Tri-Mix Injection

Papaverine hydrochloride is a benzylisoquinoline alkaloid originally isolated from opium. It has no narcotic or analgesic activity and is not a controlled substance. Drug class: vasodilator (non-selective phosphodiesterase inhibitor). In the US it is available as papaverine hydrochloride injection 30 mg/mL for intramuscular or slow intravenous use. Lake Hills Pharmacy uses it as a component of compounded intracavernosal preparations.

Papaverine injection labeling lists relief of conditions accompanied by smooth-muscle spasm: vascular spasm associated with acute myocardial infarction, angina, peripheral and pulmonary embolism, peripheral vascular disease with a vasospastic element and certain cerebral angiospastic states, and visceral spasm such as ureteral, biliary or gastrointestinal colic.

Intracavernosal use for erectile dysfunction is not a labeled use; the label notes that intracorporeal injection for impotence is not approved and has been associated with persistent priapism. Prescribers use papaverine in compounded intracavernosal preparations, alone or combined with phentolamine and alprostadil.

Papaverine inhibits phosphodiesterase isoenzymes non-selectively, raising intracellular cAMP and cGMP, and may also inhibit calcium influx. The result is direct relaxation of vascular, bronchial, gastrointestinal, biliary and urogenital smooth muscle. In the corpora cavernosa it relaxes trabecular smooth muscle and cavernosal arteries, increasing arterial inflow and compressing subtunical venules to restrict outflow. It is not selective for PDE5.

Papaverine is highly protein bound (about 90%) and is metabolized in the liver, chiefly by O-demethylation followed by glucuronide conjugation; metabolites are excreted in the urine. The plasma half-life is short, roughly 0.5 to 2 hours, with wide individual variation. After intracavernosal injection most of the effect is local, but some of the dose reaches the systemic circulation.

• Hypersensitivity to papaverine.
• Complete atrioventricular heart block (intravenous use).
• For intracavernosal use, conditions predisposing to priapism (sickle cell anemia or trait, multiple myeloma, leukemia), anatomic deformation of the penis and penile implants are treated as contraindications, consistent with intracavernosal alprostadil labeling.

• Hepatic hypersensitivity: eosinophilia, elevated liver enzymes and jaundice have been reported, including with intracavernosal use. Stop the drug if liver abnormalities appear.
• Priapism and penile fibrosis can follow intracavernosal injection; papaverine-containing mixtures carry a higher priapism risk than alprostadil alone.
• Cardiac: when conduction is depressed, papaverine can produce transient ectopic rhythms. Intravenous doses are given slowly over 1 to 2 minutes; rapid injection can cause arrhythmia.
• Use with caution in glaucoma.

• Levodopa: papaverine may reduce its antiparkinsonian effect.
• PDE5 inhibitors, nitrates, alpha-blockers and other antihypertensives or vasodilators: additive hypotension.
• Other intracavernosal or erectile dysfunction therapies: increased risk of priapism.

Local (intracavernosal): penile pain, hematoma, ecchymosis, fibrosis, nodules and priapism. Systemic: flushing, dizziness, hypotension, tachycardia, headache, sweating, drowsiness, nausea, abdominal discomfort, constipation or diarrhea, rash, and hepatic hypersensitivity.

Adequate human data are lacking. Intracavernosal use applies to men and the drug is not used for this purpose in pregnancy. Whether papaverine is excreted in human milk is unknown.

Liver tests periodically during ongoing use and whenever symptoms suggest hepatotoxicity; penile examination for fibrosis, nodules or curvature at follow-up; blood pressure and heart rate; and the duration of each erection, with prompt treatment of any erection lasting more than 4 hours.

• Papaverine Hydrochloride Injection, USP, manufacturer prescribing information.
• Erectile Dysfunction: AUA Guideline (2018), American Urological Association.
• Martindale: The Complete Drug Reference, papaverine monograph.

