A Comprehensive Monograph on Phenprocoumon: Pharmacology, Clinical Application, and Safety Profile

Section 1: Executive Summary

Phenprocoumon is a long-acting, orally administered anticoagulant agent belonging to the 4-hydroxycoumarin class of medications.[1] It represents a cornerstone of antithrombotic therapy, particularly for the long-term prevention and treatment of thromboembolic disorders in several continental European nations, where it is marketed under brand names such as Marcoumar, Marcumar, and Falithrom.[2] As a Vitamin K Antagonist (VKA), its therapeutic effect is derived from the inhibition of the Vitamin K epoxide reductase complex subunit 1 (VKORC1). This molecular action disrupts the hepatic synthesis of biologically active, gamma-carboxylated forms of coagulation factors II (prothrombin), VII, IX, and X, as well as the endogenous anticoagulant proteins C and S, thereby impeding the coagulation cascade and preventing thrombus formation.[2]

The defining pharmacokinetic characteristic of phenprocoumon is its exceptionally long elimination half-life, which averages between 150 and 160 hours (approximately 6 to 7 days).[2] This property profoundly influences every aspect of its clinical management. It results in a slow onset of therapeutic effect, a prolonged anticoagulant state even after discontinuation, and a significant risk of "International Normalized Ratio (INR) rebound" in scenarios of overdose or acute reversal.[8] This extended duration of action, however, may also contribute to more stable plasma concentrations and INR values during maintenance therapy compared to shorter-acting VKAs.

The primary clinical applications for phenprocoumon include the prophylaxis and treatment of venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of ischemic stroke and systemic embolism in patients with atrial fibrillation (AF).[5] Safe and effective use of the drug is critically dependent on regular and meticulous monitoring of the INR. This is necessitated by its narrow therapeutic index and the high degree of inter-individual variability in dose response, which is influenced by genetic factors, diet, and concomitant medications.[2]

The principal and most formidable safety concern associated with phenprocoumon therapy is bleeding. Hemorrhagic complications are common, occurring in 5% to 25% of patients, and can range in severity from minor, such as epistaxis, to severe and life-threatening events, including intracerebral or gastrointestinal hemorrhage.[2] Management of these risks requires vigilant patient monitoring and education.

From a regulatory perspective, phenprocoumon holds a unique position. While it is the predominant VKA in countries such as Germany, it has not been approved for clinical use by the U.S. Food and Drug Administration (FDA).[4] This divergence has created a notable gap in the global clinical evidence base, as the majority of pivotal trials for newer anticoagulants have used warfarin, the standard VKA in the United States, as the comparator. This monograph provides an exhaustive analysis of phenprocoumon, synthesizing data on its chemical properties, pharmacology, clinical management, and safety profile to serve as a definitive reference for clinicians and researchers.

Section 2: Drug Identification and Physicochemical Properties

A comprehensive understanding of a pharmaceutical agent begins with its fundamental chemical and physical identity. This section delineates the nomenclature, structural characteristics, and core physicochemical properties of phenprocoumon, which collectively form the basis for its pharmacological behavior.

2.1. Nomenclature and Identifiers

Phenprocoumon is identified by a variety of systematic names, common synonyms, and database-specific codes that are essential for accurate identification in scientific literature, clinical practice, and regulatory databases.

• Systematic (IUPAC) Name: The formal chemical name for the compound according to the International Union of Pure and Applied Chemistry (IUPAC) is 4-hydroxy-3-(1-phenylpropyl)chromen-2-one.[1]
• Common Synonyms and Brand Names: The drug is known by several synonyms, including Fenprocumon, Phenprocoumarol, Phenprocoumarole, and the research code Ro 1-4849.[5] It is marketed internationally under various brand names, most notably Marcoumar, Marcumar, and Falithrom.[2]
• Key Database Identifiers: To facilitate unambiguous cross-referencing across global databases, phenprocoumon is assigned numerous unique identifiers. The most critical of these are:
• CAS (Chemical Abstracts Service) Number: 435-97-2 [1]
• DrugBank ID: DB00946 [1]
• PubChem Compound ID (CID): 9908 [2]
• ChEBI (Chemical Entities of Biological Interest) ID: CHEBI:50438 [1]
• ATC (Anatomical Therapeutic Chemical) Code: B01AA04 [2]
• FDA UNII (Unique Ingredient Identifier): Q08SIO485D [1]

2.2. Chemical Structure and Formula

The molecular structure of phenprocoumon defines its classification as a coumarin derivative and is the source of its biological activity.

