 2 doses should be administered within a 24-hour period.110 If additional titration is required, dosage may be increased in increments of 5-10 mcg at intervals of at least 24 hours until optimum response is achieved.110

In clinical trials, most patients with erectile dysfunction of various etiologies responded to initial intracavernosal alprostadil doses titrated to exceeding 5 but not exceeding 20 mcg, with the dose at the end of the titration phase averaging 17.8 mcg.2,  64 Although doses ranging from 0.2-140 mcg have been reported, almost all patients who respond to alprostadil do so at doses of 60 mcg or less; therefore, doses exceeding 60-65 mcg generally are not recommended.2,  26,  32,  35,  36,  41,  64

Intraurethral Dosage

Dosage of intraurethral alprostadil should be individualized according to the patient's erectile response.98,  99,  100,  107 Since symptomatic hypotension and syncope occurred in 3 and 0.4% of patients, respectively, using intraurethral alprostadil during the initial (dose-titrating) phase, initiation and titration of dosage should be undertaken in a medical setting to monitor the patients for manifestations of such effects.98,  100 Patients should inform their clinician if they have a history of syncope.100 It is recommended that therapy with intraurethral alprostadil be initiated with low doses (e.g., 125 or 250 mcg); dosage should be titrated (in separate visits) to the lowest possible effective level in order to avoid development of hypotension or syncope, which appear to be dose related.98,  105 If no response occurs with these doses, subsequent doses may be increased in a stepwise manner to 500 or 1000 mcg, as needed.98,  107 In clinical studies, 6-10, 17-20, 20-30 or 27-56% of patients achieved adequate penile response (erections sufficient for intercourse) at intraurethral alprostadil doses during the dosage-titration phase (to establish home maintenance dosage) of 125-, 250-, 500-, or 1000 mcg, respectively.97,  98,  107

Maintenance in Patients with Erectile Dysfunction

Intracavernosal Dosage

Intracavernosal alprostadil self-injection therapy for erectile dysfunction should be initiated at the dose that was determined as optimal during titration in a medical setting (e.g., physician's office); however, the first self-administered dose should be delayed for at least 1 day after completion of supervised dose titration but also should be administered in a medical setting.2 The optimal maintenance dose should result in an erection that is maintained for no longer than 1 hour.2 Adjustments to the initial office-titrated dose often are required to maintain response in the home, but should be attempted only after consultation with a clinician (not independently by the patient), following the same initial titration guidelines.2 The manufacturers recommend that patients self-administer intracavernosal alprostadil no more frequently than 3 times weekly with at least 1 day elapsing between each dose.2,  34,  101 Follow-up monitoring of patients should be performed every 3 months to determine safety (e.g., careful examination of the penis for fibrotic changes) and the possible need for additional dosage adjustment.2,  34,  41 Alprostadil therapy should be discontinued if penile angulation, cavernosal fibrosis, or Peyronie's disease develop.2,  89 The manufacturer of Caverject^® states that efficacy of long-term alprostadil therapy for erectile dysfunction has been established for up to 6 months by an uncontrolled, self-injection study; at 6 months, the optimal dose averaged 20.7 mcg.2 Doses exceeding 60-65 mcg generally are not recommended.2,  26,  32,  35,  36,  41,  64

Prolonged erection (persisting 4-6 hours) or priapism (erection persisting 6 hours or longer) occurred in 4 or 0.4% of patients, respectively, receiving intracavernosal alprostadil in clinical studies.2,  110 However, priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, and therefore, patients should be advised to report promptly to their physician or, if unavailable, to seek alternative immediate medical attention if an erection that persists longer than 4 hours or that is extremely painful occurs.2,  34,  76,  79,  89,  102,  103 Management of priapism or prolonged erection should be according to established medical practice,2,  6,  7,  8,  11,  12,  19,  20,  23,  46,  67 and has included aspiration of cavernosal blood and/or intracavernosal injection of an α-adrenergic agonist (i.e., phenylephrine, epinephrine) or dopamine;113 priapism may be more likely during dose titration than during maintenance (home) therapy.2,  6,  7,  8,  11,  12,  19,  20,  23,  46,  64,  67,  78 Rarely, more radical therapy for priapism (e.g., cavernospongiosus or Winter's shunt) may be necessary,113 such as in patients with persistent priapism (e.g., for longer than 24 hours).73,  74,  75,  76,  77,  79,  89

The most common adverse effect associated with intracavernosal alprostadil use is penile pain, which was reported at least once in 37% of patients in clinical studies of up to 18 months' duration.2 In most cases, such pain was described as mild to moderate in intensity, although 3% of patients discontinued therapy with the drug because of penile pain.2 Patients should be advised to report to their clinician penile pain that develops or intensifies during intracavernosal alprostadil therapy.2 Patients also should be vigilant for the development of nodules or hard areas in the penis and be instructed to report any sign of infection (e.g., penile erythema, swelling, tenderness, or unusual curvature).2

