A Comprehensive Monograph on Papaverine (DB01113)

1.0 Executive Summary

Papaverine is a non-narcotic, benzylisoquinoline alkaloid derived from the opium poppy, Papaver somniferum. Structurally and pharmacologically, it is distinct from the analgesic phenanthrene alkaloids of opium, such as morphine and codeine, and lacks their central nervous system and analgesic effects.[1] The primary mechanism of action of Papaverine is direct-acting smooth muscle relaxation, achieved through a multi-faceted approach that includes non-selective inhibition of phosphodiesterase (PDE) enzymes and direct modulation of calcium channels.[4] This inhibition of PDEs leads to an accumulation of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which triggers a cascade resulting in vasodilation and spasmolysis.[6]

Clinically, this pharmacological profile underpins its approved indications for the treatment of visceral spasms of the gastrointestinal tract and vasospasms associated with cerebral and peripheral ischemia.[1] Papaverine has also found a prominent, albeit largely off-label, role in modern medicine, most notably for the management of erectile dysfunction via intracavernosal injection, where its potent local vasodilatory effects are leveraged.[1] Its use extends to intraoperative settings to prevent or relieve arterial spasm during microsurgical and cardiovascular procedures.[1]

The safety profile of Papaverine is characterized by a narrow therapeutic window, with significant risks including hepatotoxicity and cardiac arrhythmias, particularly with rapid intravenous administration.[1] The localized use for erectile dysfunction carries a specific and serious risk of priapism.[10] In recent years, Papaverine has become a subject of renewed scientific interest, with emerging research exploring its potential as an anticancer, antiviral, and anti-inflammatory agent, driven by a deeper understanding of its effects on fundamental cellular pathways such as mitochondrial metabolism and PDE10A signaling.[12] This positions Papaverine as a historic therapeutic agent with potential for modern drug repurposing.

2.0 Identification and Physicochemical Profile

This section provides a definitive summary of the chemical and physical properties of Papaverine, establishing its identity and the characteristics that govern its formulation, stability, and handling.

2.1 Nomenclature and Identifiers

Papaverine is identified across global databases and regulatory systems by a variety of names and codes.

• Primary Name: Papaverine [1]
• DrugBank ID: DB01113 [1]
• Type: Small Molecule [4]
• CAS Numbers:
• Free Base: 58-74-2 [1]
• Hydrochloride Salt: 61-25-6 [1]
• IUPAC Names:
• 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline [16]
• 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline [2]
• Synonyms and International Names: Papaverina, Papaverin, Cerespan, Papanerine, Robaxapap, Pavabid, S-M-R, Papacon, NSC 136630, and папаверин (Bulgarian), among others.[4]
• Regulatory Codes:
• ATC Codes: A03AD01 (Drugs for functional gastrointestinal disorders), G04BE02 (Drugs used in erectile dysfunction), G04BE52 (Combinations) [21]
• FDA UNII: DAA13NKG2Q [20]
• EC Number: 200-397-2 [16]

2.2 Chemical and Structural Data

The molecular structure of Papaverine is the basis for its unique pharmacological profile, distinguishing it from other opium alkaloids.

• Chemical Formula:  [4]
• Molecular Weight:
• Average: 339.385 g/mol [4]
• Monoisotopic: 339.147058165 g/mol [4]
• Hydrochloride Salt: 375.85 g/mol [3]
• Structural Identifiers:
• InChI: InChI=1S/C20H21NO4/c1-22-17-6-5-13(10-18(17)23-2)9-16-15-12-20(25-4)19(24-3)11-14(15)7-8-21-16/h5-8,10-12H,9H2,1-4H3 [1]
• InChIKey: XQYZDYMELSJDRZ-UHFFFAOYSA-N [1]
• SMILES: COC1=CC=C(CC2=C3C=C(OC)C(OC)=CC3=CC=N2)C=C1OC [16]

2.3 Physicochemical Properties

The physical properties of Papaverine and its salts are critical determinants of its pharmaceutical formulation and clinical administration.

• Appearance: Papaverine base is a white crystalline powder, which can be obtained as orthorhombic prisms.[21] The hydrochloride salt also appears as white crystals or a white crystalline powder.[3]
• Melting Point: The free base melts at 147°C.[21] One source reports a melting point of 226°C, which likely corresponds to the hydrochloride salt.[21]
• Boiling Point: The compound sublimes under vacuum.[21] An estimated boiling point is 475.36°C, while another source notes sublimation at 135°C.[20]
• Solubility: The free base is described as insoluble in water but soluble in organic solvents such as acetone, glacial acetic acid, and benzene.[21] This property necessitates its conversion to a salt for aqueous formulations. The hydrochloride salt is soluble in water (approximately 1 g in 30 mL) and alcohol (1 g in 120 mL).[3] A quantified water solubility for the base is 37.33 mg/L at 37.5°C.[21]
• Stability: Papaverine is sensitive to light and moisture.[20] Aqueous solutions of the hydrochloride salt are most stable at an acidic pH of 2.0-2.8, and product labeling reflects this sensitivity with instructions to protect from light.[20]
• pKa: 6.4 (at 25°C).[21]

The distinction between the physicochemical properties of the papaverine free base and its commonly used hydrochloride salt is of paramount clinical and pharmaceutical importance. The free base's insolubility in water renders it unsuitable for the parenteral formulations required for acute medical interventions.[21] The conversion to the hydrochloride salt dramatically increases aqueous solubility, a necessary modification that enables the production of the injectable solutions used for intravenous, intramuscular, and intracavernosal administration.[25] This direct link between a fundamental chemical property and the drug's therapeutic utility underscores the critical role of pharmaceutical chemistry in drug development. Furthermore, the inherent instability of the molecule, particularly its sensitivity to light, dictates strict storage and handling requirements, such as retaining vials in their cartons until use, to ensure the drug's potency and safety are preserved.[20]

Property	Papaverine (Base)	Papaverine Hydrochloride	Source Snippet(s)
DrugBank ID	DB01113	DBSALT000412	4
Modality	Small Molecule	Small Molecule	4
CAS Number	58-74-2	61-25-6	1
Molecular Formula			4
Average Molecular Wt.	339.39 g/mol	375.85 g/mol	3
IUPAC Name	1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline	1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline;hydrochloride	16
Appearance	White crystalline powder	White crystalline powder	21
Melting Point	147°C	~226°C	21
Water Solubility	Insoluble (37.33 mg/L at 37.5°C)	Soluble (~1 g in 30 mL)	21
pKa	6.4 (at 25°C)	N/A	21
Stability Notes	Sensitive to light and moisture	Aqueous solutions stable at pH 2.0-2.8	20

3.0 Origin and Synthesis

Understanding the origin of Papaverine provides essential context for its chemical classification and its distinct pharmacological profile relative to other compounds derived from the same natural source.

