Alprostadil

Class: Vasodilating Agents, Miscellaneous
VA Class: CV900
Chemical Name: (11α,13E,15S)-11,15-Dihydroxy-9-oxo-prost-13-en-1-oic acid
Molecular Formula: C₂₀H₃₄O₅
CAS Number: 745-65-3
Brands: Caverject, edex, Muse, Prostin VR Pediatric

• Apnea


• 
  

  Apnea reported in 10–12% of neonates with congenital heart defects receiving IV or intra-arterial alprostadil;^{1 3 44 50 53 60} usually occurs during first hour of IV or intra-arterial infusion, particularly in neonates weighing <2 kg at birth.^{1 3 44 50 53 60}

  
  


• 
  

  Use in neonates only when adequate treatment facilities for assisted ventilation are readily available;^{1 3 44 50 53 60} monitor respiratory status throughout therapy.^{1 50}

  
  

Introduction

Vasodilator and platelet-aggregation inhibitor; a naturally occurring prostaglandin E₁.^{1 5 20 98}

Uses for Alprostadil

Erectile Dysfunction

Used to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence).^{98 110 b}

Second-line therapy for treatment of ED in patients not responding to psychotherapy/behavioral therapy, vacuum constriction devices, and/or oral, selective phosphodiesterase (PDE) type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)^{19 23 65 112 s t u v} and in whom attempts at identifying and modifying any drug-related (e.g., certain antihypertensive agents) or other potentially reversible medical causes of ED have proved inadequate.^{2 19 23 65 112}

Selective oral PDE type 5 inhibitor therapy preferred as first-line treatment of ED unless contraindicated.¹¹²

Intraurethral therapy generally preferred over intracavernosal vasoactive therapy because it is less invasive; however intracavernosal therapy is most effective nonsurgical treatment for ED.¹¹²

Consider intraurethral therapy for patients with inadequate responses to or who are not candidates for selective oral PDE type 5 inhibitor therapy.¹¹²

Effective in patients with organic (neurogenic and/or mild to moderate vasculogenic) ED or with psychogenic ED.^{19 20 24 25 27 34 36 41 45 46 64 67 71}

Not recommended for simply enhancing erections in men who are not impotent† because of GU risks.⁶⁴ (See Priapism and also GU Effects, under Cautions.)

Manufacturers state that safety and efficacy of alprostadil in combination with other vasoactive therapy for erectile dysfunction not established and currently not recommended.^{64 101 b} However, American Urological Association (AUA) and other clinicians state that combination therapy with other intracavernosal vasoactive agents increased efficacy and decreased adverse effects relative to alprostadil alone.^{9 10 11 12 14 15 17 18 21 65 71 90 91 y z} Combined therapy with intraurethral alprostadil and vacuum constriction device or oral selective PDE type 5 inhibitor increased efficacy relative to alprostadil alone.¹¹²

Adjunct to other vascular testing (e.g., duplex ultrasonography, cavernosometry/cavernosography, angiography, radioisotope penogram) in differential diagnosis of ED and evaluation of hemodynamic status of erectile tissue.^{5 15 16 17 21 24 27 28 65 66 67 110 b}

Ductus Arteriosus-dependent Congenital Heart Disease

Palliative treatment in maintaining patency of ductus arteriosus in neonates with various ductal-dependent congenital heart defects (e.g., pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of aortic arch, coarctation of the aorta, transposition of great vessels).^{1 3 29 42 43 44 47 51 56 57 60}

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}

Do not use in neonates with respiratory distress syndrome.^{1 4 42 49 64} (See Respiratory Distress Syndrome under Cautions.)

Alprostadil Dosage and Administration

General

ED

• 
  

  Initiate and titrate dosage in medical setting (e.g., clinician’s office);^{7 23 34 65 98 101 110 112 b} patient must remain in this setting until complete detumescence occurs.^{5 19 32 64 112 b d h}

  
  


• 
  

  Carefully individualize dosage according to patient’s erectile response^{5 8 12 19 32 34 89 98 99 100 101 107 b} toward therapeutic goal of achieving erection satisfactory for intercourse, but persists for ≤1 hour.^{5 12 34 69 89 97 98 b h} (See Priapism under Cautions.)