Phentolamine mesylate is an imidazoline, competitive, non-selective alpha-1 and alpha-2 adrenergic antagonist. US products include phentolamine mesylate for injection (5 mg vial, intravenous or intramuscular; the original brand was Regitine), OraVerse (dental submucosal injection) and Ryzumvi (phentolamine ophthalmic solution 0.75%). Lake Hills Pharmacy uses it as a component of compounded intracavernosal preparations.

• Injection: prevention or control of hypertensive episodes in pheochromocytoma, such as before and during surgical excision; prevention or treatment of dermal necrosis and sloughing after intravenous extravasation of norepinephrine; and the phentolamine blocking test in the diagnosis of pheochromocytoma.
• OraVerse: reversal of soft-tissue anesthesia and the associated functional deficits after a dental procedure using a local anesthetic with a vasoconstrictor.
• Ryzumvi: treatment of pharmacologically induced mydriasis produced by adrenergic agonists or parasympatholytic agents.
• Intracavernosal use is not labeled. Prescribers use phentolamine in compounded combinations with papaverine, alprostadil or both for erectile dysfunction.

Phentolamine blocks postsynaptic alpha-1 and presynaptic alpha-2 receptors, causing arterial and venous vasodilation. Alpha-2 blockade increases norepinephrine release, which with baroreflex activation produces tachycardia. In the penis it opposes the adrenergic tone that maintains flaccidity, complementing smooth-muscle relaxants such as papaverine and alprostadil. In the eye it relaxes the iris dilator muscle.

After intravenous injection the effect is immediate and the plasma half-life is about 19 minutes; after intramuscular injection the effect peaks within about 20 minutes and lasts 3 to 4 hours. Phentolamine is extensively metabolized, and about 13% of an intravenous dose is excreted unchanged in the urine. Intracavernosal injection acts mainly locally, with some systemic absorption.

• Hypersensitivity to phentolamine or related compounds.
• Myocardial infarction, history of myocardial infarction, coronary insufficiency, angina or other evidence of coronary artery disease.

• Myocardial infarction, cerebrovascular spasm and cerebrovascular occlusion have been reported after administration, usually in association with marked hypotension.
• Tachycardia and cardiac arrhythmias can occur; use with caution in patients with cardiac disease.
• Hypotension: if severe, treat with norepinephrine; epinephrine should not be used, because its beta effect can lower blood pressure further when alpha receptors are blocked.
• Intracavernosal use carries the risks of priapism, penile fibrosis and hematoma.

• PDE5 inhibitors, nitrates, alpha-blockers and other antihypertensives: additive hypotension.
• Epinephrine: paradoxical fall in blood pressure.
• Other intracavernosal or erectile dysfunction therapies: increased risk of priapism.

Hypotension including orthostatic hypotension, tachycardia, arrhythmia, angina, flushing, dizziness, weakness, nasal congestion, nausea, vomiting and diarrhea. Intracavernosal use adds penile pain, hematoma, fibrosis and priapism. OraVerse commonly causes injection-site pain; Ryzumvi causes conjunctival redness and instillation-site discomfort.

Adequate human data are lacking. Intracavernosal use applies to men. Whether phentolamine is excreted in human milk is unknown.

Blood pressure and heart rate, symptoms of myocardial ischemia in patients with cardiovascular risk, penile examination for fibrosis at follow-up, and the duration of each erection, with prompt treatment of any erection lasting more than 4 hours.

• Phentolamine Mesylate for Injection, USP, manufacturer prescribing information.
• OraVerse (phentolamine mesylate) Injection Prescribing Information, Septodont.
• Ryzumvi (phentolamine ophthalmic solution) 0.75% Prescribing Information.
• Erectile Dysfunction: AUA Guideline (2018), American Urological Association.

Alprostadil is synthetic prostaglandin E1 (PGE1). US products include Caverject and Caverject Impulse (intracavernosal powder for injection, Pfizer), Edex (intracavernosal), Muse (urethral suppository) and Prostin VR Pediatric (intravenous infusion, Pfizer). Lake Hills Pharmacy uses alprostadil as a component of compounded intracavernosal preparations.