Penile fibrosis, including Peyronie's disease, developed in 3% of patients receiving intracavernosal alprostadil in clinical studies;2 in one self-injection study in which the drug was administered for up to 18 months, the incidence of fibrosis was about 8%.2 Penile hematoma and ecchymosis occurred in 3 and 2% of patients, respectively; most cases were attributed to improper administration technique.2 The manufacturers' labeling should be consulted for other less common adverse effects associated with intracavernosal alprostadil and for additional information on usual precautions associated with such therapy.2,  101

Intraurethral Dosage

Intraurethral alprostadil therapy (in the home setting) should be administered at the dose that was determined as optimal during titration in a medical setting;97,  98 no more than 2 urethral suppositories should be used within a 24-hour period.98,  100,  104,  98,  100 Erection that lasts longer than desired may be relieved by the application of an ice pack alternately to each inner thigh for a period not exceeding 10 minutes.100

Prolonged erection (persisting 4-6 hours) or priapism (erection persisting 6 hours or longer) occurred in 0.3 and less than 0.1% of patients, respectively, receiving intarurethral alprostadil in clinical studies.98 Since priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, patients should be advised to report promptly to their clinician or, if their clinician is unavailable, to seek alternative immediate medical attention if an erection occurs that persists longer than 4-6 hours or is extremely painful.2,  98,  100,  34,  78,  79,  89 The manufacturer of alprostadil urethral suppositories states that in patients who develop priapism or prolonged erection, dose should be decreased or, alternatively, discontinuance of intraurethral alprostadil therapy should be considered.98

The most common adverse effect associated with intraurethral alprostadil is penile, urethral, or testicular pain, which was reported in 36, 13, or 5% of patients, respectively.98 In most cases, such pain was described as mild and transient, although about 7% of patients discontinued therapy with the drug because of such pain.98 Urethral bleeding and/or spotting and other minor urethral abrasions were reported in about 3% of patients.98,  100 Adverse effects associated with intraurethral alprostadil that were reported in sexual partners included vaginal burning and/or itching; however, a causal relationship to the drug has not been established and it is not known if these effects were associated with resumption of sexual intercourse.98 Dizziness, symptomatic hypotension, or syncope was reported in 4, 3, or 0.4% of patients, respectively, using alprostadil urethral suppositories during the intial (dose-titrating) phase.98 Patients should be warned to avoid tasks requiring physical coordination (e.g., operating machinery, driving a motor vehicle) that could result in injury if hypotension or syncope were to occur following the use of such suppositories.98 In addition, patients should be advised to lie down and immediately raise their legs if they experience a light-headed feeling, dizziness, feeling of faintness, or rapid pulse and to promptly contact their clinician if symptoms persist.100

Diagnostic Use

When used alone as a simple test for erectile dysfunction, patients usually have been given a single 10- to 20-mcg intracavernosal dose of alprostadil and then examined 5-15 minutes later;16,  21,  24,  27,  67 if only partial erection was present, the patient could be asked to perform manual genital stimulation short of ejaculation,16 with or without visual sexual stimulation,17,  27 for up to 5 minutes and then reexamined.16 If adequate erection still could not be achieved, the dose could be titrated upward21,  28 (e.g., up to 40 mcg, possibly administered on a subsequent day).28,  66,  67 A positive response generally was interpreted as a full erection maintained for at least 30 minutes.24,  28,  67 Alternatively, characterization of the onset, degree (e.g., soft, slight tumescence, full tumescence without rigidity, full rigidity), angle, and duration of erection with a given dose can be reported.16,  21,  24,  27,  67 Specialized references should be consulted for additional information on the performance and interpretation of tests of erectile function involving intracavernosal alprostadil.7,  23,  65

When used as an adjunct to other vascular testing (e.g., duplex ultrasonography, cavernosometry/cavernosography, angiography, radioisotope penogram) as an aid in visualizing and assessing the penile vasculature in the diagnosis of erectile dysfunction, the manufacturer of Caverject^® states that a single dose of intracavernosal alprostadil that produces an erection with firm rigidity is used.2,  86 However, the clinical value of these invasive studies currently can be severely limited by factors such as lack of normative data, operator dependence, and variable interpretation of results.13,  15,  33,  65,  78,  80,  81,  82,  84,  86,  91,  92,  93 Therefore, such studies might best be performed in facilities with expertise and interest in the investigation of vascular aspects of erectile dysfunction.7,  23,  65 Additional study is needed to define further interpretive standards and associated diagnostic accuracy and predictability of treatment outcomes of these tests in patients with erectile dysfunction.33,  65,  78,  81