• Chemical Formula: The empirical formula for phenprocoumon is C18​H16​O3​.[5]
• Molecular Weight: The average molecular weight is 280.3178 g/mol, with a monoisotopic mass of 280.109944378 g/mol.[5]
• Structural Representations: The two-dimensional structure of the molecule is commonly represented using standardized chemical notation systems:
• SMILES (Simplified Molecular Input Line Entry System): CCC(C1=CC=CC=C1)C2=C(C3=CC=CC=C3OC2=O)O.[1]
• InChI (International Chemical Identifier): InChI=1S/C18H16O3/c1-2-13(12-8-4-3-5-9-12)16-17(19)14-10-6-7-11-15(14)21-18(16)20/h3-11,13,19H,2H2,1H3.[1]
• InChIKey: DQDAYGNAKTZFIW-UHFFFAOYSA-N.[1]

2.3. Physical and Chemical Properties

The physical and chemical properties of phenprocoumon dictate its formulation, stability, and pharmacokinetic characteristics such as absorption and distribution.

• Physical Description: Phenprocoumon is a solid that typically appears as a fine, white to off-white or beige crystalline powder. Under magnification, it may be observed as crystals or prisms. It is generally described as being odorless or possessing a slight, characteristic smell.[1]
• Melting Point: The melting point is consistently reported within a narrow range of 177 °C to 181 °C, with several sources specifying a precise value of 179.5 °C.[1] This high melting point is indicative of a stable crystalline solid.
• Solubility Profile: The drug's solubility is a key determinant of its absorption. It is practically insoluble in water, with a reported aqueous solubility of 12.9 mg/L.[1] However, it is soluble in various organic solvents, including chloroform and methanol, as well as in aqueous solutions of alkali hydroxides.[1] It demonstrates high solubility in dimethyl sulfoxide (DMSO), with values of ≥ 125 mg/mL reported.[19]
• Partition Coefficient (LogP): The octanol-water partition coefficient, expressed as LogP, is a measure of lipophilicity. The reported LogP value for phenprocoumon is 3.62, which indicates that it is a lipophilic (fat-soluble) molecule. This property facilitates its passage across the lipid membranes of the gastrointestinal tract, contributing to its excellent absorption.[1]
• Acidity (pKa): Phenprocoumon is an acidic compound, with the hydroxyl group on the coumarin ring being ionizable. Its acid dissociation constant (pKa) is reported to be 4.2.[2] This acidity explains its solubility in alkali hydroxide solutions.

The following table consolidates the principal identifiers and physicochemical properties of phenprocoumon for ease of reference.

Table 1: Key Identifiers and Physicochemical Properties of Phenprocoumon
Parameter	Value / Description
IUPAC Name	4-hydroxy-3-(1-phenylpropyl)chromen-2-one 1
CAS Number	435-97-2 1
DrugBank ID	DB00946 5
Chemical Formula	C18​H16​O3​ 5
Average Molecular Weight	280.32 g/mol 5
Physical Form	Fine, white to off-white crystalline powder 1
Melting Point	177–181 °C 2
Aqueous Solubility	Practically insoluble (12.9 mg/L) 1
LogP	3.62 1
pKa	4.2 2

Section 3: Pharmacology and Mechanism of Action

The therapeutic utility of phenprocoumon is rooted in its specific interaction with the molecular machinery of blood coagulation. This section provides a detailed examination of its pharmacological classification, its primary molecular target, the biochemical cascade it disrupts, and the resulting pharmacodynamic effects on hemostasis.