  
  


• 
  

  Titrate dosage slowly to lowest possible effective level to avoid priapism.^{5 12 19 32 101 b} Erections persisting >1 hour increase risk of priapism.^{5 12 34 69 89 97 98 b h} (See Priapism under Cautions.)

  
  


• 
  

  Initiate maintenance home treatment regimens at dosage determined as optimal during titration in medical setting.^{97 98 b d f} Further dosage adjustments may be required.^{b d f i} Dosage determined by clinician in medical setting should not be changed without consulting clinician.^{b e f i r}

  
  

Ductus Arteriosus-dependent Congenital Heart Disease

• 
  

  Use only by trained personnel in facilities providing pediatric intensive care.^{1 3 44 50 53 60} Monitor respiratory status of neonate throughout administration; facilities and equipment for assisted ventilation should be readily available.^{1 50} (See Boxed Warning.)

  
  


• 
  

  Adjust dosage using lowest possible effective dosage for shortest period necessary to provide desired effects.¹

  
  


• 
  

  If long-term infusion considered (e.g., when surgery deferred in poor-risk neonate), carefully weigh risks of prolonged therapy against anticipated benefits.^{1 44 47 49 50 54 55 58 59} (See GI Effects, Musculoskeletal Effects, and also Cardiovascular and Cerebrovascular Effects, under Cautions.)

  
  


• 
  

  In neonates with restricted pulmonary blood flow, monitor measures of improved blood oxygenation.^{1 3 29 42 43 44 54 56 57 60 70}

  
  


• 
  

  In neonates with restricted systemic blood flow, monitor measures of improved systemic BP and blood pH.^{1 3 29 43 44 48 51 54 56 57 60}

  
  


• 
  

  Periodically monitor arterial BP via umbilical artery catheter, auscultation, or Doppler transducer.^{1 50} (See Cardiovascular and Cerebrovascular Effects under Cautions.)

  
  

Administration

Administer by continuous IV or intra-arterial infusion to maintain patency of ductus arteriosus in neonates with congenital heart disease.¹

Administer by intracavernosal injection for treatment and diagnosis of ED or by intraurethral suppository for treatment of ED.^{97 98 100 101 b}

IV and Intra-arterial Infusion

For solution and compatibility information, see Compatibility under Stability.

To maintain patency of ductus arteriosus, administer by continuous IV infusion into a large vein (peripheral or central);^{1 44} preferred route of administration.^{1 3 50}

Alternatively, administer by controlled intra-arterial infusion through an umbilical^{1 3 57 70} artery catheter placed at ductal opening or main pulmonary artery.^{1 44 56 57 70}

If flushing occurs during intra-arterial infusion, reposition catheter or convert to IV infusion.^{1 3 50 54 55}

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 should be used; inadvertent rapid administration could result in toxicity (e.g., apnea).^{1 50 60 70} (See Boxed Warning.)

Dilution

Alprostadil for injection concentrate must be diluted prior to IV or intra-arterial infusion.¹

Add 1 mL of alprostadil concentrate to 0.9% sodium chloride or 5% dextrose injection to provide solution containing 2–20 mcg/mL of drug, depending on controlled-infusion device employed and needs of neonate.^{1 64}

When using a device with a volumetric infusion chamber, add appropriate volume of diluent to chamber first and then add 1 mL of drug concentrate to diluent.¹

Dilution of Alprostadil Concentrate for Injectiona

Add 1 vial (volume of 500 mcg/mL concentrate)	to Compatible IV Solution (volume of solution)	to Make (final dilution concentration)
1 mL	250 mL	2 mcg/mL
1 mL	100 mL	5 mcg/mL
1 mL	50 mL	10 mcg/mL
1 mL	25 mL	20 mcg/mL