3.1 Natural Occurrence and Classification

Papaverine is a naturally occurring alkaloid isolated from the opium poppy, Papaver somniferum, where it constitutes between 0.5% and 3.0% of the total alkaloid content of opium.[1] It is chemically classified as a benzylisoquinoline alkaloid.[2] This classification is fundamentally important because it distinguishes Papaverine from the narcotic alkaloids of opium, such as morphine and codeine, which belong to the phenanthrene class.[3] The absence of the phenanthrene nucleus in Papaverine's structure is the molecular basis for its lack of analgesic, euphoric, and addictive properties, which are the hallmark effects of the opiate analgesics.[1] This profound structural and pharmacological divergence, despite a shared botanical origin, is a critical concept for dispelling any misconception that Papaverine is a narcotic. Its primary action is on smooth muscle, with minimal effects on the central nervous system at therapeutic doses.[3]

Due to its consistent presence in raw opium, Papaverine and its metabolites can serve as chemical markers in forensic science. Their detection in samples of illicit heroin can help law enforcement agencies profile and identify the geographic source of the drug, and their presence in the urine of users can distinguish the use of street heroin from pharmaceutical-grade diacetylmorphine.[1]

3.2 Biosynthesis and Manufacturing

In the opium poppy, the biosynthesis of Papaverine begins with the amino acid L-tyrosine. Through a series of enzymatic reactions, two L-tyrosine derivatives—dopamine and 4-hydroxyphenylacetaldehyde—are condensed by the enzyme norcoclaurine synthase (NCS) to form (S)-norcoclaurine. This molecule serves as the common precursor for all benzylisoquinoline alkaloids. Subsequent enzymatic steps involving hydroxylases and methyltransferases lead to the formation of Papaverine.[2]

While it can be extracted from its natural source, Papaverine can also be prepared synthetically. Pharmaceutical manufacturing processes have been developed to produce specific salt forms designed to improve its physicochemical properties for clinical use. For example, a described process for manufacturing papaverine adenylate involves reacting papaverine base with adenosine-5'-monophosphoric acid in an aqueous ethanol solution. This reaction yields a highly water-soluble, crystalline product suitable for oral administration.[21]

4.0 Pharmacology

The therapeutic effects of Papaverine are derived from its complex interactions with multiple molecular targets, leading to a potent and direct relaxant effect on smooth muscle. This section details its mechanism of action, the resulting physiological effects, and its pharmacokinetic profile.

4.1 Mechanism of Action (MOA)

The mechanism of action for Papaverine is multifactorial and not yet fully elucidated, but it is primarily centered on two complementary pathways that lead to smooth muscle relaxation: inhibition of phosphodiesterases and direct modulation of calcium channels.[4]

4.1.1 Phosphodiesterase (PDE) Inhibition

The most well-characterized mechanism is Papaverine's function as a non-selective, non-xanthine inhibitor of PDE enzymes.[4] PDEs are responsible for the intracellular degradation of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). By inhibiting these enzymes, Papaverine causes intracellular levels of both cAMP and cGMP to rise.[2]

The accumulation of these cyclic nucleotides activates downstream signaling cascades:

• Elevated cAMP activates Protein Kinase A (PKA).
• Elevated cGMP activates Protein Kinase G (PKG).

Both PKA and PKG phosphorylate a variety of target proteins within the smooth muscle cell. This leads to several key events: a reduction in intracellular free calcium () concentrations through sequestration into the sarcoplasmic reticulum and extrusion from the cell, and the activation of myosin light-chain phosphatase (MLCP), which dephosphorylates the myosin light chains.[6] Since phosphorylation of myosin is required for its interaction with actin to produce contraction, this dephosphorylation leads directly to smooth muscle relaxation and vasodilation.[7] Papaverine has been shown to inhibit several PDE subtypes, including PDE4B and, notably, PDE10A, which is found predominantly in the striatum of the brain and may be responsible for some of the central nervous system effects observed in animal studies.[1]

4.1.2 Direct Calcium Channel Inhibition

In addition to its effects on cyclic nucleotides, Papaverine is believed to act directly on calcium channels in the cell membrane.[4] By inhibiting these channels, it blocks the influx of extracellular calcium into the smooth muscle cell. Since this influx is a primary trigger for muscle contraction, this direct inhibitory action complements the PDE-mediated mechanism, further contributing to muscle relaxation and vasodilation.[4]

4.1.3 Other Potential Mechanisms

Research suggests other contributing mechanisms may be at play. Papaverine may interact with adenosine receptors, which could amplify its vasodilatory properties.[6] Furthermore, some studies indicate it may alter mitochondrial respiration, an effect that is being explored in the context of its potential anticancer activity.[1]

The multi-target nature of Papaverine's mechanism of action explains both its broad therapeutic utility and its diverse side effect profile. Its ability to act on fundamental cellular relaxation pathways common to various smooth muscle types allows it to be effective for visceral, vascular, and bronchial spasms. However, this same lack of specificity means it can also affect unintended targets, such as cardiac muscle ion channels, leading to adverse effects like arrhythmias.[1]

4.2 Pharmacodynamics

The physiological effects of Papaverine are a direct consequence of its ability to induce smooth muscle relaxation.