3.1. Pharmacological Class

Phenprocoumon is structurally classified as a 4-hydroxycoumarin, a chemical scaffold it shares with other well-known oral anticoagulants such as warfarin and acenocoumarol.[1] Based on its mechanism of action, it is functionally categorized as a Vitamin K Antagonist (VKA). This classification defines its therapeutic strategy: creating a functional state of vitamin K deficiency to impair coagulation, thereby distinguishing it from newer classes of direct oral anticoagulants (DOACs) that target specific clotting factors directly.[2]

3.2. Primary Molecular Target and Mechanism of Action

The anticoagulant effect of phenprocoumon is achieved through the targeted inhibition of a key enzyme within the vitamin K metabolic cycle.

• Primary Molecular Target: The sole molecular target responsible for the anticoagulant activity of phenprocoumon is the enzyme Vitamin K epoxide reductase complex subunit 1 (VKORC1).[2]
• Disruption of the Vitamin K Cycle: To appreciate the effect of this inhibition, it is essential to understand the physiological role of the vitamin K cycle. In the body, the reduced form of vitamin K, known as vitamin K hydroquinone (KH2​), serves as an indispensable cofactor for the enzyme γ-glutamyl carboxylase. This enzyme performs a critical post-translational modification on several precursor proteins involved in coagulation by adding a carboxyl group to specific glutamate (Glu) residues, converting them to gamma-carboxyglutamate (Gla) residues.[5] This carboxylation is vital for the biological function of these proteins, as the Gla residues enable them to bind calcium ions and subsequently anchor to phospholipid surfaces, a necessary step for their participation in the coagulation cascade. During this carboxylation reaction, KH2​ is oxidized to an inactive form, vitamin K 2,3-epoxide. The VKORC1 enzyme is responsible for the crucial recycling step of reducing vitamin K 2,3-epoxide back to its active KH2​ form, thus perpetuating the cycle.[6] Phenprocoumon binds to and inhibits VKORC1, effectively breaking this recycling pathway. The resulting depletion of active KH2​ leads to a functional deficiency of vitamin K, despite adequate dietary intake.[5]
• Downstream Consequences on Coagulation Factors: The functional vitamin K deficiency induced by phenprocoumon has profound downstream effects. The γ-glutamyl carboxylase enzyme, deprived of its essential KH2​ cofactor, is unable to properly carboxylate the vitamin K-dependent proteins. This leads to the hepatic synthesis and release of under-carboxylated or non-carboxylated forms of these proteins into the circulation. These inactive forms, often referred to as Proteins Induced by Vitamin K Absence or Antagonism (PIVKAs), are unable to bind calcium and participate effectively in hemostasis. The proteins affected include the pro-coagulant clotting factors prothrombin (Factor II), Factor VII, Factor IX, and Factor X, as well as the endogenous anticoagulant proteins, Protein C and Protein S.[2] The net result is a significant impairment of the coagulation cascade, which abrogates the generation of thrombin and ultimately prevents the formation and propagation of fibrin clots.[5]
• Stereoselectivity: Phenprocoumon is administered clinically as a racemic mixture of its two enantiomers. However, there is a marked difference in their pharmacological potency. The S(-)-enantiomer is significantly more potent as an anticoagulant than its R(+)-counterpart.[2] This stereoselectivity has important implications for its metabolism and the potential for pharmacogenomic variability in patient response.

3.3. Onset and Duration of Anticoagulant Effect

The indirect mechanism of action of phenprocoumon dictates a characteristic delay in its onset and a prolonged duration of its effect.

