Alprostadil

Dosage for Alprostadil is highly individualized and must be titrated (carefully adjusted) by a healthcare provider to find the lowest effective dose that produces a satisfactory erection not exceeding one hour in duration.

Intracavernosal Injection (e.g., Caverject, Edex)

• Initial Dose: For ED of vasculogenic, psychogenic, or mixed etiology, the starting dose is typically 2.5 mcg. For ED of pure neurogenic origin (e.g., spinal cord injury), the starting dose is often lower, at 1.25 mcg.
• Titration: If there is no response, the dose may be increased in increments of 2.5 mcg to 5 mcg until the desired response is achieved. Most men find an effective dose between 5 mcg and 20 mcg.
• Maximum Frequency: Do not use more than 3 times per week, with at least 24 hours between each dose.

Intraurethral Suppository (e.g., MUSE)

• Initial Dose: The usual starting dose is 125 mcg or 250 mcg.
• Titration: Based on the response, the dose may be increased to 500 mcg or 1000 mcg under medical supervision.
• Maximum Frequency: No more than 2 doses should be used within a 24-hour period.

Alprostadil (Prostin VR Pediatric) is used in neonates to maintain the patency of the ductus arteriosus. It is administered via continuous intravenous or intra-arterial infusion.

• Standard Infusion Rate: The initial dose is typically 0.05 to 0.1 mcg per kilogram of body weight per minute (mcg/kg/min).
• Maintenance: Once a therapeutic response is achieved (e.g., increased oxygen saturation or improved blood pressure), the infusion rate is usually reduced to the lowest possible dose (often 0.01 to 0.05 mcg/kg/min) that maintains the effect.

Renal Impairment

Because Alprostadil is primarily metabolized in the lungs, significant dose adjustments are generally not required for patients with renal impairment when used for ED. However, caution is advised in neonates with renal dysfunction as it may affect the clearance of metabolites.

Hepatic Impairment

No specific dosage adjustments are typically provided for hepatic impairment, but since the liver plays a secondary role in metabolism, patients with severe liver disease should be monitored closely for systemic side effects.

Elderly Patients

Clinical studies have not identified significant differences in response between older and younger men. However, elderly patients may have a higher prevalence of cardiovascular disease, necessitating a cautious approach to the initial dose.

Intracavernosal Injection

1. 1Preparation: Wash your hands and clean the injection site on the side of the penis with an alcohol swab. Avoid any visible veins.
2. 2Injection: Use a 27- to 30-gauge needle. Insert the needle at a 90-degree angle into the corpus cavernosum (the 2 o'clock or 10 o'clock positions).
3. 3Post-Injection: Apply pressure to the injection site for at least 5 minutes to prevent bruising (hematoma).

Intraurethral Suppository

1. 1Urination: It is essential to urinate immediately before administration, as a moist urethra helps the pellet dissolve.
2. 2Insertion: While sitting or standing, stretch the penis to its full length and insert the applicator stem into the urethra. Depress the button to release the pellet.
3. 3Absorption: Roll the penis between your hands for 30 to 60 seconds to ensure the medication is evenly distributed.

For ED, Alprostadil is used on an as-needed basis. If you miss a planned use, there is no need to 'make up' the dose. For neonates, Alprostadil is a continuous infusion; if the infusion is interrupted, it is a medical emergency and must be restarted immediately by hospital staff.

In adults, an overdose of Alprostadil usually manifests as priapism (a painful erection lasting longer than 4 hours). This requires immediate medical intervention to prevent permanent tissue damage. In neonates, overdose symptoms include apnea (stopped breathing), bradycardia (slow heart rate), and severe hypotension (low blood pressure). If an overdose is suspected, the infusion must be slowed or stopped immediately, and supportive care initiated.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

The most frequently reported side effects of Alprostadil are localized to the site of administration.

• Penile Pain: Occurring in approximately 30% of injection users and 10-20% of suppository users, this is often described as a dull ache or a burning sensation in the penis or groin area. It typically subsides as the drug is metabolized.
• Urethral Burning: Common with the MUSE pellet, this sensation occurs during or shortly after insertion.
• Minor Bleeding or Bruising: Small spots of blood or a 'black and blue' mark at the injection site are common, especially if pressure is not applied correctly after the needle is withdrawn.

• Penile Fibrosis: With long-term use of injections, some men may develop small nodules (lumps) or a curvature of the penis (Peyronie's disease). Regular examination by a doctor is required.
• Headache: Systemic absorption can lead to vasodilation in the brain, resulting in tension-like headaches.
• Dizziness: A slight drop in blood pressure may cause lightheadedness, especially when moving from a sitting to a standing position.
• Vaginal Burning/Itching in Partners: If a condom is not used, the Alprostadil in the urethra can cause irritation to the female partner.