• Effects on Vascular Smooth Muscle (Vasodilation): The most characteristic pharmacodynamic effect of Papaverine is the relaxation of vascular smooth muscle, particularly in larger arteries.[3] This effect is especially prominent when the vessels are in a state of spasm.[3] It causes dilation of the coronary, systemic peripheral, cerebral, and pulmonary arteries.[3] In the cerebral vasculature, this leads to an increase in cerebral blood flow and a decrease in cerebral vascular resistance, effects that are achieved without altering overall oxygen consumption.[4]
• Effects on Non-Vascular Smooth Muscle (Antispasmodic): The relaxant effect extends to non-vascular (visceral) smooth muscle. Papaverine relieves spasms in the gastrointestinal tract, the biliary tract, the ureters, and the bronchial musculature.[1] This antispasmodic action is a direct effect on the muscle cell itself and is independent of muscle innervation; the muscle remains responsive to other contractile stimuli.[3]
• Cardiovascular and Cardiac Effects: Papaverine exerts direct effects on cardiac muscle, depressing conduction and prolonging the refractory period in a manner similar to the antiarrhythmic agent quinidine.[4] It may also exhibit positive chronotropic (heart rate) and inotropic (contractility) effects, possibly through stimulation of catecholamine release or interference with adenosine uptake.[31] However, these cardiac effects also represent a significant risk; high doses or rapid intravenous injection can provoke transient ectopic ventricular rhythms, premature beats, or paroxysmal tachycardia.[3]
• Central Nervous System (CNS) Effects: At standard therapeutic doses, Papaverine has minimal to no effect on the central nervous system.[3] However, very large doses can produce sedation and sleepiness.[3] Chronic administration in animal models has been associated with motor and cognitive deficits and increased anxiety, which may be linked to its inhibition of the brain-specific PDE10A enzyme.[1]

4.3 Pharmacokinetics (ADME Profile)

The absorption, distribution, metabolism, and excretion (ADME) of Papaverine are characterized by significant variability, which has important clinical implications.

• Absorption: When administered orally, Papaverine exhibits variable absorption. The average oral bioavailability is approximately 54%, and absorption from extended-release capsule formulations can be particularly poor.[33]
• Distribution: Once absorbed, Papaverine is highly bound to plasma proteins (approximately 90%).[11] It distributes widely throughout the body, with a considerable fraction localizing in adipose tissue and the liver.[26] The reported volume of distribution is 1.52 ± 0.45 L/kg.[11]
• Metabolism: Papaverine is extensively metabolized in the liver.[26]
• Elimination: The inactive metabolites are excreted primarily via the kidneys in the urine.[3] The elimination half-life of Papaverine is notably variable, with reports ranging from as short as 0.5–2 hours to as long as 24 hours.[11]

This high degree of pharmacokinetic variability, especially in its oral bioavailability and elimination half-life, presents a significant clinical challenge. It makes predicting a patient's plasma concentration and response to a standard oral dose difficult. This unreliability is a key reason why parenteral routes of administration (intravenous, intramuscular, intracavernosal) are often preferred for conditions requiring a rapid and predictable therapeutic effect, as these routes bypass the uncertainties of gastrointestinal absorption.[3] The development of extended-release oral formulations was a pharmaceutical strategy designed to mitigate the short and variable half-life by providing more sustained plasma levels, although issues with poor absorption may persist.[24]

5.0 Clinical Applications and Therapeutic Efficacy

Papaverine's potent spasmolytic and vasodilatory properties have been applied to a range of clinical conditions, evolving from broad systemic uses to more specialized, localized applications.

5.1 Approved and Recommended Indications

The primary indication for Papaverine, as approved by the U.S. Food and Drug Administration (FDA), is for the relief of cerebral and peripheral ischemia associated with arterial spasm and for myocardial ischemia complicated by arrhythmias.[8]

Based on its mechanism of action, it is also recommended for a variety of conditions characterized by smooth muscle spasm [3]:

• Vascular Spasm: This includes vasospasms associated with acute myocardial infarction (coronary occlusion), angina pectoris, peripheral vascular disease, and pulmonary embolism.[3] It is also used to treat cerebral vasospasm following subarachnoid hemorrhage, often in conjunction with balloon angioplasty.[1]
• Visceral Spasm: It is effective in treating spasms of the smooth muscle of the gastrointestinal tract, bile ducts, and ureter, alleviating associated pain and dysfunction.[1]

5.2 Established Off-Label and Other Applications

Over time, the clinical use of Papaverine has shifted, with off-label and specialized applications now defining much of its modern therapeutic identity.

• Erectile Dysfunction (ED): Papaverine was one of the first effective pharmacological treatments for ED and remains in use, typically as part of compounded preparations.
• Administration: It is administered via intracavernosal injection directly into the penile tissue. Its direct smooth muscle relaxant effect causes dilation of the cavernosal arteries and relaxation of the sinusoidal trabeculae, leading to increased blood inflow, engorgement of the corpora cavernosa, and a rigid erection.[1]
• Combination Therapy: To improve efficacy and reduce the risk of side effects, particularly priapism, Papaverine is often used in combination with other vasoactive agents like phentolamine (an alpha-blocker) and/or alprostadil (prostaglandin E1). These multi-agent formulations are commonly known as "Bi-mix" or "Tri-mix".[36] A clinical trial (NCT03033537) was conducted to compare the efficacy of papaverine/verapamil versus papaverine/phentolamine combinations.[37]
• Topical Formulations: A topical gel formulation has also been investigated. While it has been shown to increase penile blood flow to some extent, it has demonstrated limited success in producing full clinical erections compared to the injection and is not widely used.[1]
• Intraoperative Vasospasm: Papaverine is widely used in surgical settings to prevent or treat vasospasm. In cardiovascular surgery, such as coronary artery bypass grafting (CABG), it is applied topically or injected intraluminally into arterial grafts (e.g., the internal mammary artery) to maximize vasodilation and ensure adequate blood flow.[1] It is also used in microsurgery to relax small blood vessels during delicate procedures.[1]
• Acute Mesenteric Ischemia: Papaverine is used in the management of acute mesenteric ischemia, a life-threatening condition caused by reduced blood flow to the intestines.[1] In 2017, it received an FDA Orphan Drug Designation for this indication, recognizing the need for effective treatments for this rare condition, although it has not yet received formal marketing approval for this specific use.[39]
• Migraine Prophylaxis: As an off-label use, Papaverine is sometimes prescribed for the prevention of migraine headaches. It is not a first-line therapy but may be considered when primary and secondary preventative medications are ineffective, contraindicated, or not tolerated.[1]
• Cryopreservation: In laboratory and clinical settings, Papaverine is used as a component of cryopreservation solutions for blood vessels. Its vasodilatory action helps to maintain the functional integrity of the vessels during the freezing and thawing process.[1]

The evolution of Papaverine's clinical use illustrates a common trajectory for older medications. While newer, more specific agents with better safety profiles have largely replaced its systemic use for its original, broad indications, its potent and direct mechanism of action remains highly valuable in specific niche applications. The ability to deliver the drug locally—directly into the penis for ED or onto an artery during surgery—maximizes its powerful therapeutic effect at the target site while minimizing the systemic exposure that is responsible for its most significant adverse effects. This shift from systemic to targeted local therapy has allowed Papaverine to retain a relevant place in the modern pharmacopeia.