Rate of Administration

Sample infusion rates to deliver a dosage of 0.1 mcg/kg of body weight per minute can be obtained from the following table: ^a

Infusion Rates to Provide Dosage of 0.1 mcg/kg per Minute

Final Dilution Concentration	Infusion rate
2 mcg/mL	0.05 mL/minute per kg of body weight
5 mcg/mL	0.02 mL/minute per kg of body weight
10 mcg/mL	0.01 mL/minute per kg of body weight
20 mcg/mL	0.005 mL/minute per kg of body weight

Decrease rate of infusion immediately if clinically important decrease in arterial BP, fever, or hypotension occurs.^{1 3 50} (See Cardiovascular and Cerebrovascular Effects under Cautions.) Once symptoms subside, increase rate cautiously, if necessary.^{1 3 50}

Intracavernosal Administration

Administer by intracavernosal injection into the penis.^{22 24 27 67 69 71 83 89 101 e i r}

Vary injection site to minimize adverse effects related to repeated local injection.^{8 89 111 b e r}

Prior to administration using Caverject impulse dual-chambered syringe system, set dose to be delivered 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

Reconstituted solutions of alprostadil for intracavernosal injection are intended for single-use only.^{2 28 101 110} Properly dispose of single-use delivery device and any remaining solution following use.^{110 111}

Reconstitution

Caverject: Reconstitute vial labeled as containing 20 or 40 mcg of alprostadil powder with 1 mL of bacteriostatic or sterile water for injection (with benzyl alcohol) supplied by manufacturer, to provide a solution containing 20.5 or 41.1 mcg/mL, respectively, and delivering 20 or 40 mcg/mL.^b (See Pediatric Use under Cautions.) Use a 3 mL syringe with a 27- to 30-gauge, 0.5-inch needle.^b Swirl contents of vial gently until clear solution obtained.^e Withdraw desired dose of reconstituted solution into same syringe prior to administration.^e

Caverject impulse dual-chambered syringe system: Reconstitute by turning plunger rod clockwise until rod meets resistance^{110 111} to force diluent (sterile bacteriostatic water for injection) into chamber containing sterile powder.¹¹¹ Mix contents of syringe thoroughly by turning device upside down several times until solution is clear.^{110 111}

edex dual-chambered system: Place cartridge containing alprostadil lyophilized powder into edex injection device^r and push plunger of device until 2 gray rubber stoppers touch to force diluent (1.075 mL of 0.9% sodium chloride injection) into upper chamber containing drug powder.^{d r} Gently move injection device back and forth until solution is clear.^r Do not use if cartridge is damaged or cake of drug powder is substantially <(3/8) inch in thickness.¹⁰¹

Intracavernosal Injection Technique

Hold head (glans) of penis (if uncircumcised, pull back foreskin initially) between thumb and forefinger, and stretch lengthwise along thigh while sitting upright or slightly reclined.^{22 24 27 67 69 71 83 89 101 e i r} Inject into a corpus cavernosum of the penis (underneath the tunica albuginea along dorsolateral aspect of proximal third of penis) using a steady motion.^{22 24 27 64 67 69 71 83 89 101 110 111 e i r} Avoid blood vessels, corpus spongiosum, subcutaneous tissue, urethra, and dorsal neural vascular structures as injection sites.^{5 7 8 28 34 83 b d e h i}

Inject dose slowly (over 5–10 seconds);^{22 27 64 71 83 101 110 111 r} apply pressure to injection site with alcohol swab for 5 minutes (or until bleeding stops) after needle is withdrawn.^{7 22 25 67 71 83 89 101 111 e r} If bleeding continues or recurs, abstain from intercourse.^r (See Hematologic Effects under Cautions.)