• Delayed Onset of Action: The anticoagulant effect of phenprocoumon is not immediate upon administration. This is because the drug has no effect on the pool of already-circulating, fully carboxylated clotting factors. A therapeutic effect is only observed once these existing active factors are naturally cleared from the circulation and replaced by the newly synthesized, inactive PIVKAs. The onset of this effect typically begins 36 to 72 hours after the first dose, with the full, stable anticoagulant effect not being achieved until four to six days of continuous therapy.[2] The rate of onset is governed by the biological half-lives of the individual clotting factors. Factor VII has the shortest half-life (approximately 6 hours), leading to an initial rise in the INR, while prothrombin (Factor II) has the longest half-life (approximately 50-60 hours), meaning its depletion takes several days.[23]
• Prolonged Duration of Action: Consistent with its very long pharmacokinetic half-life, the anticoagulant effect of phenprocoumon is highly persistent. After discontinuation of the drug, its inhibitory effect on coagulation remains for at least 7 to 10 days, and it can take up to two weeks for the INR to return to a normal baseline.[2] This long "washout" period is a critical consideration when planning elective surgeries or managing bleeding events.
• Mechanism Distinction: It is crucial to emphasize that phenprocoumon, like all VKAs, is an anticoagulant, not a thrombolytic. It has no direct effect on an already-formed thrombus and does not reverse ischemic tissue damage.[5] Its therapeutic goal is to prevent the further extension of an existing clot and to prevent the formation of new, secondary thromboembolic events, which can have serious or fatal consequences.[5]

The mechanism of action, which affects both pro-coagulant and anti-coagulant proteins, gives rise to a transient, clinically significant phenomenon at the start of therapy. The endogenous anticoagulant proteins, Protein C and Protein S, have relatively short biological half-lives (approximately 8 and 24 hours, respectively) compared to some of the key pro-coagulant factors like prothrombin (Factor II, half-life ~50-60 hours).[23] Upon initiation of phenprocoumon therapy, the levels of these natural anticoagulants decrease more rapidly than the levels of the long-lived pro-coagulant factors. This creates a temporary imbalance in the hemostatic system, resulting in a paradoxical, transient pro-thrombotic or hypercoagulable state during the first few days of treatment. This biochemical reality directly informs a critical clinical practice: for patients with an acute thromboembolic event, VKA therapy must be initiated concurrently with a rapid-acting parenteral anticoagulant, such as heparin or low-molecular-weight heparin (LMWH).[2] The heparin provides immediate anticoagulation, effectively "bridging" the patient over this vulnerable pro-thrombotic window until phenprocoumon has depleted the pro-coagulant factors sufficiently to achieve a stable, therapeutic anticoagulant effect.

Section 4: Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination (ADME)

The clinical behavior, efficacy, and safety profile of phenprocoumon are fundamentally governed by its pharmacokinetic properties. The disposition of the drug within the body—its absorption, distribution, metabolism, and elimination (ADME)—is characterized by several key features, most notably its exceptionally long elimination half-life, which dictates its clinical utility and challenges.

4.1. Absorption

• Route of Administration: Phenprocoumon is formulated for and administered exclusively by the oral route.[2]
• Bioavailability: Following oral administration, the drug is absorbed rapidly and essentially completely from the gastrointestinal tract. Its oral bioavailability is reported to be close to 100%, meaning that nearly the entire administered dose reaches the systemic circulation.[2] This high and consistent absorption contributes to a predictable dose-concentration relationship, although the ultimate dose-response relationship is subject to other variabilities.
• Time to Maximum Concentration (Tmax​): Peak plasma concentrations of phenprocoumon are typically achieved approximately 2.25 hours after oral ingestion.[25]

4.2. Distribution

Once in the systemic circulation, phenprocoumon distributes throughout the body, with its distribution pattern heavily influenced by its high affinity for plasma proteins.

• Plasma Protein Binding: Phenprocoumon exhibits an extremely high degree of binding to plasma proteins, with approximately 99% of the drug in circulation being bound, primarily to albumin.[2] This extensive binding has several major consequences. Firstly, it creates a large circulating reservoir of the drug, which contributes significantly to its long duration of action and slow elimination. Secondly, only the small, unbound (free) fraction of the drug, approximately 1%, is pharmacologically active and available to diffuse into tissues to inhibit VKORC1 in the liver.[7] Thirdly, this high level of protein binding makes phenprocoumon susceptible to clinically significant drug-drug interactions, wherein co-administered drugs can displace it from albumin, transiently increasing the free fraction and potentiating its anticoagulant effect.[2]
• Apparent Volume of Distribution (Vd​): The apparent volume of distribution is a theoretical volume that describes the extent to which a drug distributes into body tissues relative to the plasma. For phenprocoumon, human studies have reported a Vd​ of 13.6 L in a 67 kg individual, which corresponds to approximately 0.20 L/kg.[26] This relatively low Vd​ is consistent with a drug that is largely confined to the plasma and extracellular fluid compartments, a direct consequence of its extensive plasma protein binding.[27] It indicates that the drug does not distribute extensively into deep tissue compartments.