Ductus Arteriosus-dependent Congenital Heart Disease

Alprostadil dosage for maintaining patency of the ductus arteriosus is adjusted according to therapeutic response and tolerance, using the lowest possible effective dosage for the shortest period necessary to provide desired effects.1 Therapy with the drug usually is continued until surgical repair is complete, usually within 24-48 hours after initiation, although the drug occasionally is continued postoperatively (e.g., to improve pulmonary blood flow in neonates with cyanotic congenital heart disease).1,  3,  44 If long-term alprostadil infusion is considered (e.g., when surgery is deferred in a poor-risk neonate), the risks of prolonged therapy should be weighed carefully against the anticipated benefits.1,  44,  47,  49,  50,  54,  55,  58,  59 Neonates receiving recommended dosages for longer than 120 hours should be monitored closely for evidence of antral hyperplasia and gastric outlet obstruction.1,  59 Other potential risks of prolonged therapy include cortical hyperostosis of long bones and morphologic changes in the pulmonary arteries.1,  3,  50 In some infants (e.g., those with very small branch pulmonary arteries, those with severe cyanotic congenital heart disease), alprostadil therapy has been continued cautiously for several weeks to months.1,  3,  44,  47,  49,  50,  54,  55,  58,  59

In neonates with restricted pulmonary blood flow, monitoring for adequate response to alprostadil should include measures of improved blood oxygenation.1,  3,  29,  42,  43,  44,  54,  56,  57,  60,  70 For neonates with restricted systemic blood flow, such monitoring should include measures of improved systemic blood pressure and blood pH.1,  3,  29,  43,  44,  48,  51,  54,  56,  57,  60

The usual initial neonatal dosage of alprostadil for maintaining patency of the ductus arteriosus is continuous infusion of 0.05-0.1 mcg/kg per minute.1,  3 Based on experience from clinical studies, the manufacturer of Prostin VR Pediatric^® recommends an initial dosage of 0.1 mcg/kg per minute;1,  3 however, adequate clinical response has been reported with an initial dosage of 0.05 mcg/kg per minute,1,  70 and some neonates may respond to lower initial dosages.3,  43,  49,  57,  58,  60,  70,  95,  96 If response to the initial dosage is inadequate, dosage can be increased gradually up to 0.4 mcg/kg per minute; however, dosages exceeding 0.1 mcg/kg per minute generally have not been shown to produce additional benefit.1,  3,  57,  60 After a therapeutic response is achieved (increased PO₂ in infants with restricted pulmonary blood flow or increased systemic blood pressure and blood pH in infants with restricted systemic blood flow), the infusion rate should be reduced to provide the lowest possible dosage that maintains the response; such downward titration of dosage often is accomplished by progressively halving the alprostadil dose (e.g., from 0.1 down to 0.05 down to 0.025 mcg/kg per minute, etc) until the lowest effective dose is reached.1,  3 If complications occur, a lower infusion rate or discontinuance of the drug may be considered.1,  60 A maintenance infusion rate of 0.025-0.01 mcg/kg per minute may be adequate to maintain response.1 Lower maintenance infusion rates of 0.002-0.005 mcg/kg per minute also have been effective for maintenance in some neonates prior to surgery.3,  60

Description

Alprostadil, the naturally occurring prostaglandin E₁, is a vasodilating agent and a platelet-aggregation inhibitor and is prepared synthetically for commercial use.1,  5,  20,  98 Parenteral alprostadil is commercially available as a sterile powder for injection with (Caverject^® Impulse^®)110 or without alfadex (α-cyclodextrin) (Caverject^®),2,  110 as an alcoholic solution (Prostin VR Pediatric^®),1 and as a lyophilized powder with alfadex (Edex^®).101 The inclusion complex enhances the water solubility of alprostadil.101 Alprostadil also is available as a urethral (micro) suppository, measuring 1.4 mm in diameter and 3 or 6 mm in length (Muse^®).98 Prostaglandins of the E series occur naturally in the seminal vesicles and cavernous tissues of males and in the placenta and ductus arteriosus of the fetus.5,  20,  22,  23,  26,  28,  34,  44,  67,  98 Alprostadil relaxes the smooth muscles of the corpus cavernosum and the ductus arteriosus.1,  2,  3,  6,  8,  10,  20,  29,  44 Alprostadil is absorbed through the urethral mucosa and then distributed to corpus spongiosum and corpus cavernosum when administered as a urethral suppository.97,  98

Penile Effects

Alprostadil induces erection by relaxing trabecular smooth muscle and dilating cavernosal arteries and their branches (i.e., the helicine arterioles of the penis).2,  11,  15,  19,  20,  21,  24,  27,  28,  34,  46,  64,  65,  71,  98,  101,  102 As a result, the lacunar spaces expand and blood becomes entrapped secondary to compression of venules against the tunica albuginea (i.e., the corporal veno-occlusive mechanism).2,  11,  16,  19,  20,  22,  64,  65,  72 For sufficient tumescence and rigidity to occur, the tunica albuginea must be sufficiently stiff to compress the venules penetrating it and thus block venous outflow.20,  65,  72