6.0 Emerging Research and Investigational Uses

Recent scientific inquiry has refocused on Papaverine, exploring its potential for repurposing in major therapeutic areas beyond its traditional use as a vasodilator. This research is driven by a more sophisticated understanding of its effects on fundamental cellular signaling pathways.

6.1 Anticancer Potential

Preclinical research has identified Papaverine as a potential anticancer agent with selective activity against various tumor cell lines.[40]

• Mechanism: The proposed anticancer mechanism is multifaceted. It is thought to involve the inhibition of the PDE10A enzyme, which disrupts critical downstream cell survival and proliferation pathways, including the PI3K/Akt/mTOR pathway.[29] Additionally, Papaverine may exert its effects by directly targeting mitochondrial metabolism, a key area of vulnerability for many cancer cells.[13] Studies have shown that it can induce cell cycle arrest and cell death (apoptosis) in cancer cell lines such as adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2).[29]
• Clinical Investigation: This promising preclinical data has led to clinical investigation. A Phase I clinical trial (NCT05136846) is currently underway to evaluate the safety and determine the maximum tolerated dose of Papaverine when administered in combination with standard chemoradiation for patients with Stage II, III, or IV non-small cell lung cancer (NSCLC).[13] The hypothesis is that Papaverine may function as a radiosensitizer, making cancer cells more susceptible to the effects of radiation therapy, or may inhibit tumor growth through its metabolic effects.[13]

6.2 Antiviral Activity

A growing body of in-vitro evidence suggests that Papaverine possesses broad-spectrum antiviral activity.

• SARS-CoV-2: It has been shown to prevent the cytopathic (cell-damaging) effects of SARS-CoV-2 in cell culture models, suggesting a potential role in mitigating the severity of COVID-19.[12]
• HIV: Papaverine inhibits the replication of HIV by interfering with multiple stages of the viral life cycle. It appears to block the activity of the reverse transcriptase enzyme and also affect late-stage replication steps after the viral genetic material has been integrated into the host cell genome.[5]
• Other Viruses: Its antiviral activity extends to a range of other viruses, including Cytomegalovirus (CMV), Measles virus, Respiratory Syncytial Virus (RSV), and various strains of Influenza virus.[5] The mechanisms appear to be virus-specific, involving actions such as inhibiting viral RNA synthesis or interfering with host cell signaling pathways (e.g., cAMP/MEK/ERK) that the viruses hijack for their own replication.[14]

6.3 Anti-inflammatory and Neuroprotective Properties

Papaverine has demonstrated significant anti-inflammatory and neuroprotective effects in preclinical models.

• Mechanism: It has been shown to reduce the production and release of key pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), from immune cells like microglia and macrophages.[12] This anti-inflammatory action is mediated through the modulation of the cAMP/PKA and MEK/Erk signaling pathways.[14]
• Therapeutic Potential: By dampening neuroinflammation, Papaverine may have a therapeutic role in neurodegenerative diseases such as Parkinson's disease, where chronic inflammation contributes to neuronal damage.[43]

This recent wave of research exemplifies a sophisticated approach to drug repurposing. By leveraging modern knowledge of molecular biology and cell signaling, scientists are uncovering new therapeutic possibilities for a drug discovered in the 19th century. The initial clinical use of Papaverine was based on its observable physiological effect—smooth muscle relaxation. Today's research is hypothesis-driven, investigating how its known molecular actions—such as PDE10A inhibition and modulation of mitochondrial function—can be applied to the complex pathologies of cancer, viral infections, and neuroinflammation. These investigations highlight the potential for old drugs to find new life as their underlying mechanisms become more clearly understood.

7.0 Safety and Tolerability Profile

The clinical use of Papaverine is limited by a significant safety profile and a narrow therapeutic window, necessitating careful patient selection, dosing, and monitoring.

7.1 Adverse Drug Reactions (ADRs)

Adverse effects associated with Papaverine can affect multiple organ systems and vary in frequency.

• Frequent ADRs:
• Cardiovascular: Polymorphic ventricular tachycardia [1]
• Gastrointestinal: Constipation [1]
• Hepatic: Interference with the sulphobromophthalein retention test, increased transaminase levels, and increased alkaline phosphatase levels [1]
• Neurological: Somnolence (drowsiness) and vertigo [1]
• Rare ADRs:
• Cardiovascular: Arterial hypotension, tachycardia [1]
• Dermatologic: Flushing of the face, hyperhidrosis (excessive sweating), cutaneous eruption [1]
• General: Loss of appetite, headache, allergic reaction [1]
• Hepatic: Jaundice, mixed hepatitis, chronic active hepatitis [1]
• Hematologic: Eosinophilia, thrombopenia (low platelet count) [1]
• Neurological: Paradoxical aggravation of cerebral vasospasm [1]
• Route-Specific ADRs (Intracavernosal Injection):
• Priapism: The most serious complication is a prolonged, painful erection lasting more than four hours. This is a medical emergency that can lead to ischemic damage to the penile tissue and permanent erectile dysfunction if not treated promptly.[10]
• Local Site Reactions: Penile fibrosis (scar tissue formation), development of nodules or lumps, penile curvature (Peyronie's-like condition), hematoma (bruising), and pain at the injection site are known complications of long-term use.[10]
• Mechanical Issues: Needle breakage during self-injection has been reported, sometimes requiring surgical removal.[32]

7.2 Contraindications

The use of Papaverine is strictly prohibited in certain patient populations due to the high risk of severe adverse events.