4.3. Metabolism

Phenprocoumon is eliminated from the body primarily through metabolic transformation in the liver.

• Site and Pathway of Metabolism: The drug undergoes stereoselective metabolism by hepatic microsomal enzymes.[5] The principal metabolic pathway is oxidation via hydroxylation, which converts the active parent drug into pharmacologically inactive hydroxylated metabolites.[5] The three main metabolites identified are 7-hydroxyphenprocoumon (accounting for ~60% of metabolic clearance), 6-hydroxyphenprocoumon (~25%), and 4'-hydroxyphenprocoumon.[30] A minor pathway involves conjugation of these metabolites with glucuronic acid.[2]
• Cytochrome P450 (CYP) Enzymes: The hydroxylation of phenprocoumon is catalyzed by enzymes of the cytochrome P450 superfamily. The two major enzymes implicated in its metabolism are CYP2C9 and CYP3A4.[2] The relative contribution of these enzymes varies depending on the enantiomer being metabolized, which is clinically relevant because the S(-)-enantiomer is the more potent anticoagulant [30]:
• Metabolism of S(-)-phenprocoumon: The clearance of the more active S-enantiomer is driven primarily by CYP2C9 (responsible for ~65% of 7-hydroxylation and ~60% of 6-hydroxylation), with a significant contribution from CYP3A4.
• Metabolism of R(+)-phenprocoumon: The clearance of the less active R-enantiomer involves a more balanced contribution from both CYP2C9 and CYP3A4. Notably, the formation of R-4'-hydroxyphenprocoumon appears to be exclusively catalyzed by CYP3A4.

4.4. Elimination

The inactive metabolites of phenprocoumon are cleared from the body through renal and biliary routes.

• Route of Elimination: After hepatic metabolism, the inactive hydroxylated and glucuronidated metabolites are predominantly excreted by the kidneys into the urine.[2] There is also evidence suggesting that a significant portion of unchanged phenprocoumon is excreted in both the bile and urine, a characteristic that distinguishes it from warfarin, whose elimination is almost entirely dependent on metabolism.[32] Some of the metabolites that are excreted into the bile may undergo enterohepatic circulation, potentially contributing to the drug's long retention in the body.[2]
• Elimination Half-Life (t1/2​): The elimination half-life is the most clinically defining pharmacokinetic parameter of phenprocoumon. It is exceptionally long, with an average value consistently reported to be between 150 and 160 hours, or approximately 6 to 7 days.[2] This value is subject to considerable inter-individual variability, with a wide range of 72 to 270 hours cited in the literature.[8] In acute clinical situations, such as major bleeding events where intensive supportive care is provided, the observed half-life may be shorter, with studies reporting values around 5.3 days (127 hours).[8]

The exceptionally long half-life of phenprocoumon can be viewed as a double-edged sword, presenting both therapeutic advantages and significant clinical challenges. On one hand, this pharmacokinetic property results in relatively stable plasma concentrations, which are less susceptible to minor fluctuations caused by a single missed dose or slight variations in dosing times. This stability is the likely underlying reason for the clinical observation that patients on phenprocoumon often achieve more consistent INR values and may require less frequent monitoring compared to those on shorter-acting VKAs like warfarin, potentially leading to a more stable overall anticoagulant effect.[35]