If solution does not inject easily or if a burning pain at injection site occurs, reposition needle by moving needle slightly or partially withdrawing needle until solution can be injected easily and painlessly.^{i r}

If needle bends severely at anytime during reconstitution or injection, discard needle, and replace with new unused needle.^e

Rate of Administration

Inject slowly (over 5–10 seconds).^{22 27 64 71 83 101 110 111 r}

Intraurethral Administration

Administer intraurethrally as a suppository.^{97 98 99 100 104 105 106}

Urinate immediately prior to administration and gently shake penis to remove excess urine.^{97 100 105 106} Microsuppository (medicated pellet) is designed to dissolve in small quantity of urine remaining in urethra after urination.⁹⁹

Insert intraurethral suppository according to manufacturer's instructions.^{97 100} After insertion, inspect applicator to confirm that urethral suppository is no longer in applicator tip.¹⁰⁰ If some residual medication is left in applicator, repeat insertion procedure.¹⁰⁰ Urination or dribbling immediately following intraurethral administration may result in loss of drug from urethral area.¹⁰⁰

After insertion of suppository, hold penis upright, and stretch to its full length.¹⁰⁰ Roll penis firmly between hands for ≥10 seconds to ensure that drug distributes adequately along walls of urethra.¹⁰⁰ If a burning sensation occurs, roll penis for additional 30–60 seconds or until burning subsides.¹⁰⁰

After administration, increase blood flow to penis by sitting, standing, or walking for 10 minutes.^{100 106} Lying down (especially on back) immediately after administration may reduce penile blood flow and subsequent development of erection.^{100 106} During sexual activity, use positions that favor blood flow into penis.¹⁰⁰

Dosage

Pediatric Patients

Ductus Arteriosus-dependent Congenital Heart Disease

IV and Intra-arterial Infusion

Neonates: Initially, 0.1 mcg/kg per minute.^{1 3 a} However, adequate clinical response reported with 0.05 mcg/kg per minute^{1 70} in some neonates.^{3 43 49 57 58 60 70 95 96}

If response inadequate, may increase dosage gradually to ≤0.4 mcg/kg per minute.^{1 3 57 60 a} However, dosages >0.1 mcg/kg per minute generally have not produced additional benefit.^{1 3 57 60 a}

After therapeutic response achieved, reduce infusion rate to provide the lowest possible dosage that maintains response; progressively taper dosage from 0.1 down to 0.05 to 0.025 to 0.01 mcg/kg per minute until lowest effective dose reached.^{1 3}

Continue therapy until surgical repair is complete, usually ≤24–48 hours after initiation.^{3 44}

If complications occur, consider lower infusion rate or discontinuance of infusion.^{1 60} (See IV and Intra-arterial Infusion: Rate of Administration under Dosage and Administration.)

If apnea or bradycardia occurs, discontinue infusion and initiate appropriate treatment.^{1 50} In some cases, reinitiate infusion cautiously if continued therapy considered necessary.^{1 3 42 50 64}

Adults

ED

Initiation and Titration for ED of Neurogenic, Vasculogenic, Psychogenic, or Mixed Etiology

Intraurethral Suppository

Initially, 125 or 250 mcg.^{98 105} If no response, increase subsequent doses in a stepwise manner to 500 mcg or 1 mg, as needed, on separate occasions.^{98 107} Use ≤2 urethral suppositories within 24 hours.^{98 100 104}

Initiation and Titration for ED of Pure Neurogenic Etiology

Intracavernosal Injection

Caverject vials and single-use, dual-chambered injection device: Initially, 1.25 mcg.^{89 110 b} If no response, double second dose to 2.5 mcg after ≤1 hour.^{64 110 b} Do not administer >2 doses within 24 hours.^{64 110 x} If additional dosage titration required, administer 5 mcg during next 24 hours.^{110 b} Increase subsequent dosage in 5-mcg increments, with each incremental increase separated by ≥24 hours, until optimum response achieved.^{110 b} (See General: ED, under Dosage and Administration.)

edex reusable dual-chambered injection device: Initially, 1.25 mcg.^d If no response, double second dose to 2.5 mcg after ≤1 hour; if still no response, increase to 5 mcg after ≤1 hour.^{d z} Increase subsequent dosage in 5-mcg increments, until optimum response achieved.^{d z} (See General: ED, under Dosage and Administration.) If a partial response observed at any point in dosage titration, wait ≥1 day before resuming dose titration.^{d z}