• Absolute Contraindication: Intravenous injection of Papaverine is contraindicated in patients with complete atrioventricular (AV) heart block, as it can further depress cardiac conduction and precipitate life-threatening arrhythmias.[3]
• Contraindications for Intracavernosal Use:
• Patients with conditions that predispose them to priapism, such as sickle cell anemia, multiple myeloma, or leukemia.[32]
• Patients with anatomical deformations of the penis, such as severe angulation, cavernosal fibrosis, or Peyronie's disease.[32]

7.3 Precautions and Warnings

Close monitoring and caution are required when administering Papaverine to patients with certain underlying conditions.

• Cardiovascular: It should be used with extreme caution in patients with any degree of depressed cardiac conduction, as it may induce ventricular ectopic rhythms.[3] Caution is also warranted in patients with unstable cardiovascular disease, or who have had a recent stroke or myocardial infarction.[32]
• Hepatic: Papaverine can cause hepatotoxicity. The medication must be discontinued immediately if the patient develops signs of hepatic hypersensitivity (e.g., jaundice, gastrointestinal symptoms, eosinophilia) or if liver function tests become elevated. Rarely, this has progressed to cirrhosis.[3]
• Glaucoma: The drug should be used with caution in patients with glaucoma.[3]
• CNS Effects: Patients should be advised that Papaverine may cause drowsiness and dizziness and should avoid operating heavy machinery or driving until they know how the medication affects them.[34]
• Bleeding Risk: Patients receiving anticoagulant therapy (e.g., warfarin, heparin) may have an increased propensity for bleeding and hematoma formation following intramuscular or intracavernosal injection.[32]

The safety profile of Papaverine is defined by two primary organ system toxicities: cardiac and hepatic. The risk of potentially fatal arrhythmias, especially with intravenous use, combined with the potential for severe, drug-induced liver injury, creates a narrow margin between therapeutic and toxic doses. This underscores the necessity for meticulous patient selection—avoiding those with underlying cardiac conduction defects or liver disease—and careful monitoring of cardiac rhythm and liver function during therapy. These significant systemic risks are a major factor in the clinical shift towards more localized applications of the drug, where systemic exposure and its attendant dangers can be minimized.

7.4 Use in Specific Populations

• Pregnancy: Papaverine is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[3]
• Lactation: It is not known whether Papaverine is excreted in human milk. Because many drugs are, caution should be exercised when administering it to a nursing woman.[3]
• Pediatrics: The safety and effectiveness of Papaverine in children have not been established.[44]
• Geriatrics: Elderly patients may exhibit reduced tolerance to cold temperatures while taking Papaverine. While no specific age-related dosage adjustments are recommended, therapy should be initiated with caution in this population.[10]

7.5 Overdosage

Overdose with Papaverine can lead to severe systemic toxicity.

• Mechanism: In large overdoses, Papaverine acts as a potent inhibitor of cellular respiration and a weak calcium antagonist.[25]
• Symptoms: Reported manifestations of a 15 g oral overdose include metabolic acidosis with compensatory hyperventilation, hyperglycemia, and hypokalemia.[25] Other potential effects include severe hypotension, CNS depression, and convulsions.
• Management: Treatment is supportive and symptomatic. It includes meticulous monitoring of vital signs, blood gases, and blood chemistry. Convulsions may be managed with benzodiazepines (e.g., diazepam). Hypotension should be treated with intravenous fluids, leg elevation, and, if necessary, an inotropic vasopressor like dopamine or norepinephrine.[3]

8.0 Drug Interactions and Incompatibilities

The co-administration of Papaverine with other medications can lead to clinically significant interactions, and it is physically incompatible with certain intravenous solutions.

8.1 Pharmacodynamic Interactions

These interactions occur when drugs with similar or opposing effects are used together.

• CNS Depressants: Papaverine can cause sedation, an effect that is additive with other CNS depressants. Concomitant use with alcohol, benzodiazepines, barbiturates, opioids, and other sedatives or hypnotics can lead to enhanced sedation and drowsiness.[30]
• Antihypertensive Agents: Due to its vasodilatory properties, Papaverine may have an additive effect with other antihypertensive drugs, beta-blockers, calcium channel blockers, and other vasodilators, increasing the risk of significant hypotension.[4]
• QTc-Prolonging Drugs: Papaverine has the potential to cause polymorphic ventricular tachycardia, suggesting an effect on cardiac repolarization. Co-administration with other drugs known to prolong the QTc interval (e.g., certain antiarrhythmics, antipsychotics, macrolide antibiotics, and fluoroquinolones) may increase the risk of life-threatening arrhythmias like Torsades de Pointes.[4]
• Levodopa: Clinical reports suggest that Papaverine may antagonize the therapeutic effects of levodopa in patients with Parkinson's disease, potentially by blocking dopamine receptors.[24]
• Other PDE Inhibitors: Co-administration with other PDE inhibitors, such as sildenafil for erectile dysfunction or theophylline for asthma, may result in additive effects. This could potentially enhance both the therapeutic response and the risk of adverse effects (e.g., hypotension, headache).[48]

8.2 Physicochemical Incompatibilities

Papaverine is physically incompatible with certain intravenous fluids, meaning they should not be mixed in the same container or line.