On the other hand, this same long half-life introduces considerable inflexibility and risk into its management. It dictates that achieving a therapeutic steady-state concentration after initiating or adjusting a dose is a slow process, taking approximately four weeks.[2] This makes initial dose titration a lengthy and meticulous process. More critically, in situations requiring urgent reversal of anticoagulation, such as for emergency surgery or in the event of a major hemorrhage, the drug's profound and persistent effect poses a major challenge. Even after cessation, the anticoagulant effect lingers for more than a week.[2] This persistence is the direct cause of a dangerous clinical phenomenon known as "INR rebound".[8] Rapid-acting reversal agents, such as prothrombin complex concentrates (PCCs), can temporarily replenish clotting factors and normalize the INR. However, these agents have a much shorter duration of action than phenprocoumon. As the PCCs are cleared from the body, the long-acting phenprocoumon, still present in the system at therapeutic concentrations, re-exerts its inhibitory effect on VKORC1, causing the INR to dangerously rise again. This pharmacokinetic reality fundamentally shapes clinical strategy, necessitating slow dose adjustments, prolonged bridging therapy when discontinuing the drug, and, most importantly, the administration of repeated doses of vitamin K over several days to ensure sustained synthesis of new clotting factors for effective and lasting reversal of an overdose.[8] The therapeutic stability offered during maintenance therapy is thus traded for a lack of responsiveness and heightened risk in acute clinical scenarios.

The following table summarizes the key pharmacokinetic parameters of phenprocoumon.

Table 2: Summary of Pharmacokinetic Parameters for Phenprocoumon
Parameter	Value / Description
Route of Administration	Oral 2
Bioavailability	~100% 2
Time to Peak Plasma Concentration (Tmax​)	~2.25 hours 25
Plasma Protein Binding	~99% (primarily to albumin) 2
Apparent Volume of Distribution (Vd​)	~0.20 L/kg 26
Primary Metabolizing Enzymes	CYP2C9 and CYP3A4 2
Elimination Half-Life (t1/2​)	150–160 hours (6–7 days) 2
Route of Elimination	Primarily renal excretion of inactive metabolites; some biliary and renal excretion of unchanged drug 2

Section 5: Clinical Applications and Patient Management

The clinical use of phenprocoumon requires a thorough understanding of its indications, a highly individualized approach to dosing and administration, and a commitment to rigorous patient monitoring. This section details the practical aspects of managing patients on phenprocoumon therapy, integrating its pharmacological properties with established clinical strategies.

5.1. Approved Indications and Therapeutic Use

Phenprocoumon is established as a long-term oral anticoagulant for the prophylaxis and treatment of a range of thromboembolic disorders.[2] Its primary role is to prevent the formation and propagation of pathological blood clots. The specific clinical indications for its use include:

• Venous Thromboembolism (VTE): For the treatment and secondary prevention of VTE, which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE).[5]
• Atrial Fibrillation (AF): For the prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation who have one or more risk factors for stroke.[5]
• Post-Myocardial Infarction (MI): For long-term secondary prevention in patients who have had an MI and are at an increased risk of subsequent thromboembolic events.[2]
• Valvular Heart Disease and Prosthetic Heart Valves: For thromboprophylaxis in patients with certain types of valvular heart disease or following the surgical implantation of artificial heart valves.[2]
• Other High-Risk Conditions: For the management of patients with inherited or acquired thrombophilias, such as antithrombin III deficiency, who are at a high baseline risk for thrombosis.[2]

5.2. Dosage, Administration, and Monitoring

The successful application of phenprocoumon therapy is critically dependent on a carefully managed regimen of dosing and monitoring, tailored to each individual patient.