The precise mechanism(s) of action of alprostadil-induced cavernosal effects has not been established but appears to differ from that of papaverine.6,  8,  12,  20,  25,  64 Although both agents appear to increase the intracellular concentrations of cyclic AMP,11,  12,  21 papaverine inhibits the inactivation of cyclic AMP via oxidative phosphorylation and interferes with calcium mobilization during muscle contraction,11,  12,  21,  71 while 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.6,  8,  12,  97 In addition, alprostadil may antagonize the vasoconstrictive actions of norepinephrine by preventing the neuronal release of this amine and may enhance the actions of nonadrenergic, noncholinergic vasodilatory neurotransmitters.6,  8,  12,  20,  21,  33,  46,  62,  67,  71 Data from studies employing combination therapy suggest a possible additive effect between alprostadil and papaverine in promoting intracavernosal arterial smooth muscle relaxation, but additional study is necessary.12,  14,  21,  64 In addition, the mechanisms of erection are complex, and the exact nature of neurotransmitters (e.g., acetylcholine, norepinephrine) involved as well as the various steps leading to relaxation of the vascular smooth muscles remain to be more fully elucidated; nitric oxide released from endothelial cells currently is hypothesized as being the principal nonadrenergic, noncholinergic neurotransmitter involved, but others (e.g., neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal polypeptide) also may be involved.6,  10,  11,  13,  18,  20,  33,  65

Alprostadil does not directly affect ejaculation or orgasm.2,  5,  28,  83,  89

Effects on the Ductus Arteriosus

In neonates with a closing ductus arteriosus, alprostadil markedly relaxes, and thus may reopen, the ductus.1,  3,  4,  29 Thus in neonates with congenital cardiopulmonary defects that restrict pulmonary or systemic blood flow and who depend on a patent ductus arteriosus for blood oxygenation and lower body perfusion, the drug may improve cardiovascular status (e.g., blood flow and oxygenation) by maintaining ductal patency until corrective or palliative surgery can be performed.1,  3,  4,  42,  47 In those with restricted pulmonary blood flow, alprostadil increases blood oxygenation in a substantial proportion of such neonates, with the most marked improvement generally occurring in those with low pretreatment blood PO₂.1,  29,  42,  43,  44,  55 In those with restricted systemic blood flow, the drug can increase systemic blood pressure, decrease the ratio of pulmonary artery to aortic pressures, and increase blood pH in those with acidosis.1,  43,  44,  48,  51,  57,  60

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Pharmacia & Upjohn Company. Prostin VR Pediatric^® (alprostadil sterile solution) injection prescribing information. NY, NY; 2020 May.

2. Pharmacia & Upjohn Company. Caverject^® (alprostadil) injection for intracavernosal use prescribing information. Kalamazoo, MI; 1999 Feb.

3. Roehl SL, Townsend RJ. Alprostadil^® (Prostin VR Pediatric Sterile Solution, The Upjohn Company). Drug Intell Clin Pharm . 1982; 16:823-32. [PubMed 6756848]

4. Friedman WF. Diseases of the heart, pericadium, aorta, and pulmonary vascular bed: congenital heart disease in infancy and childhood. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 4th ed. Philadelphia: W.B. Saunders Company; 1992:887-965.

5. The Upjohn Company. Caverject^® sterile powder (alprostadil for injection) product information. Kalamazoo, MI; Undated.

6. Martinez-Pineiro L, Lopez-Tello J, Dorrego JMA et al. Preliminary results of a comparative study with intracavernous sodium nitroprusside and prostaglandin E1 in patients with erectile dysfunction. J Urol . 1995; 153:1487-90. [PubMed 7714974]

7. Whitehead ED. Impotence: should primary care physicians give penile injections? Geriatrics . 1995; 50:14. Letter. (IDIS 341817)

8. von Heyden B, Donatucci CF, Marshall GA et al. A prostaglandin E1 dose- response study in man. J Urol . 1993; 150:1825-8. [PubMed 8230515]

9. Govier FE, McClure RD, Weissman RM et al. Experience with triple-drug therapy in a pharmacological erection program. J Urol . 1993; 150:1822-4. [PubMed 8230514]

10. Djamilian M, Stief CG, Kuczyk M et al. Followup results of a combination of calcitonin gene-related peptide and prostaglandin E1 in the treatment of erectile dysfunction. J Urol . 1993; 149:1296-8. [PubMed 8479019]

11. Montorsi F, Guazzoni G, Bergamaschi F et al. Four-drug intracavernous therapy for impotence due to corporeal veno-occlusive dysfunction. J Urol . 1993; 149:1291-5. [PubMed 7683061]

12. von Heyden B, Donatucci CF, Kaula N et al. Intracavernous pharmacotherapy for impotence: selection of appropriate agent and dose. J Urol . 1993; 149:1288-90. [PubMed 8479018]

13. Porst H. Prostaglandin E1 and the nitric oxide donor linsidomine for erectile failure: a diagnostic comparative study of 40 patients. J Urol . 1993; 149:1280-3. [PubMed 8479015]

14. Allen RP, Engel RM, Smolev JK et al. Objective double-blind evaluation of erectile function with intracorporeal papaverine in combination with phentolamine and/or prostaglandin E1. J Urol . 1992; 148:1181-3. [PubMed 1404632]