• Syncope (Fainting): Rare but possible, usually related to a rapid drop in blood pressure.
• Tachycardia (Rapid Heartbeat): The body may reflexively increase heart rate in response to peripheral vasodilation.
• Leg Pain: Some patients report aching in the legs or pelvis following administration.

> Warning: Stop using Alprostadil and call your doctor or seek emergency care immediately if you experience any of the following:

1. 1Priapism: An erection that lasts longer than 4 hours. This is a surgical emergency. If not treated, it can lead to penile tissue death (necrosis) and permanent loss of erectile function.
2. 2Severe Penile Pain or Swelling: Significant swelling, redness, or intense pain may indicate an infection or a vascular complication.
3. 3Signs of an Allergic Reaction: Hives, difficulty breathing, or swelling of the face, lips, tongue, or throat (anaphylaxis).
4. 4Fainting or Severe Dizziness: This may indicate a dangerous drop in systemic blood pressure.
5. 5Neonatal Apnea: In infants, if the baby stops breathing or has a bluish tint to the skin, immediate resuscitation is required.

The primary concern with long-term Alprostadil use is the development of penile fibrosis or Peyronie's disease. Studies suggest that approximately 2% to 5% of long-term injection users may develop some degree of fibrotic tissue. This is why rotating the injection site and using the lowest effective dose is critical. In neonates, long-term infusion (over several weeks) has been associated with cortical proliferation of long bones (thickening of the bone surface), which typically reverses once the drug is discontinued.

There are currently no FDA black box warnings for Alprostadil in its common formulations (Caverject, Edex, MUSE, Prostin VR). However, the labeling for neonatal use carries strong warnings regarding the risk of apnea, particularly in infants weighing less than 2 kg at birth. Monitoring in a neonatal intensive care unit (NICU) is mandatory.

Report any unusual symptoms to your healthcare provider. For more information, you may contact the FDA's MedWatch program at 1-800-FDA-1088.

Alprostadil is a potent vasodilator that requires careful administration. Patients using the injection or suppository forms for ED must be trained by a healthcare professional on the correct technique. Improper injection can lead to permanent injury. Furthermore, Alprostadil does not protect against sexually transmitted infections (STIs), including HIV; appropriate barrier methods should still be used.

No FDA black box warnings for Alprostadil. However, clinical guidelines emphasize that Alprostadil should only be used in settings where emergency resuscitation (for neonates) or urological intervention (for priapism) is readily available.

• Priapism Risk: Patients with conditions that predispose them to priapism, such as sickle cell anemia, multiple myeloma, or leukemia, must use Alprostadil with extreme caution, as the risk of a prolonged erection is significantly higher.
• Cardiovascular Health: Because sexual activity puts a strain on the heart, and Alprostadil can cause minor changes in blood pressure, patients with unstable angina, recent heart attack, or severe heart failure should discuss the safety of Alprostadil with their cardiologist.
• Penile Fibrosis: Long-term use of the injection form can cause scarring of the penile tissue. Patients should inspect their penis regularly for any new lumps or curves.
• Neonatal Apnea: Apnea (cessation of breathing) occurs in 10-12% of neonates with congenital heart defects treated with Alprostadil. It is most common in infants with low birth weight and usually appears during the first hour of infusion.
• Bleeding Risk: Patients taking anticoagulants (blood thinners) like warfarin or clopidogrel are at an increased risk of bleeding or hematoma at the injection site.

• Adults: Regular follow-up visits (every 3 to 6 months) with a urologist are recommended to check for penile fibrosis and to reassess the effective dose.
• Neonates: Continuous monitoring of respiratory rate, heart rate, and arterial blood gases is mandatory. In infants with obstructive left heart lesions, monitoring of blood pressure and pH is also required.
• Bone Health: For neonates on long-term therapy, periodic X-rays may be needed to monitor for bone changes (cortical proliferation).

Alprostadil can occasionally cause dizziness or syncope (fainting). Patients should not drive or operate heavy machinery for at least one hour after administration until they are certain they do not experience these side effects.

Alcohol is a known vasodilator and can also impair erectile function. Combining alcohol with Alprostadil may increase the risk of dizziness, fainting, and a drop in blood pressure. It is generally advised to limit alcohol consumption when using this medication.