Initiation and Titration for ED of Vasculogenic, Psychogenic, or Mixed Etiology

Intracavernosal Injection

Caverject vials and single-use, dual-chambered injection devices: Initially, 2.5 mcg.^{8 110 b} If partial response observed, double dose to 5 mcg after ≤1 hour.^{110 b} If no response, increase second dose to 7.5 mcg after ≤1 hour.^{110 b} Administer ≤2 doses within ≤24 hours.^{110 x} If additional titration required, increase dosage in increments of 5–10 mcg at intervals of ≥24 hours until optimum response achieved.^{110 b z} (See General: ED, under Dosage and Administration.)

edex reusable dual-chambered injection device: Initially, 2.5 mcg.^d If no response, increase second dose to 7.5 mcg after ≤1 hour, followed by increments of 5–10 mcg at intervals of ≤1 hour until a response occurs.^{d z} If partial response observed with 2.5 mcg, wait ≥24 hours before doubling dose to 5 mcg, followed by increments of 5–10 mcg at intervals of ≥24 hours until optimum response achieved.^{d z} (See General: ED, under Dosage and Administration.)

Maintenance (Self-administration)

Intraurethral Suppository

Initially, self-administer dose determined as optimal during titration in a medical setting (e.g., physician’s office);^{97 98} administer ≤2 urethral suppositories within a 24-hour period.^{98 100 104}

Intracavernosal Injection

Initially, self-administer dose determined as optimal during titration in a medical setting (e.g., physician’s office); administer no more frequently than 3 times weekly with >1 day elapsing between each dose.^{2 34 101 b d e h i r}

If required, adjust dosage only after consultation with a clinician (not independently by the patient), following the same initial titration guidelines.^{2 b e f i r}

Diagnostic Use

Intracavernosal Injection

Adjunct to other vascular testing: Use single dose that produces firm erection.^{86 110 b}

Prescribing Limits

Pediatric Patients

Ductus Arteriosus-dependent Congenital Heart Disease

IV or Intra-arterial Infusion

Maximum: ≤0.4 mcg/kg per minute.^{1 3 57 60 a}

Adults

ED

Initiation and Titration

Intraurethral Suppository

Maximum 2 suppositories within 24 hours.^{98 100 104}

Intracavernosal Injection

Caverject vials and single-use, dual-chambered injection devices: Generally, maximum 60–65 mcg.^{26 32 35 36 41 64 110 b} Administer maximum 2 injections within 24 hours.^{h x}

edex reusable dual-chambered injection device: Dosages >40 mcg not evaluated.^d If a response occurs, allow >1 day interval between doses.^d

Maintenance (Self-administration)

Intraurethral Suppository

Maximum 2 urethral suppositories within a 24-hour period.^{98 100 104}

Intracavernosal Injection

Maximum frequency ≤3 injections weekly with ≥1 day elapsing between each dose.^{34 101 110 b z}

Cautions for Alprostadil

Contraindications

• 
  

  Intraurethral suppository or intracavernosal injection: Conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia, thrombocythemia, polycythemia, propensity to develop venous thrombosis, hyperviscosity syndrome).^{8 19 32 64 76 89 97 98 100 b d}

  
  


• 
  

  Intraurethral suppository or intracavernosal injection: Anatomic deformation of penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).^{8 19 32 64 76 89 97 98 100 b d}

  
  


• 
  

  Intraurethral suppository or intracavernosal injection: Men for whom sexual activity is inadvisable (e.g., underlying cardiovascular status).^{8 19 32 64 76 89 97 98 100 b h y} (See Assessment of Patients with Erectile Dysfunction under Cautions.)