15. Meuleman EJH, Bemelmans BLH, Doesburg WH et al. Penile pharmacological duplex ultrasonography: a dose-effect study comparing papaverine, papaverine/phentolamine and prostaglandin E1. J Urol . 1992; 148:63-6. [PubMed 1613884]

16. Donatucci CF, Lue TF. The combined intracavernous injection and stimulation test: diagnostic accuracy. J Urol . 1992; 148:61-2. [PubMed 1613883]

17. Bennett AH, Carpenter AJ, Barada JH. An improved vasoactive drug combination for a pharmacological erection program. J Urol . 1991; 146:1564-5. [PubMed 1719248]

18. Stief CG, Wetterauer U, Schaebsdau FH et al. Calcitonin-gene-related peptide: a possible role in human penile erection and its therapeutic application in impotent patients. J Urol . 1991; 146:1010-4. [PubMed 1895414]

19. Gerber GS, Levine LA. Pharmacological erection program using prostaglandin E1. J Urol . 1991; 146:786-9. [PubMed 1875494]

20. Artoux MJ, McQueen KD. Alprostadil in impotence. DICP . 1991; 25:363-6. [PubMed 1926907]

21. Floth A, Schramek P. Intracavernous injection of prostaglandin E1 in combination with papaverine: enhanced effectiveness in comparison with papaverine plus phentolamine and prostaglandin E1 alone. J Urol . 1991; 145:56-9. [PubMed 1984099]

22. Earle CM, Keogh EJ, Wisniewski ZS et al. Prostaglandin E1 therapy for impotence, comparison with papaverine. J Urol . 1990; 143:57-9. [PubMed 2294263]

23. Whitehead ED, Klyde BJ, Zussman S et al. Treatment alternatives for impotence. Postgrad Med . 1990; 88:139-52. [PubMed 2199954]

24. Hwang TIS, Yang CR, Wang SJ et al. Impotence evaluated by the use of prostaglandin E1. J Urol . 1989; 141:1357-9. [PubMed 2724434]

25. Sarosdy MF, Hudnall CH, Erickson DR et al. A prospective double-blind trial of intracorporeal papaverine versus prostaglandin E1 in the treatment of impotence. J Urol . 1989; 141:551-3. [PubMed 2645420]

26. Lee LM, Stevenson RWD, Szasz G. Prostaglandin E1 versus phentolamine/papaverine for the treatment of erectile impotence: a double-blind comparison. J Urol . 1989; 141: 549-50. [PubMed 2918589]

27. Ishii N, Watanabe H, Irisawa C et al. Intracavernous injection of prostaglandin E1 for the treatment of erectile impotence. J Urol . 1989; 141:323-5. [PubMed 2913354]

28. Stackl W, Hasun R, Marberger M. Intracavernous injection of prostaglandin E1 in impotent men. J Urol . 1988; 140:66-8. [PubMed 3379700]

29. Hiraishi S, Fujino N, Saito K et al. Responsiveness of the ductus arteriosus to prostaglandin E1 assessed by combined cross sectional and pulsed Doppler echocardiography. Br Heart J . 1988; 62:140-7.

30. Godschalk MF, Chen J, Katz PG et al. Treatment of erectile failure with prostaglandin E1: a double-blind, placebo-controlled, dose-response study. J Urol . 1994; 151:1530-2. [PubMed 8189563]

31. Chen J, Godschalk M, Katz PG et al. The lowest effective dose of prostaglandin E1 as treatment for erectile dysfunction. J Urol . 1995; 153:80-1. [PubMed 7966797]

32. Godschalk MF, Chen J, Katz PG et al. Prostaglandin E1 as treatment for erectile failure in elderly men. J Am Geriatr Soc . 1994; 42:1263-5. [PubMed 7983289]

33. Goldstein I. Editorial: Impotence. J Urol . 1994; 151:1533-4. [PubMed 8189564]

34. Linet OI, Neff LL. Intracavernous prostaglandin E1 in erectile dysfunction. Clin Investig . 1994; 72:139-49. [PubMed 8186662]

35. Linet OI, Ogrinc FG. Dose-escalating study with maintenance phase using alprostadil (prostaglandin E1, PGE1) sterile powder in patients with erectile dysfunction. Technical Report No. 9124-93-006. The Upjohn Company: Kalamazoo, MI; 1993 Dec 3.

36. Weber RE, Linet OI, Hansen BA et al. Dose-escalating study using alprostadil (prostaglandin E₁, PGE₁) sterile powder (S.Po.) in patients with erectile dysfunction of vasculogenic origin. Technical Report No. 9124-93-008. The Upjohn Company: Kalamazoo, MI; 1995 Jan 25.