For ED, Alprostadil can be stopped at any time without withdrawal symptoms. For neonates, the drug should never be stopped abruptly, as this can lead to the rapid closure of the ductus arteriosus and a life-threatening decline in oxygen levels. Discontinuation in a hospital setting is done by slowly tapering the infusion rate.

> Important: Discuss all your medical conditions with your healthcare provider before starting Alprostadil.

• Other ED Medications: Alprostadil should not be used in combination with other erectile dysfunction treatments, such as oral PDE5 inhibitors (Sildenafil, Tadalafil, Vardenafil) or other injectable agents (like Trimix, unless specifically directed by a specialist). Combining these can lead to an extremely high risk of priapism and severe hypotension.
• Nitrates: While the interaction is less severe than with oral ED drugs, using Alprostadil with nitrates (e.g., nitroglycerin for chest pain) can cause an additive vasodilatory effect, leading to dangerously low blood pressure.

• Antihypertensives (Blood Pressure Meds): Alprostadil may enhance the effects of medications used to treat high blood pressure (e.g., beta-blockers, ACE inhibitors, diuretics). This can result in increased dizziness or fainting. Patients should be cautious when starting Alprostadil if they are already on a multi-drug regimen for hypertension.
• Anticoagulants and Antiplatelets: Drugs like Warfarin (Coumadin), Heparin, Rivaroxaban (Xarelto), or Aspirin increase the risk of bleeding at the site of injection or urethral insertion. Patients should use a smaller needle and apply pressure for a longer duration (10+ minutes) after injection.
• Sympathomimetics: Medications that constrict blood vessels (like certain decongestants or stimulants) may reduce the effectiveness of Alprostadil, as they work in direct opposition to its vasodilatory mechanism.

• Alpha-Blockers: Medications like Tamsulosin (Flomax) or Terazosin used for prostate issues can lower blood pressure. When used with Alprostadil, the risk of orthostatic hypotension (dizziness upon standing) is increased.
• MAO Inhibitors: Some older antidepressants may theoretically interfere with the metabolism of prostaglandins, though the clinical significance of this with Alprostadil is poorly documented.

• High-Fat Meals: Unlike some oral ED medications, Alprostadil's efficacy is not affected by food intake because it bypasses the digestive system.
• Grapefruit Juice: There are no known interactions between grapefruit juice and Alprostadil, as the drug is not significantly metabolized by the CYP3A4 enzyme system.
• Caffeine: Excessive caffeine may cause vasoconstriction, which could theoretically slightly reduce the effectiveness of the drug, though this is rarely clinically significant.

• Ginkgo Biloba / Garlic / Ginseng: These supplements have mild antiplatelet effects and may increase the risk of bruising at the injection site.
• St. John’s Wort: While it affects many drugs via CYP450 induction, it does not have a known interaction with Alprostadil due to the drug's unique metabolic pathway in the lungs.
• Yohimbe: This herbal supplement is sometimes used for ED but can cause heart palpitations and high blood pressure, complicating the safety profile of Alprostadil.

Alprostadil is not known to interfere with common laboratory tests, such as blood chemistry panels, liver function tests, or urinalysis. In neonates, however, it may affect arterial blood gas (ABG) readings by improving oxygenation, which is the intended therapeutic effect.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. A complete medication review is essential for safety.

Alprostadil must NEVER be used in the following circumstances:

1. 1Predisposition to Priapism: Patients with sickle cell anemia or trait, multiple myeloma, or leukemia are at a high risk for prolonged, painful erections that can cause permanent damage.
2. 2Anatomical Deformities of the Penis: Conditions such as angulation, cavernosal fibrosis, or Peyronie's disease make the use of injections or suppositories dangerous and potentially ineffective.
3. 3Penile Implants: Alprostadil should not be used in men who have a functional or non-functional penile prosthesis.
4. 4Hypersensitivity: Anyone with a known allergy to Alprostadil or any of the inactive ingredients (such as the lactose or alfadex used in the formulations) must avoid the drug.
5. 5Conditions Where Sexual Activity is Inadvisable: Men for whom sexual exertion poses a significant risk to their cardiovascular health (e.g., severe heart disease).
6. 6Neonatal Respiratory Distress Syndrome: Alprostadil should not be used as a primary treatment for RDS (hyaline membrane disease) unless a ductal-dependent heart defect is also present.

These conditions require a careful risk-benefit analysis by a physician:

• Bleeding Disorders: Patients with hemophilia or severe thrombocytopenia (low platelets) may experience uncontrollable bleeding at the injection site.
• Unstable Cardiovascular Disease: Recent stroke or myocardial infarction (heart attack) within the last 6 months.
• Active Penile Infection: Balanitis (inflammation of the head of the penis) or urethritis should be treated before using Alprostadil.