• Caverject and Edex: erectile dysfunction due to neurogenic, vasculogenic, psychogenic or mixed etiology; Caverject is also labeled as an adjunct in the diagnosis of erectile dysfunction.
• Muse: treatment of erectile dysfunction.
• Prostin VR Pediatric: palliative therapy to temporarily maintain patency of the ductus arteriosus until surgery in neonates with ductal-dependent congenital heart defects.
• Prescribers use alprostadil in compounded intracavernosal combinations with papaverine and phentolamine.

Alprostadil binds prostaglandin E receptors on smooth muscle, activating adenylyl cyclase and raising intracellular cAMP. In the corpora cavernosa this relaxes trabecular smooth muscle and dilates cavernosal arteries, expanding the sinusoidal spaces and compressing venous outflow. The same action relaxes ductus arteriosus smooth muscle in neonates. Alprostadil also inhibits platelet aggregation.

Alprostadil is cleared rapidly, mainly in the lungs, where most of a circulating dose is metabolized in a single pass by oxidation to 15-keto-PGE1 and further metabolites that are excreted in the urine. Its plasma half-life is a few minutes. After intracavernosal or urethral dosing, most of the drug acts locally and peripheral plasma concentrations are low and brief.

• Hypersensitivity to alprostadil or any component.
• Intracavernosal and urethral use: conditions predisposing to priapism (sickle cell anemia or trait, multiple myeloma, leukemia); anatomic deformation of the penis (angulation, cavernosal fibrosis, Peyronie's disease); penile implants; men for whom sexual activity is inadvisable or contraindicated.
• Muse: sexual intercourse with a pregnant woman unless a condom barrier is used.
• Prostin VR Pediatric: the label lists no contraindications; its precautions state that it should not be used in neonates with respiratory distress syndrome.

• Priapism: an erection lasting more than 4 hours needs prompt treatment to prevent permanent damage.
• Penile fibrosis, nodules and Peyronie's-type curvature can develop with repeated intracavernosal use; regular follow-up is advised and treatment stops if they appear.
• Bleeding and hematoma at the injection site are more likely with anticoagulants. Hypotension and syncope can occur.
• Prolonged neonatal infusion can cause cortical proliferation of the long bones and, beyond about 120 hours, gastric outlet obstruction from antral hyperplasia.

• Anticoagulants and antiplatelet drugs: increased penile bleeding and hematoma.
• Antihypertensives and vasodilators: additive hypotension.
• Other vasoactive agents or erectile dysfunction treatments: combination use has not been studied in labeling and raises priapism risk.
• Sympathomimetics may reduce the erectile effect.

Intracavernosal: penile pain (most common), prolonged erection, priapism, fibrosis, hematoma and ecchymosis, injection-site bleeding, dizziness and hypotension. Urethral: urethral pain or burning, minor urethral bleeding, testicular pain and partner vaginal burning. Neonatal infusion: apnea, fever, flushing, bradycardia, seizures, diarrhea and cortical hyperostosis.

The erectile dysfunction products are for men and are not used in women. Prostaglandins can stimulate uterine contractions, so Muse labeling requires a condom barrier with a pregnant partner. Use in pregnancy or lactation for other purposes is not established.

For erectile dysfunction use: penile examination for fibrosis or curvature at follow-up, duration of erections, injection-site bleeding and blood pressure. For neonatal infusion: continuous respiratory status, heart rate, arterial pressure and blood oxygenation.

• Caverject (alprostadil) for Injection Prescribing Information, Pfizer.
• Caverject Impulse (alprostadil) Prescribing Information, Pfizer.
• Edex (alprostadil) Prescribing Information.
• Muse (alprostadil) Urethral Suppository Prescribing Information.
• Prostin VR Pediatric (alprostadil) Injection Prescribing Information, Pfizer.
• Erectile Dysfunction: AUA Guideline (2018), American Urological Association.