37. Weber RE, Ogrinc FG, Hansen JP et al. Dose-escalating study using alprostadil sterile powder (prostaglandin E₁, PGE₁) in patients with erectile dysfunction of neurogenic origin secondary to spinal cord injury. Technical Report No. 9124-93-009. The Upjohn Company: Kalamazoo, MI; 1993 Nov 29.

38. Linet OI, Ogrinc FG, Hansen JP. No-effect and minumum-effective dose- finding study of alprostadil (prostaglandin E₁,PGE₁) sterile powder (S.Po.) in patients with erectile dysfunction. Technical Report No. 9124-93-003. The Upjohn Company: Kalamazoo, MI; 1993 Dec 1.

39. Linet OI, Ogrinc FG. Long-term safety study with alprostadil sterile powder (alprostadil S.Po.; prostaglandin E₁, PGE₁) in patients with erectile dysfunction. Technical Report No. 9124-93-007. The Upjohn Company: Kalamazoo, MI; 1993 Dec 10.

40. Linet OI, Ogrinc FG. Dose-escalating study with maintenance phase using alprostadil (prostaglandin E₁, PGE₁) sterile powder (S.Po.) in elderly patients with erectile dysfunction. Technical Report No. 9124-95-002. The Upjohn Company: Kalamazoo, MI; 1995 Jan 17.

41. Linet OI. Clinical pharmacology of alprostadil. In: Goldstein I, Lue TF, eds. The role of alprostadil in the diagnosis and treatment of erectile dysfunction. Princeton: Excerpta Medica; 1993:28-39.

42. Chessman KH, Alpert BS. Pharmacological manipulation of the ductus arteriosus in neonates. Hosp Pharm . 1988; 23:825-7,830,833-4,841.

43. Freed MD, Heymann MA, Lewis AB et al. Prostaglandin E₁ in infants with ductus arteriosus-dependent congenital heart disease. Circulation . 1981; 64:899-905. [PubMed 7285305]

44. Heymann MA, Clyman RI. Evaluation of alprostadil (prostaglandin E₁) in the management of congenital heart disease in infancy. Pharmacother . 1982; 2:148-55.

45. Schramek P. Dose-dependent effect and side-effect of prostaglandin E1 in erectile dysfunction. Br J Clin Pharmacol . 1989; 28:567-71. [PubMed 2686740]

46. Waldhauser M, Schramek P. Efficiency and side effects of prostaglandin E1 in the treatment of erectile dysfunction. J Urol . 1988; 140:525-7. [PubMed 3045341]

47. Silove ED. Pharmacological manipulation of the ductus arteriosus. Arc Dis Child . 1986; 61:827-9.

48. Sell JE, Jonas RA, Mayer JE et al. The results of a surgical program for interrupted aortic arch. J Thorac Cardiovasc Surg . 1988; 96:864-77. [PubMed 3193799]

49. Yokota M, Muraoka R, Aoshima M et al. Modified Blalock-Taussig shunt following long-term administration of prostaglandin E1 for ductus-dependent neonates with cyanotic congenital heart disease. J Thorac Cardiovasc Surg . 1985; 90:399-403. [PubMed 4033176]

50. Lewis AB, Freed MD, Heymann MA et al. Side effects of therapy with prostaglandin E1 in infants with critical congenital heart disease. Circulation . 1981; 64:893-8. [PubMed 7285304]

51. Zahka KG, Roland MA, Cutilletta AF et al. Management of aortic arch interruption with prostaglandin E1 infusion and microporous expanded polytetrafluoroethylene grafts. Am J Cardiol . 1980; 46:1001-5. [PubMed 7446413]

52. Freed MD. Evaluation of alprostadil. Pharmacother . 1982; 2:155.

53. Lewis AB. Evaluation of alprostadil. Pharmacother . 1982; 2:155.

54. Buck ML. Prostaglandin E1 treatment of congenital heart disease: use prior to neonatal transport. DICP . 1991; 25:408-9. [PubMed 1926911]

55. Barst RJ, Gersony WM. The pharmacological treatment of patent ductus arteriosus: a review of the evidence. Drugs . 1989; 38:249-66. [PubMed 2670518]

56. Graham TP Jr, Atwood GF, Boucek RJ Jr. Pharmacologic dilatation of the ductus arteriosus with prostaglandin E₁ in infants with congenital heart disease. South Med J . 1978; 71:1238-41, 1246. [PubMed 81528]

57. Heymann MA, Berman W, Rudolph AM et al. Dilatation of the ductus arteriosus by prostaglandin E₁ in aortic arch abnormalities. Circulation . 1979; 59:169-73. [PubMed 758109]

58. Haworth SG, Sauer U, Bühlmeyer K. Effect of prostaglandin E₁ on pulmonary circulation in pulmonary atresia. Br Heart J . 1980; 43:306-14. [PubMed 7437177]

59. Peled N, Dagan O, Babyn P et al. Gastric-outlet obstruction induced by prostaglandin therapy in neonates. N Engl J Med . 1992; 327:505-10. [PubMed 1635565]

60. Hallidie-Smith KA. Prostaglandin E₁ in suspected ductus dependent cardiac malformation. Arch Dis Child . 1984; 59:1020-6. [PubMed 6542338]

61. Reviewers' comments (personal observations) on papaverine.

62. Mahmoud KZ, El Dakhli MR, Fahmi IM et al. Comparative value of prostaglandin E1 and papaverine in treatment of erectile failure: double-blind crossover study among Egyptian patients. J Urol . 1992; 147:623-6. [PubMed 1538443]

63. Pruitt A. The cardiovascular system. In: Behrman RE, Kliegman RM, Nelson WE, et al, eds. Nelson textbook of pediatrics. 14th ed. Philadelphia: W.B. Saunders Company; 1992: 1125-227.