• Lactated Ringer's Injection: Papaverine Hydrochloride injection should not be added to Lactated Ringer's Injection, as this will cause a precipitate to form.[33]
• Heparin: Papaverine will also precipitate when mixed with heparin.[36]

Interacting Drug/Class	Potential Effect	Mechanism	Clinical Management	Source Snippet(s)
CNS Depressants (Alcohol, Benzodiazepines, Opioids)	Increased sedation, drowsiness, dizziness	Additive pharmacodynamic effect on the central nervous system	Use with caution. Monitor for excessive sedation. Advise patients against operating machinery.	30
Antihypertensives / Vasodilators (Beta-blockers, Calcium Channel Blockers, ACE inhibitors)	Increased risk of hypotension	Additive vasodilatory and blood pressure-lowering effects	Monitor blood pressure closely, especially upon initiation of therapy. Dose adjustments may be necessary.	4
QTc-Prolonging Agents (e.g., Amiodarone, Sotalol, Quetiapine, Macrolides)	Increased risk of serious cardiac arrhythmias (Torsades de Pointes)	Additive effect on cardiac repolarization (QTc interval prolongation)	Concomitant use should be approached with extreme caution or avoided. ECG monitoring is recommended.	4
Levodopa	Decreased antiparkinsonian effect of levodopa	Potential dopamine receptor blockade by Papaverine	This combination may be ineffective and should generally be avoided. Monitor for worsening of Parkinson's symptoms.	24
Other PDE Inhibitors (e.g., Sildenafil, Theophylline, Caffeine)	Potentiated therapeutic and adverse effects (e.g., vasodilation, hypotension, headache)	Inhibition of the same or similar enzyme pathways, leading to further increases in cAMP/cGMP	Use with caution. Monitor for signs of excessive vasodilation. Dose reduction of one or both agents may be required.	48

9.0 Dosage, Administration, and Formulations

The clinical use of Papaverine is highly dependent on its formulation and route of administration, which are tailored to specific therapeutic goals and risk profiles.

9.1 Formulations and Salt Forms

Papaverine is available in several forms, primarily as its hydrochloride salt to ensure water solubility for parenteral use.

• Oral Formulations:
• Tablets: Available in strengths of 100 mg to 300 mg.[33]
• Extended-Release Capsules: Commonly available as 150 mg capsules, designed for prolonged release to provide more stable plasma concentrations.[24]
• Parenteral Formulation:
• Papaverine Hydrochloride Injection, USP: This is a sterile, clear, colorless to pale-yellow solution typically supplied at a concentration of 30 mg/mL. It is available in 2 mL single-dose vials and 10 mL multiple-dose vials. The multiple-dose vials may contain a preservative such as chlorobutanol 0.5%.[25]
• Topical Formulations:
• A topical gel has been developed and studied for the treatment of erectile dysfunction but is not commercially approved and is considered investigational.[1]
• Other Salt Forms: While the hydrochloride is the most common salt, Papaverine has also been formulated as the codecarboxylate, adenylate, and teprosylate salts.[1]

9.2 Dosing and Administration

Dosage and administration route are determined by the clinical indication and the desired onset and duration of action.

• Oral Administration (for chronic circulatory disorders):
• Extended-Release Capsules: The usual adult dose is 150 mg every 12 hours. This may be increased to 150 mg every 8 hours or 300 mg every 12 hours in more difficult cases.[24] Capsules should be swallowed whole and not crushed or chewed.[34]
• Tablets: The typical adult dose is 100 to 300 mg administered three to five times per day.[33]
• Parenteral Administration (for acute spasms):
• Intravenous (IV) / Intramuscular (IM): For arterial spasm, the usual dose is 30 to 120 mg, which may be repeated every 3 hours as needed.[33] For the treatment of cardiac extrasystoles, two doses may be given 10 minutes apart.[3]
• IV Administration Technique: When given intravenously for an immediate effect, Papaverine must be injected slowly over 1 to 2 minutes. Rapid injection can cause severe adverse effects, including life-threatening cardiac arrhythmias and fatal apnea.[3]
• Intracavernosal Injection (for erectile dysfunction):
• Dosing: The dose must be carefully titrated for each individual patient by a specialist. The effective dose typically ranges from 2.5 mg to 60 mg.[32]
• Administration: This route requires specialized training for both the physician and the patient if self-administration is planned.[32] The injection is made directly into the corpus cavernosum (the erectile tissue on the side of the penis), avoiding the midline, urethra, and any visible superficial veins. The injection site should be alternated between the left and right sides with each use to minimize the risk of local tissue damage and fibrosis.[10]
• Frequency: Use should be limited, for example, to no more than three times per week and not on consecutive days, to reduce the risk of long-term complications.[10]

The choice of administration route for Papaverine is a critical clinical decision that fundamentally defines its therapeutic application and risk profile. Oral therapy is reserved for chronic, non-acute conditions where convenience is a factor, but its utility is limited by erratic pharmacokinetics. Systemic parenteral (IV/IM) administration is used for acute, severe spasms where a rapid and reliable effect is necessary, but this route carries the highest risk of systemic toxicity, particularly cardiac arrhythmias. In contrast, localized routes of administration, such as intracavernosal injection for ED or direct application during surgery, are designed to deliver a high concentration of the drug directly to the target tissue. This strategy maximizes the potent local therapeutic effect while minimizing systemic absorption, thereby mitigating the most severe systemic risks. This route-dependent risk-benefit profile explains why specialized training is mandatory for procedures like intracavernosal injection.

10.0 Regulatory and Commercial Information

The regulatory status of Papaverine in the United States is complex, reflecting its long history of clinical use that predates modern drug approval standards.

10.1 Regulatory Status

• Prescription Status: Papaverine is a prescription-only (℞-only) medication in the United States and other jurisdictions like Australia.[1]
• FDA Approval Status: The regulatory standing of Papaverine is nuanced.
• Approved Indications: The FDA recognizes an approved indication for Papaverine for the "relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias".[8] Historical documents indicate that some forms of Papaverine have been available since at least the 1960s, likely placing them under the purview of regulations that existed before the current standards for proving efficacy were established.[51]
• "Unapproved" Marketed Products: Despite the existence of an approved indication, some currently marketed injectable Papaverine products carry the explicit disclaimer, "This drug product is not FDA approved".[44] This apparent contradiction likely arises because these specific products may be considered "grandfathered" drugs that were on the market before the 1962 Kefauver-Harris Drug Amendments, or they are marketed under other regulatory provisions for older drugs that have not undergone the rigorous New Drug Application (NDA) process required for modern pharmaceuticals. An FDA database file for one such product lists its approval status as "Unapproved other".[52]
• Off-Label Use: The widespread use of Papaverine for erectile dysfunction is considered off-label. Payers may explicitly exclude coverage for this indication, and the FDA has not found compounded topical preparations for this use to be proven safe or effective.[8]
• Orphan Drug Designations:
• Mesenteric Ischemia: On August 3, 2017, Papaverine received an orphan drug designation for the treatment of mesenteric ischemia. This designation facilitates development for a rare disease but does not constitute marketing approval.[39]
• Sexual Dysfunction in Spinal Cord Injury: A previous orphan designation, granted on February 6, 1992, for a topical gel formulation for sexual dysfunction in spinal cord injury patients, was later withdrawn or revoked.[53]