There is a potential for cross-sensitivity with other prostaglandins (such as Misoprostol or Latanoprost). If a patient has had a severe reaction to any prostaglandin analog, Alprostadil should be used with extreme caution or avoided entirely.

> Important: Your healthcare provider will evaluate your complete medical history before prescribing Alprostadil.

FDA Pregnancy Category: X (for ED use) / Category C (for neonatal use).

Alprostadil is not indicated for use in women. However, it is known that Alprostadil is present in the semen of men using the drug. While the amounts are small, Alprostadil can cause uterine contractions. Therefore, if a man uses Alprostadil while his partner is pregnant, a condom MUST be used to prevent the medication from coming into contact with the woman's vagina and potentially causing premature labor or miscarriage.

It is not known if Alprostadil is excreted in human milk. Since the drug is not indicated for use in nursing mothers, and its half-life is extremely short, the risk to a nursing infant from a father's use of the medication is non-existent. For the neonates receiving the drug directly, breastfeeding is usually paused in favor of controlled IV nutrition and monitoring in the NICU.

Alprostadil is a 'standard of care' medication for neonates with ductal-dependent congenital heart defects. It is approved for use from birth. The primary concern in this population is apnea, which occurs in about 10-12% of treated infants. It is NOT approved for use in children or adolescents for any other purpose, including the treatment of ED.

Clinical trials of Alprostadil for ED included a significant number of men over the age of 65. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, older men are more likely to have underlying cardiovascular conditions and may be taking multiple medications (polypharmacy), which increases the risk of drug interactions and dizziness.

In patients with kidney disease, the primary metabolites of Alprostadil may accumulate. While the parent drug is cleared by the lungs, the safety of long-term metabolite accumulation in patients with end-stage renal disease (ESRD) has not been fully studied. No specific dose adjustment is recommended, but close monitoring is advised.

Because the lungs are the primary site of metabolism, liver disease does not significantly alter the pharmacokinetics of Alprostadil. However, patients with severe hepatic impairment (Child-Pugh Class C) should be started on the lowest possible dose and monitored for signs of systemic toxicity, such as flushing and hypotension.

> Important: Special populations require individualized medical assessment to ensure safety and efficacy.

Alprostadil is a synthetic form of Prostaglandin E1 (PGE1). Its primary molecular mechanism involves binding to EP (E-prostanoid) receptors, specifically the EP2 and EP4 subtypes, which are coupled to the Gs protein. This binding stimulates the enzyme adenylate cyclase, increasing the production of cyclic AMP (cAMP).

In smooth muscle cells, elevated cAMP levels activate protein kinase A (PKA), which leads to the phosphorylation of proteins that regulate calcium channels. The end result is a decrease in intracellular calcium and the relaxation of smooth muscle. In the penis, this allows for arterial dilation and engorgement. In the neonate, this prevents the muscular wall of the ductus arteriosus from contracting and closing.

• Onset of Action: For ED, an erection typically begins within 5 to 20 minutes after administration. In neonates, improvements in blood oxygenation are usually seen within 15 to 30 minutes of starting the infusion.
• Duration: The effects in adults usually last 30 to 60 minutes. In neonates, the effect lasts as long as the continuous infusion is maintained.
• Tolerance: There is no evidence of pharmacological tolerance (reduced effect over time) with Alprostadil, although the underlying disease (like worsening vascular health) may require dose increases.

| Parameter | Value |

|---|---|

| Bioavailability | High (local); <1% (systemic after lung pass) |

| Protein Binding | ~81% (primarily to albumin) |

| Half-life | 5 to 10 minutes (Adults); slightly longer in neonates |

| Tmax | 5 to 15 minutes (Local) |

| Metabolism | Pulmonary (15-hydroxyprostaglandin dehydrogenase) |

| Excretion | Renal (90% as metabolites) |

• Molecular Formula: C20H34O5
• Molecular Weight: 354.49 g/mol
• Solubility: Soluble in ethanol, dimethyl sulfoxide (DMSO), and dimethyl formamide; sparingly soluble in water.
• Description: Alprostadil is a white to off-white crystalline powder. It is a 20-carbon fatty acid chain with a cyclopentane ring.

Alprostadil is classified as a Prostaglandin Analog and a Vasodilator. It is related to other prostaglandins like Misoprostol (used for stomach protection and labor induction) and Latanoprost (used for glaucoma), but it has a much higher affinity for the receptors that control vascular smooth muscle relaxation.