64. The Upjohn Company, Kalamazoo, MI: Personal communication.

65. National Institutes of Health Office of Medical Applications of Research. Consensus Conference: impotence. JAMA . 1993; 270:83-90. [PubMed 8510302]

66. Porst H. Prostaglandin E₁ in male impotence—its diagnostic and therapeutic use in 2000 patients. Int J Impotence Res . 1992; 4(Suppl 2):A88.

67. Ravnik-Oblak M, Oblak C, Vodusek DB et al. Intracavernous injection of prostaglandin E₁ in impotent diabetic men. Int J Impotence Res . 1990; 2:143-49.

68. Hirsch IH, Bagley DH, Christinzio J. Dosage considerations in the self- administration of PGE-1 for erectile dysfunction. J Urol . 1990; 143(Suppl):305A.

69. Weiske WH. Long-term results in self-injection therapy (SIT) with PGE-1 in 220 patients. Int J Impot Res . 1992; 4(Suppl 2):A87. [PubMed 25530677]

70. Benson LN, Olley PM, Patel RG et al. Role of prostaglandin E₁ infusion in the management of transposition of the great arteries. Am J Cardiol . 1979; 44:691-6. [PubMed 484498]

71. Montorsi F, Guazzoni G, Bergamaschi F et al. Clinical reliability of multi-drug intracavernous vasoactive pharmacotherapy for diabetic impotence. Acta Diabetol . 1994; 31:1-5. [PubMed 8043890]

72. Matsumoto AM. The testis and male sexual function. In: Wyngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil textbook of medicine. 19th ed. Philadelphia: W.B. Saunders Company; 1992:1333-55.

73. Lindoro J, Castro JC, Cruz F et al. Treatment of priapism. Lancet . 1984; 2:1348. [PubMed 6150362]

74. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther . 1987; 29:95-6. [PubMed 3670212]

75. Robinette MA, Moffat MJ. Intracorporal injection of papaverine and phentolamine in the management of impotence. Br J Urol . 1986; 58:692-5. [PubMed 3801830]

76. Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence. J Urol . 1987; 137:829-36. [PubMed 3553617]

77. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther . 1990; 32:116-7. [PubMed 2255296]

78. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med . 1989; 321:1648-59. [PubMed 2685600]

79. Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ . 1994; 308:957-61. [PubMed 8173405]

80. Murray FT, Geisser M, Murphy TC. Evaluation and treatment of erectile dysfunction. Am J Med Sci . 1995; 309:99-109. [PubMed 7847449]

81. Bookstein JJ, Valji K, Parsons L et al. Penile pharmacocavernosography and cavernosometry in the evaluation of impotence. J Urol . 1987; 137:772-6. [PubMed 3560346]

82. Montague DK, Lakin MM, VanderBrug Medendorp S et al. Infusion pharmacocavernosometry and nocturnal penile tumescence findings in men with erectile dysfunction. J Urol . 1991; 145:768-71. [PubMed 2005697]

83. Duffy LM, Sidi AA, Lange PH. Vasoactive intracavernous pharmacotherapy—the nursing role in teaching self-injection therapy. J Urol . 1987; 138:1198-200. [PubMed 3669166]

84. Delcour C, Wespes E, Vandenbosch G et al. Opacification of the glans penis during cavernosography. J Urol . 1988; 139:732-3. [PubMed 3352032]

85. Whitehead ED, Klyde BJ, Zussman S et al. Diagnostic evaluation of impotence. Postgrad Med . 1990; 88:123-36. [PubMed 2199953]

86. Kim SC, Kim KB, Oh CH. Diagnostic value of the radioisotope erection penogram for vasculogenic impotence. J Urol . 1990; 144:888-93. [PubMed 2169002]

87. Petty R. Erectile impotence. Practitioner . 1993; 237:828-31. [PubMed 8255874]

88. Gerstenberg TC, Nordling J, Hald T et al. Standardized evaluation of erectile dysfunction in 95 consecutive patients. J Urol . 1989; 141:857-62. [PubMed 2926880]

89. Bénard F, Lue TF. Self-administration in the pharmacological treatment of impotence. Drugs . 1990; 39:394-8. [PubMed 2184008]