The regulatory landscape for Papaverine is a clear example of the complexities surrounding legacy drugs in a modern regulatory framework. Its long history means it has established, approved uses, yet specific products on the market today may not have undergone the same level of scrutiny as new chemical entities. This creates a confusing environment for clinicians, pharmacists, and payers, who must navigate the disconnect between the drug's official indications and its common clinical applications. This ambiguity is reflected in insurance policies that may cover the drug for its formal indication (often with prior authorization) while explicitly denying coverage for its most frequent off-label use in erectile dysfunction.[9]

10.2 Brand Names

Papaverine is available as a generic medication and under various brand names globally.

• US Brand Names: Pavabid, Cerespan, Therapav, ParaTime SR, Vasal, Vaso-Pav, Vasospan.[5]
• Foreign Brand Names: Cerebid, Pavacap, Omnopon, Pantopon (as part of a combination of opium alkaloids).[1]

11.0 Conclusion and Future Perspectives

Papaverine is a non-narcotic benzylisoquinoline opium alkaloid that has maintained a place in clinical medicine for over a century. Its therapeutic value is rooted in its potent, direct-acting smooth muscle relaxant properties, which are mediated by a multi-target mechanism involving non-selective phosphodiesterase inhibition and direct modulation of calcium ion channels. This broad mechanism allows it to effectively relieve both vascular and visceral spasms.

The clinical role of Papaverine has undergone a significant evolution. Initially used for a wide range of systemic circulatory and spasmodic disorders, its application has become more focused and specialized over time. The challenges posed by its variable oral pharmacokinetics and a narrow therapeutic window, defined by risks of cardiotoxicity and hepatotoxicity, have led to a decline in its systemic use. In its place, Papaverine has found durable, niche roles in localized applications where its powerful effects can be precisely targeted while minimizing systemic exposure. Its use in intracavernosal injection therapy for erectile dysfunction and as an intraoperative agent to prevent arterial vasospasm are prime examples of this modern, risk-mitigated approach.

The most compelling future direction for Papaverine lies in the potential for drug repurposing. Emerging preclinical and early-phase clinical research is actively investigating its utility in oncology, virology, and the treatment of neuroinflammatory conditions. This renewed interest is not arbitrary but is founded on a modern, mechanism-based understanding of how Papaverine's effects on fundamental cellular pathways—such as PDE10A signaling and mitochondrial metabolism—can be leveraged against complex diseases. The ongoing clinical trial in non-small cell lung cancer represents a critical step in this journey. Realizing the full potential of this century-old molecule will require continued rigorous investigation to fully elucidate these novel mechanisms and to definitively establish its safety and efficacy in these new therapeutic contexts.