• Administration: The medication is administered as oral tablets.[2]
• Dosing Regimen: Due to its narrow therapeutic window and high inter-individual variability, there is no standard fixed dose of phenprocoumon. Dosing must be highly individualized and guided by frequent laboratory monitoring.
• Initiation (Loading Dose): Therapy is typically initiated with a higher loading dose to more rapidly deplete the existing pool of clotting factors and achieve a therapeutic effect. A common starting regimen involves a single dose of 6 to 15 mg on the first day, followed by 6 to 9 mg on the second day.[2]
• Maintenance Dose: Following the initial loading phase, the dose is adjusted to a daily maintenance dose, which typically falls within the range of 1.5 to 6 mg, based on the patient's INR response.[9]
• Monitoring with the International Normalized Ratio (INR): The cornerstone of safe and effective phenprocoumon management is the regular monitoring of the patient's coagulation status using the International Normalized Ratio (INR). The INR is a laboratory measurement derived from the prothrombin time (PT) that standardizes the results across different laboratories and reagents.[2]
• Therapeutic Target Range: For the majority of clinical indications, including VTE and AF, the target therapeutic INR range is 2.0 to 3.0.[8] An INR below this range indicates insufficient anticoagulation and a risk of thrombosis, while an INR above this range signifies excessive anticoagulation and an increased risk of bleeding.
• Monitoring Frequency: The frequency of INR testing is highest at the beginning of therapy. It is measured daily until the target INR is reached and stabilized. The testing interval is then gradually extended, first to twice or three times a week, and eventually, for stable patients, to every two to four weeks.[2] This long-term, often lifelong, monitoring is absolutely essential to maintain the patient within the narrow therapeutic window and to adjust for the many factors that can influence the dose-response relationship.[2]

5.3. Pharmacogenomic Considerations

A significant portion of the observed inter-individual variability in phenprocoumon dose requirements can be attributed to genetic polymorphisms in genes that code for its target enzyme and its primary metabolizing enzymes.[2]

• VKORC1 Polymorphisms: Genetic variations in the VKORC1 gene, which encodes the drug's molecular target, are the most important predictors of dose requirement. Specific single nucleotide polymorphisms (SNPs), such as the c.-1639 G>A variant, are strongly associated with sensitivity to the drug. Patients carrying the 'A' allele generally require lower maintenance doses to achieve the target INR, whereas those with the 'G' allele are less sensitive and require higher doses.[36]
• CYP2C9 Polymorphisms: Genetic variants in the CYP2C9 gene, which encodes one of the key enzymes responsible for metabolizing phenprocoumon, also influence the dose-response relationship. The CYP2C9*2 and CYP2C9*3 alleles are associated with reduced enzyme activity. Individuals who are carriers of these alleles metabolize the drug more slowly, leading to higher plasma concentrations and typically requiring lower maintenance doses to avoid over-anticoagulation.[5] However, the clinical utility of CYP2C9 genotyping for phenprocoumon dose prediction is a subject of debate. The evidence base for a strong, independent association between CYP2C9 variants and phenprocoumon dose requirements has been described as "extremely mixed".[30] This is likely because alternative metabolic pathways (e.g., via CYP3A4) can compensate for reduced CYP2C9 function. Consequently, some pharmacogenomic advisory bodies, such as the Dutch Pharmacogenomics Working Group (DPWG), have concluded that the evidence is insufficient to issue a specific dosing recommendation based on CYP2C9 genotype alone, stating that routine INR monitoring is sufficient to manage these variations.[30]

Section 6: Safety Profile, Interactions, and Overdose Management

While an effective anticoagulant, phenprocoumon possesses a narrow therapeutic index and a significant potential for adverse events and interactions. Its safety profile is dominated by the risk of hemorrhage, and its management requires constant vigilance for drug-drug and drug-food interactions, as well as a clear protocol for managing overdose.

6.1. Adverse Effects

• Bleeding (Hemorrhage): The most common, predictable, and serious adverse effect of phenprocoumon therapy is bleeding. It is a direct extension of the drug's therapeutic action. The incidence of bleeding is reported to be between 5% and 25% of treated patients.[2] Hemorrhagic events can occur in virtually any organ or tissue and vary widely in severity:
• Minor Bleeding: Includes relatively harmless events such as epistaxis (nosebleeds), ecchymosis (bruising), petechiae, and hematuria.[2]
• Major and Life-Threatening Bleeding: Includes severe hemorrhage in critical sites such as intracerebral, subdural, gastrointestinal, adrenal, or pericardial spaces.[2] A multicenter observational study found that 85% of hospital admissions for phenprocoumon-related adverse drug reactions (ADRs) were due to hemorrhage, with the gastrointestinal tract being the most common site.[46]
• Hepatic Injury: Although less common than bleeding, phenprocoumon-associated liver injury is a recognized serious ADR. In the same observational study, it accounted for 2.7% of ADR-related hospitalizations.[46] The injury typically presents with a hepatocellular (hepatitis-like) pattern of elevated liver enzymes and can, in some cases, lead to permanent liver damage.[46]
• Other Adverse Effects: A range of other, less frequent side effects have been associated with phenprocoumon use, including:
• Purple Toe Syndrome: A rare complication characterized by painful, purplish discoloration of the toes.[12]
• Calciphylaxis: A rare but severe condition involving calcification of small blood vessels in the skin and fat tissue.[12]
• Dermatological Effects: Reversible hair loss (alopecia) and allergic skin rashes.[12]
• General Symptoms: Nausea and headache have also been reported.[12]

