Alprostadil

G04B - Urologicals ATC G04BE01 Small molecule approved 1981 Parenteral Topical Natural product Black-box warning

JFDA label: CAVERJECT POWD FOR INJ

⚠ Black-Box Warning

Apnea (Prostin VR Pediatric):

Mechanism of Action

Agonist of Prostaglandin E2 receptor EP1 subtype — Prostanoid EP1 receptor agonist; Agonist of Prostaglandin E2 receptor EP2 subtype — Prostanoid EP2 receptor agonist

Target	Action	Gene / class
Prostaglandin E2 receptor EP1 subtype efficacy	AGONIST	PTGER1
Prostaglandin E2 receptor EP2 subtype efficacy	AGONIST	PTGER2

Indications

Approved

Caverject, Edex, Caverject Impulse
Erectile dysfunction
Muse
Patent ductus arteriosus (Prostin VR Pediatric)

Off-label

Raynaud phenomenon

Contraindications

Source: Lexicomp

Intracavernous: Hypersensitivity to alprostadil or any component of the formulation Absolute
conditions predisposing men to priapism (eg, sickle cell anemia or trait, multiple myeloma, leukemia) Absolute
men who are prone to venous thrombosis or who have a hyperviscosity syndrome (eg, sickle cell anemia or trait, thrombocythemia, polycythemia, multiple myeloma) predisposing them to priapism Absolute
men with anatomical deformation or fibrotic conditions of the penis (eg, angulation, cavernosal fibrosis, or Peyronie disease) Absolute
penile implants IV: There are no contraindications listed in the manufacturer's labeling. Transurethral: Hypersensitivity to alprostadil or any component of the formulation Absolute
sexual intercourse with a pregnant woman unless a condom barrier is being used Documentation of allergenic cross-reactivity for prostaglandins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty Absolute
urethral stricture, balanitis, severe hypospadias and curvature, and in men with acute or chronic urethritis Absolute
use in men for whom sexual activity is inadvisable Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (7)

Very Common Flushing

Common Bradycardia · cardiac arrest · edema · Hypertension · hypotension · tachycardia

Nervous system disorders (4)

Common Dizziness · headache · pain · seizure

Renal and urinary disorders (8)

Common penile disease · penile rash · penile swelling · Peyronie's disease · Prolonged erection · Testicular pain · urethral bleeding (minor) · vulvovaginal pruritus (female partner)

Blood and lymphatic system disorders (1)

Common Disseminated intravascular coagulation

Metabolism and nutrition disorders (1)

Common Hypokalemia

Gastrointestinal disorders (1)

Common Diarrhea

Musculoskeletal and connective tissue disorders (1)

Common Back pain

Infections and infestations (1)

Common Sepsis

General disorders and administration site conditions (4)

Very Common Fever

Common Bruising at injection site · hematoma at injection site · Local pain (in structures other than the injection site)

Other (2)

Very Common Genitourinary: Penile pain · urethral burning

Respiratory, thoracic and mediastinal disorders (6)

Very Common Apnea

Common Cough · flu-like symptoms · nasal congestion · sinusitis · upper respiratory tract infection

Dosing

Source: Lexicomp

Erectile dysfunction: Intracavernous (Caverject, Caverject Impulse, Edex): Individualize dose by careful titration; doses >40 mcg (Edex) or >60 mcg (Caverject) are not recommended: Initial dose must be titrated in health care provider setting. Patient must stay in the health care setting until complete detumescence occurs; if there is no response, then the next higher dose may be given within 1 hour; if there is still no response, a 1-day interval before giving the next dose is recommended; increasing the dose or concentration in the treatment of impotence results in increasing pain and discomfort. Initial dose titration: According to the prescribing information for Caverject and Caverject Impulse, no more than 2 doses during the initial titration should be given within a 24 hour period. Vasculogenic, psychogenic, or mixed etiology: Initiate dosage titration at 2.5 mcg. If there is a partial response, increase dose by 2.5 mcg to a dose of 5 mcg and then, in increments of 5 to 10 mcg (depending on erectile response) until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. If there is no response to the initial 2.5 mcg dose, the second dose may be increased to 7.5 mcg and administered within 1 hour, followed by increments of 5 to 10 mcg (Edex). If there is a response, then there should be at least a 24 hour interval before the next dose is given. Neurogenic etiology (eg, spinal cord injury): Note: Caverject powder must be used to prepare a 1.25 mcg dose: Initiate dosage titration at 1.25 mcg; if there's a partial response, may increase to a dose of 2.5 mcg within 1 hour and if necessary, to a dose of 5 mcg; may increase further in increments of 5 mcg until the dose is reached that produces an erection suitable for intercourse, not lasting >1 hour. Maintenance: Once an appropriate dose has been determined, patient may self-administer injections at a frequency of no more than 3 times/week with at least 24 hours between doses Intraurethral (Muse Pellet): Initial: 125 to 250 mcg Maintenance: Administer as needed to achieve an erection; duration of action is about 30 to 60 minutes; use only two systems per 24-hour period Raynaud phenomenon (off-labeled use): IV: 60 mcg over 3 hours once daily for 5 consecutive days (loading dose) followed by maintenance dosing of 60 mcg over 3 hours once every 30 days for 2 doses (Marasini 2004) or 60 mcg over 3 hours once daily for 6 consecutive days (Bartolone 1999) or 40 mcg (at a rate of 3 to 5 ng/kg/minute) twice daily for a minimum duration of 7 days and repeated every 3 to 4 weeks (Lamprecht 1998)

(For additional information see "Alprostadil: Pediatric drug information") 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.