90. Montague DK. Editorial: treatment of erectile dysfunction. J Urol . 1993; 150:1833. [PubMed 8230516]

91. Montague DK. Impotence therapy. J Urol . 1993; 149:1313. [PubMed 8479023]

92. Shabsigh R, Fishman IJ, Quesada ET et al. Evaluation of vasculogenic erectile impotence using penile duplex ultrasonography. J Urol . 1989; 142:1469-74. [PubMed 2685366]

93. Oates CP, Pickard RS, Powell PH et al. The use of duplex ultrasound in the assessment of arterial supply to the penis in vasculogenic impotence. J Urol . 1995; 153:354-7. [PubMed 7815582]

94. Gannaway WL, Hoagland RJ, Inciardi JF et al. Chemical stability of alprostadil (PGE-1) in combination with common injectable medications. Int Pharm Abstr . 1990; 27:323.

95. Sone K, Tashiro M, Fujinaga T et al. Long-term low-dose prostaglandin E₁ administration. J Pediatr . 1980; 97:866-7. [PubMed 7431186]

96. Henry GW, Hurwitz RA, Girod DA et al. Prostaglandin treatment of infants with cyanotic congenital heart disease. J Pediatr . 1980; 96:158.

97. Padma-Nathan H, Hellstrom WJG, Kaiser FE et al. Treatment of men with erectile dysfunction with transurethral alprostadil. N Engl J Med . 1997; 336:1-7. [PubMed 8970933]

98. Vivus. Muse (alprostadil) urethral suppository prescribing information. Menlo Park, CA; 1997 Aug.

99. Hellstrom WJG, Bennett AH, Gesundheit N et al. A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil. Urol . 1996; 48:851-6. [PubMed 8973666]

100. Vivus. Muse^® (alprostadil) urethral suppository patient information. Menlo Park, CA. 1997 Aug.

101. Schwarz Pharma. Edex^® (alprostadil) sterile powder for injection prescribing information. Milwaukee, WI; 1998 Jun.

102. Pharmacia & Upjohn. Caverject^® (alprostadil) aqueous injection prescribing information. Kalamazoo, MI; 1999 Mar.

103. Pharmacia & Upjohn. Caverject^® (alprostadil) aqueous injection patient information. Kalamazoo, MI; 1998 June.

104. Anon. Intraurethral alprostadil for impotence. Med Lett Drugs Ther . 1997; 39:32. [PubMed 9121395]

105. Peterson CA, Bennett AH, Hellstrom WJG et al. Erectile response to transurethral alprostadil, prazosin and alprostadil-prazosin combinations. J Urol . 1998; 159:1523-8. [PubMed 9554347]

106. Werthman P, Rajfer J. MUSE therapy: preliminary clinical observations. Urology . 1997; 50:809-11. [PubMed 9372900]

107. Porst H. Transurethral alprostadil with MUSE^® (medicated urethral system for erection) vs intracavernous alprostadil — a comparative study in 103 patients with erectile dysfunction. Int J Impot Res . 1997; 9:187-92. [PubMed 9442415]

108. GensiaSicor Pharmaceuticals. Alprostadil injection prescribing information. Irvine, CA; 1998 Jul.

109. Bedford Laboratories. Alprostadil injection prescribing information. Bedford, OH; 1999 Jan.

110. Pharmacia & Upjohn Company. Caverject Impulse^® (alprostadil) dual chamber system for intracavernosal use prescribing information. Kalamazoo, MI; 2002 Jun.

111. Pharmacia & Upjohn Company. Caverject impulse^® (alprostadil) dual chamber system for intracavernosal use patient information. Kalamazoo, MI; 2002 Jun.

112. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available from website. Accessed 2005 Oct. 20. [Web]

113. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Priapism: Guideline on the management of priapism. 2003. Available from website. Accessed 2005 Oct. 20. [Web]

161. Guay AT, Spark RF, Bansal S et al; American Association of Clinical Endocrinologists Male Sexual Dysfunction Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: a couple's problem--2003 update. Endocr Pract. 2003 Jan-Feb;9(1):77-95. doi: 10.4158/EP.9.1.77. PMID: 12917096.

189. Burnett AL, Nehra A, Breau RH et al.. Erectile Dysfunction: AUA Guideline. J Urol. 2018 Sep;200(3):633-641. doi: 10.1016/j.juro.2018.05.004. Epub 2018 May 7. Erratum in: J Urol. 2022 Mar;207(3):743. PMID: 29746858

249. ASHP. Standardize 4 Safety: pediatric continuous infusion standard. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]

601. Karakus S, Burnett AL. The medical and surgical treatment of erectile dysfunction: a review and update. Can J Urol. 2020 Aug;27(S3):28-35. PMID: 32876000

602. Smith WB 2nd, McCaslin IR, Gokce A, Mandava SH, Trost L, Hellstrom WJ. PDE5 inhibitors: considerations for preference and long-term adherence. Int J Clin Pract. 2013 Aug;67(8):768-80. doi: 10.1111/ijcp.12074. PMID: 23869678