Works cited

1. Papaverine - Wikipedia, accessed October 12, 2025, https://en.wikipedia.org/wiki/Papaverine
2. Papaverine and Its Mechanism of Action | Encyclopedia MDPI, accessed October 12, 2025, https://encyclopedia.pub/entry/42831
3. Papaverine Hydrochloride Injection, USP - American Regent, accessed October 12, 2025, https://www.americanregent.com/media/1796/papaverine-prescribing-information.pdf
4. Papaverine: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed October 12, 2025, https://go.drugbank.com/drugs/DB01113
5. Definition of papaverine hydrochloride - NCI Drug Dictionary, accessed October 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/papaverine-hydrochloride
6. What is the mechanism of Papaverine Hydrochloride? - Patsnap Synapse, accessed October 12, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-papaverine-hydrochloride
7. pmc.ncbi.nlm.nih.gov, accessed October 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10095881/#:~:text=Papaverine%20blocks%20cAMP%20and%20cGMP,smooth%20muscle%20relaxation%20(1).
8. Papaverine Compounding Powder, accessed October 12, 2025, https://info.caremark.com/content/dam/enterprise/caremark/microsites/dig/pdfs/pa-fep/fep-rationale/FEP_Rationale_PapaverinePowder.pdf
9. Papaverine Powder - FepBlue, accessed October 12, 2025, https://www.fepblue.org/-/media/PDFs/Medical-Policies/2024/October/Pharmacy-Policies/Remove-and-Replace/5_40_025-Papaverine-powder.pdf
10. Papaverine (injection route) - Side effects & dosage - Mayo Clinic, accessed October 12, 2025, https://www.mayoclinic.org/drugs-supplements/papaverine-injection-route/description/drg-20065314
11. Pharmacokinetics of Intraluminally Administered Serum Papaverine for Spasm Prophylaxis of the Internal Mammary Artery - IMR Press, accessed October 12, 2025, https://www.imrpress.com/journal/HSF/16/5/10.1532/HSF98.2013201/pdf
12. Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application - PubMed, accessed October 12, 2025, https://pubmed.ncbi.nlm.nih.gov/37049912/
13. Papaverine in Combination with Chemoradiation for the Treatment of Stage II, III, or IV Non-small Cell Lung Cancer - NCI, accessed October 12, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-07691
14. (PDF) Papaverine: A Miraculous Alkaloid from Opium and Its ..., accessed October 12, 2025, https://www.researchgate.net/publication/369665316_Papaverine_A_Miraculous_Alkaloid_from_Opium_and_Its_Multimedicinal_Application
15. Papaverine | CAS 58-74-2 | SCBT - Santa Cruz Biotechnology, accessed October 12, 2025, https://www.scbt.com/p/papaverine-58-74-2
16. Identity - ECHA CHEM, accessed October 12, 2025, https://chem.echa.europa.eu/100.000.361/identity
17. Papaverine Hydrochloride - LGC Standards, accessed October 12, 2025, https://www.lgcstandards.com/BD/en/Papaverine-Hydrochloride/p/MM1225.00
18. Papaverine hydrochloride | DrugBank Online, accessed October 12, 2025, https://go.drugbank.com/salts/DBSALT000412
19. Papaverine (NSC 136630, CAS Number: 58-74-2) | Cayman Chemical, accessed October 12, 2025, https://www.caymanchem.com/product/10011133/papaverine
20. Papaverine | C20H21NO4 | CID 4680 - PubChem, accessed October 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Papaverine
21. PAPAVERINE | 58-74-2 - ChemicalBook, accessed October 12, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4689771.htm
22. Papaverine - the NIST WebBook - National Institute of Standards and Technology, accessed October 12, 2025, https://webbook.nist.gov/cgi/cbook.cgi?ID=C58742&Mask=200
23. KEGG DRUG: Papaverine, accessed October 12, 2025, https://www.genome.jp/dbget-bin/www_bget?drug:D07425
24. Papaverine (Papaverine): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed October 12, 2025, https://www.rxlist.com/papaverine-drug.htm
25. PAPAVERINE HYDROCHLORIDE INJECTION, USP - DailyMed, accessed October 12, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9e5e2ce4-7a57-4c61-a826-64c8d11d038e
26. PAPAVERINE HYDROCHLORIDE INJECTION, USP - DailyMed, accessed October 12, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5ba6e650-a5b5-4381-a62a-b7a6df73e8e6
27. Pharmacological Properties and Therapeutic Potential of Papaverine: A Comprehensive Review - ResearchGate, accessed October 12, 2025, https://www.researchgate.net/publication/390145360_Pharmacological_Properties_and_Therapeutic_Potential_of_Papaverine_A_Comprehensive_Review
28. Vascular spasm | DrugBank Online, accessed October 12, 2025, https://go.drugbank.com/indications/DBCOND0022791
29. The Biological Relevance of Papaverine in Cancer Cells - MDPI, accessed October 12, 2025, https://www.mdpi.com/2073-4409/11/21/3385
30. What Is Papaverine and What Is It Used For? - Prof. Dr. Özgür Kılıçkesmez, accessed October 12, 2025, https://ozgurkilickesmez.com/en/what-is-papaverine-and-what-is-it-used-for/
31. Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application - PMC, accessed October 12, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10095881/
32. HKG CLD Papaverine hydrochloride Solution for Injection, accessed October 12, 2025, https://labeling.pfizer.com/ShowLabeling.aspx?id=13991
33. PAPAVERINE (Systemic) Introduction VA CLASSIFICATION (Primary)¾CV500 Note, accessed October 12, 2025, https://simsrc.edu.in/pdf_df/P-drugs/Papaverine.pdf
34. Papaverine: MedlinePlus Drug Information, accessed October 12, 2025, https://medlineplus.gov/druginfo/meds/a682707.html
35. Papaverine Hydrochloride (papaverine hydrochloride) - Complete Drug Label Info, PA Forms, & Patient Education (2025) - Prescriber Point, accessed October 12, 2025, https://prescriberpoint.com/therapies/papaverine-hydrochloride-9e5e2ce
36. Papaverine – Knowledge and References - Taylor & Francis, accessed October 12, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Papaverine/
37. Study Details | NCT03033537 | Intracavernosal Injection of Papaverine/Verapamil Versus Papaverine/Phentolamine in Erectile Dysfunction | ClinicalTrials.gov, accessed October 12, 2025, https://www.clinicaltrials.gov/study/NCT03033537
38. Papaverine Topical Gel for Treatment of Erectile Dysfunction | Journal of Urology, accessed October 12, 2025, https://www.auajournals.org/doi/10.1097/00005392-199502000-00019
39. Search Orphan Drug Designations and Approvals - FDA, accessed October 12, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=581417
40. Novel Papaverine Metal Complexes with Potential Anticancer Activities - MDPI, accessed October 12, 2025, https://www.mdpi.com/1420-3049/25/22/5447
41. Clinical Trials Using Papaverine Hydrochloride - NCI, accessed October 12, 2025, https://www.cancer.gov/research/participate/clinical-trials/intervention/papaverine-hydrochloride?pn=1
42. Study Details | NCT05136846 | Papaverine in Combination With Chemoradiation for the Treatment of Stage II-III Non-small Cell Lung Cancer | ClinicalTrials.gov, accessed October 12, 2025, https://clinicaltrials.gov/study/NCT05136846
43. Phoenix Medical Journal » Submission » Pharmacological Properties and Therapeutic Potential of Papaverine: A Comprehensive Review - DergiPark, accessed October 12, 2025, https://dergipark.org.tr/en/pub/phnx/issue/90645/1570322
44. Papaverine HCL / Products / American Regent, accessed October 12, 2025, https://americanregent.com/our-products/papaverine-hcl-injection-usp
45. Papaverine (oral route) - Side effects & dosage - Mayo Clinic, accessed October 12, 2025, https://www.mayoclinic.org/drugs-supplements/papaverine-oral-route/description/drg-20065323
46. papaverine hydrochloride - Drug Summary - PDR.Net, accessed October 12, 2025, https://www.pdr.net/drug-summary/Papaverine-Hydrochloride-papaverine-hydrochloride-24173
47. ParaTime SR (papaverine) dosing, indications, interactions, adverse ..., accessed October 12, 2025, https://reference.medscape.com/drug/paratime-sr-papaverine-342403
48. Showing BioInteractions for Papaverine (DB01113) | DrugBank Online, accessed October 12, 2025, https://go.drugbank.com/drugs/DB01113/biointeractions
49. Papaverine: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed October 12, 2025, https://www.rxlist.com/papaverine/generic-drug.htm
50. Papaverine HCL Injection, USP - Nexus Pharmaceuticals, accessed October 12, 2025, https://www.nexuspharma.net/molecule/papaverine-hcl-injection-usp/
51. www.fda.gov, accessed October 12, 2025, https://www.fda.gov/media/159995/download
52. b82546c4-bd74-4475-84e7-e5ce0574a55a.xml - accessdata.fda.gov, accessed October 12, 2025, https://www.accessdata.fda.gov/spl/data/b82546c4-bd74-4475-84e7-e5ce0574a55a/b82546c4-bd74-4475-84e7-e5ce0574a55a.xml
53. Search Orphan Drug Designations and Approvals - FDA, accessed October 12, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=64991