Use lowest effective dose. In clinical studies with Edex, higher minimally effective doses and a higher rate of lack of effect were noted. Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Apnea

Prostin VR Pediatric: Apnea may occur in 10% to 12% of neonates with congenital heart defects, especially in those weighing Apnea usually appears during the first hour of drug infusion.

Hypotension/syncope

Intracavernous injections can increase peripheral blood levels of alprostadil, resulting in hypotension. Syncope has also been reported. Avoid use in men with known cavernosal venous leakage. Patients must be cautioned to avoid tasks such as operating machinery or driving following administration where injury could result if hypotension or syncope were to occur.

Penile fibrosis

May occur when used for erectile dysfunction; discontinue use in men who develop penile angulation or cavernosal fibrosis.

Priapism/prolonged erection

May occur when used for erectile dysfunction; instruct patient to seek immediate medical assistance if an erection persists ≥4 hours; discontinue therapy if priapism or prolonged erection occurs or if signs of penile fibrosis develop (penile angulation, cavernosal fibrosis, or Peyronie disease). To minimize the chances of prolonged erection or priapism, titrate slowly to the lowest effective dose. Use is contraindicated in men who have conditions that predispose them to priapism (eg, sickle cell anemia or trait, multiple myeloma, leukemia). Underlying causes of erectile dysfunction should be evaluated and treated prior to therapy. Disease related concerns:

Cardiovascular disease

Treatment for erectile dysfunction should not be used in men whom sexual activity is inadvisable because of underlying cardiovascular status. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Neonates

Prostin VR Pediatric: Use with caution in neonates with bleeding tendencies. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Other warnings/precautions:

Administration

Muse: Urethral abrasion resulting in minor bleeding or spotting may occur from improper administration.

Needle breakage

Caverject and Caverject Impulse: A superfine needle is used for administration. Needle breakage (a portion of the needle remaining in the penis) has been reported; hospitalization and surgical removal may be necessary.

Patency of ductus arteriosus

Appropriate use: Prostin VR Pediatric: Infuse for the shortest time at the lowest dose consistent with good patient care. Use for >120 hours has been associated with antral hyperplasia and gastric outlet obstruction.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies. Alprostadil is not indicated for use in women. The manufacturer of Muse recommends a condom barrier when being used during sexual intercourse with a pregnant woman.

Lactation

Alprostadil is not indicated for use in women.

Monitoring

Clinical pearl	Blood pressure, respiratory rate, heart rate, temperature, degree of penile pain, duration of erection, adequate detumescence after dosing, signs of infection

Chemistry & Properties

Formula	C20H34O5
Molecular weight	354.49 g/mol
IUPAC name	7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]heptanoic acid
CAS	745-65-3
PubChem CID	5280723
InChIKey	`GMVPRGQOIOIIMI-DWKJAMRDSA-N`
logP	3.48 (XLogP 3.2)
Polar surface area	94.83 Å²
H-bond acceptors / donors	4 / 3
Drug-likeness (QED)	0.35
Lipinski violations	0

SMILES

CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—

Receptor binding (top 9)

Target	Action	Affinity
EP4 receptor (PTGER4)	Agonist	pEC50 9.5
EP4 receptor (PTGER4)	Agonist	pKi 8.8
EP2 receptor (PTGER2)	Agonist	pKi 8.0
DP1 receptor (PTGDR)	Agonist	pKi 7.3
EP1 receptor (PTGER1)	Agonist	pKi 6.8
CatSper1 (CATSPER1)	Activator	pEC50 6.3
CatSper2 (CATSPER2)	Activator	pEC50 6.3
CatSper3 (CATSPER3)	Activator	pEC50 6.3
CatSper4 (CATSPER4)	Activator	pEC50 6.3

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)MRP5 (Inhibitor)OAT1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP3A1 (Inhibitor)OATP4A1 (Inhibitor)P-gp (Inhibitor)MRP2 (Substrate)MRP3 (Substrate)MRP4 (Substrate)OATP3A1 (Substrate)OATP4A1 (Substrate)P-gp (Substrate)

Drug–drug interactions (16, DDInter)

Interacting drug	Severity	Management
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Canagliflozin	moderate
Dapagliflozin	moderate
Empagliflozin	moderate
Epoprostenol	moderate
Ertugliflozin	moderate
Heparin	moderate
Iloprost	moderate
Lorcaserin	moderate
Minoxidil (topical)	moderate
Nitrous acid	moderate
Pentoxifylline	moderate
Sapropterin	moderate
Selexipag	moderate
Treprostinil	moderate

Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
CAVERJECT POWD FOR INJ	Powder for Injection 10 mcg	Vial+Dil.	Khoury Drug Store	8.170
CAVERJECT	Pre-filled Syringe 20 mcg	1 vial	Khoury Drug Store	10.420
Prostavasin Infusion Ampoules	Infusion 20 mcg	10	Suleiman Tannous & Sons Co. Ltd	—