  
  


• 
  

  Intraurethral suppository or intracavernosal injection: Women and children, including neonates.^{d h}

  
  


• 
  

  Intraurethral suppository or intracavernosal injection: Use with penile implants.^{101 b d}

  
  


• 
  

  Intraurethral suppository: Certain GU tract disorders (e.g., urethral stricture or obstruction, balanitis, acute or chronic urethritis, severe hypospadias and curvature, anuria).^{97 98 99 100 105}

  
  


• 
  

  Intraurethral suppository: Use with indwelling urethral catheter.^{97 98 99 100 105}

  
  


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  Intraurethral suppository: Unprotected sexual intercourse with pregnant women.^{98 100 104} (See Pregnancy under Cautions.)

  
  


• 
  

  Known hypersensitivity to alprostadil or other prostaglandins.^{98 d}

  
  

Warnings/Precautions

Warnings

Apnea

Risk of respiratory depression and apnea in neonates with congenital heart defects.^{1 3 44 50 53 60} (See Boxed Warning.)

GI Effects

Risk of gastric outlet obstruction secondary to antral hyperplasia in neonates receiving alprostadil injection for arteriosus-dependent congenital heart disease; associated with prolonged therapy (e.g., cumulative dose and duration of therapy).^{1 3 44 47 49 50 52 54 55 58 59 95}

Closely monitor neonates receiving recommended dosages for >120 hours for evidence of antral hyperplasia and gastric outlet obstruction.^{1 59} During prolonged therapy, carefully weigh possible risk of gastric outlet obstruction against potential benefits.^{1 3 44 47 49 50 52 54 55 58 59 95}

Priapism

Possible prolonged erection (persisting for 4–6 hours) or priapism (erection persisting for >6 hours).^{98 112 b d}

May result in penile tissue damage and permanent loss of potency if not treated immediately^{110 d r} (e.g., aspiration of cavernosal blood, intracavernosal injection of an α-adrenergic agonist or dopamine).^{6 7 8 11 12 19 20 23 46 67 83 89 98 113 b}

Minimize risk of prolonged erection by slowly titrating to lowest possible effective dosage.^{110 b d} Consider decreased dosage or discontinuance in patients who develop priapism or prolonged erection.⁹⁸ (See General: ED, under Dosage and Administration.)

Cardiovascular and Cerebrovascular Effects

Risk of symptomatic hypotension and syncope in patients using intraurethral alprostadil;^{110 d} monitor patients during dosage initiation and titration for manifestations of such effects.^{98 100}

Hypotension and/or dizziness reported following intracavernosal administration; may result from increased peripheral blood levels of prostaglandin E₁, especially in patients with significant corpora cavernosa venous leakage.^{110 d}

Possible hypotension and bradycardia in neonates receiving IV or intra-arterial therapy.^{1 3 50} If bradycardia occurs, discontinue infusion and institute appropriate therapy;^{1 50} (See Dosage: Pediatric Patients under Dosage and Administration) if hypotension occurs, reduce infusion rate and institute appropriate therapy, if necessary.^{1 3 50} (See IV and Intra-arterial Infusion: Rate of Administration under Dosage and Administration.)

Morphologic changes in ductal and pulmonary arteries observed in infants receiving short- or long-term IV or intra-arterial therapy at usual recommended dosages.^a

General Precautions

Respiratory Distress Syndrome

Do not use in neonates with respiratory distress syndrome;^{1 4 42 49 64} closure of ductus arteriosus is necessary to prevent overload of pulmonary circulation in such neonates.^{4 42 49 55}

Prior to initiating therapy in neonates, make a differential diagnosis between neonatal respiratory distress syndrome (hyaline membrane disease) and cyanotic heart disease (restricted pulmonary blood flow).¹ If full diagnostic facilities not readily available, use cyanosis (evidenced by PO₂ <40 mm Hg) and radiographic evidence of restricted pulmonary blood flow as indicators of cyanotic heart disease.¹

GU Effects

Penile fibrosis, including Peyronie’s disease, reported following intracavernosal administration.^{110 b d}

Examine patients (e.g., every 3 months) for any changes in penis and assess therapeutic benefit.