Alprostadil

Name: Alprostadil

Alprostadil Overview

Alprostadil is a prescription medication used to certain types of erectile dysfunction. Alprostadil belongs to a group of drugs called vasodilators. These work by relaxing the muscles and blood vessels in the penis so that an erection can occur.

Common side effects of alprostadil include lower body aches, warmth or burning sensation in the urethra, and light headedness or dizziness. Do not drive or operate heavy machinery until you know how alprostadil affects you.

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 response5 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 drug 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 umbilical1 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 resistance110 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 devicer 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 minute1 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

Alprostadil Description

Alprostadil injection USP for intravascular infusion contains 500 micrograms Alprostadil, more commonly known as prostaglandin E1, in 1 mL dehydrated alcohol.

The chemical name for Alprostadil is (1R,2R,3R)-3-Hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentane heptanoic acid, and the molecular weight is 354.49.

Alprostadil is a white to off-white crystalline powder with a melting point between 110° and 116°C. Its solubility at 35°C is 8000 micrograms per 100 mL double distilled water. Alprostadil has a molecular formula of C20H34O5.

Alprostadil - Clinical Pharmacology

Alprostadil (prostaglandin E1) is one of a family of naturally occurring acidic lipids with various pharmacologic effects. Vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle are among the most notable of these effects. Intravenous doses of 1 to 10 micrograms of Alprostadil per kilogram of body weight lower the blood pressure in mammals by decreasing peripheral resistance. Reflex increases in cardiac output and rate accompany the reduction in blood pressure.

Smooth muscle of the ductus arteriosus is especially sensitive to Alprostadil, and strips of lamb ductus markedly relax in the presence of the drug. In addition, administration of Alprostadil reopened the closing ductus of new-born rats, rabbits, and lambs. These observations led to the investigation of Alprostadil in infants who had congenital defects which restricted the pulmonary or systemic blood flow and who depended on a patent ductus arteriosus for adequate blood oxygenation and lower body perfusion.

In infants with restricted pulmonary blood flow, about 50% responded to Alprostadil infusion with at least a 10 torr increase in blood pO2 (mean increase about 14 torr and mean increase in oxygen saturation about 23%). In general, patients who responded best had low pretreatment blood pO2 and were 4 days old or less.

In infants with restricted systemic blood flow, Alprostadil often increased pH in those having acidosis, increased systemic blood pressure, and decreased the ratio of pulmonary artery pressure to aortic pressure.

Alprostadil must be infused continuously because it is very rapidly metabolized. As much as 80% of the circulating Alprostadil may be metabolized in one pass through the lungs, primarily by β- and ω-oxidation. The metabolites are excreted primarily by the kidney, and excretion is essentially complete within 24 hours after administration. No unchanged Alprostadil has been found in the urine, and there is no evidence of tissue retention of Alprostadil or its metabolites.

Precautions

General Precautions

Cortical proliferation of the long bones, first observed in dogs, has also been observed in infants during long-term infusions of Alprostadil. The cortical proliferation in infants regressed after withdrawal of the drug.

In infants treated with Alprostadil injection at the usual doses for 10 hours to 12 days and who died of causes unrelated to ductus structural weakness, tissue sections of the ductus and pulmonary arteries have shown intimal lacerations, a decrease in medial muscularity and disruption of the medial and internal elastic lamina. Localized and aneurysmal dilatations and vessel wall edema also were seen compared to a series of pathological specimens from infants not treated with Alprostadil injection. The incidence of such structural alterations has not been defined.

Because Alprostadil inhibits platelet aggregation, use Alprostadil injection cautiously in neonates with bleeding tendencies.

Alprostadil injection should not be used in neonates with respiratory distress syndrome. A differential diagnosis should be made between respiratory distress syndrome (hyaline membrane disease) and cyanotic heart disease (restricted pulmonary blood flow). If full diagnostic facilities are not immediately available, cyanosis (pO2 less than 40 torr) and restricted pulmonary blood flow apparent on an X-ray are appropriate indicators of congenital heart defects.

Necessary Monitoring

In all neonates, arterial pressure should be monitored intermittently by umbilical artery catheter, auscultation, or with a Doppler transducer. Should arterial pressure fall significantly, decrease the rate of infusion immediately.

In infants with restricted pulmonary blood flow, measure efficacy of Alprostadil injection by monitoring improvement in blood oxygenation. In infants with restricted systemic blood flow, measure efficacy by monitoring improvement of systemic blood pressure and blood pH.

Drug Interactions

No drug interactions have been reported between Alprostadil injection and the therapy standard in neonates with restricted pulmonary or systemic blood flow. Standard therapy includes antibiotics, such as penicillin and gentamicin; vasopressors, such as dopamine and isoproterenol; cardiac glycosides; and diuretics, such as furosemide.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies and fertility studies have not been done. The Ames and Alkaline Elution assays reveal no potential for mutagenesis.

Use Labeled Indications

Patent ductus arteriosus (Prostin VR Pediatric): Temporary maintenance of patency of ductus arteriosus in neonates with ductal-dependent congenital heart disease until surgery can be performed. These defects include cyanotic (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, Fallot's tetralogy, transposition of the great vessels) and acyanotic (eg, interruption of aortic arch, coarctation of aorta, hypoplastic left ventricle) heart disease.

Erectile dysfunction:

Caverject, Edex, Caverject Impulse: Treatment of erectile dysfunction due to vasculogenic, psychogenic, neurogenic, or mixed etiology; Caverject may be a useful adjunct to other diagnostic tests in the diagnosis of erectile dysfunction

Muse: Treatment of erectile dysfunction

Dosing Pediatric

Patent ductus arteriosus IV:

Prostin VR Pediatric: IV continuous infusion into a large vein, or alternatively through an umbilical artery catheter placed at the ductal opening: 0.05-0.1 mcg/kg/minute with therapeutic response, rate is reduced to lowest effective dosage. With unsatisfactory response, rate is increased gradually; maintenance: 0.01-0.4 mcg/kg/minute.

Note: Alprostadil is usually given at an infusion rate of 0.1 mcg/kg/minute, but it is often possible to reduce the dosage to 1/2 or even 1/10 without losing the therapeutic effect.

Note: Therapeutic response is indicated by increased pH in those with acidosis or by an increase in oxygenation (PO2) usually evident within 30 minutes.

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