6.2. Contraindications and Precautions

The use of phenprocoumon is strictly contraindicated in situations where the inherent risk of bleeding outweighs the potential therapeutic benefit.

• Absolute Contraindications:
• Pregnancy: Phenprocoumon crosses the placenta and is a known teratogen, capable of causing developmental toxicity and fetal harm. It is therefore contraindicated during pregnancy.[1]
• High-Risk Bleeding Conditions: Patients with pre-existing conditions that confer a high risk of bleeding, such as severe hemorrhagic diathesis, active peptic ulcer disease, bacterial endocarditis, aortic or cerebral aneurysms.[2]
• Recent or Planned Surgery: Especially recent major trauma or surgery involving the central nervous system or eye.[2]
• Severe Organ Dysfunction: Severe, uncompensated hepatic or renal insufficiency.[47]
• Precautions:
• Enhanced vigilance and more frequent monitoring are required in elderly and pediatric populations.[47]
• Caution is necessary for patients with known or suspected deficiency of Protein C or Protein S, as they may be at higher risk for thrombosis-related skin necrosis upon initiation of therapy.[47]
• Intramuscular injections must be avoided in patients receiving phenprocoumon due to the high risk of painful hematoma formation at the injection site.[47]

6.3. Drug-Drug and Drug-Food Interactions

Phenprocoumon is highly susceptible to a vast number of clinically significant interactions, which can dangerously potentiate or inhibit its anticoagulant effect. These interactions arise from its narrow therapeutic index, extensive plasma protein binding, and dependence on CYP450 enzymes for metabolism.[2]

• Pharmacodynamic Interactions (Altering Bleeding Risk without Necessarily Changing INR): These interactions involve drugs that affect hemostasis through separate mechanisms, leading to an additive or synergistic increase in bleeding risk.
• Antiplatelet Agents: Co-administration with aspirin or P2Y12 inhibitors like clopidogrel significantly increases the risk of bleeding.[2]
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Drugs like ibuprofen and diclofenac inhibit platelet function and can cause gastrointestinal mucosal injury, compounding the bleeding risk.[2]
• Selective Serotonin Reuptake Inhibitors (SSRIs): Antidepressants such as citalopram and sertraline can impair platelet aggregation and have been associated with an increased risk of bleeding when combined with VKAs.[46]
• Pharmacokinetic Interactions (Altering Phenprocoumon Levels and INR): These interactions interfere with the ADME properties of phenprocoumon.
• CYP450 Enzyme Inhibitors: Drugs that inhibit CYP2C9 or CYP3A4 will decrease the metabolism of phenprocoumon, leading to higher plasma levels and an elevated INR. Potent inhibitors include the antiarrhythmic amiodarone, macrolide antibiotics (e.g., clarithromycin), and azole antifungals (e.g., fluconazole).[2] Grapefruit juice is a known inhibitor of CYP3A4 and can also interact.[2]
• CYP450 Enzyme Inducers: Drugs that induce CYP enzymes will increase the metabolism of phenprocoumon, leading to lower plasma levels and a reduced INR, potentially causing therapeutic failure. The herbal supplement St. John's Wort is a well-known inducer.[2]
• Protein-Binding Displacement: Drugs that are also highly protein-bound, such as certain NSAIDs, can displace phenprocoumon from its binding sites on albumin. This transiently increases the concentration of free, active drug, which can lead to a rapid increase in INR and bleeding risk.[2]
• Drug-Food and Supplement Interactions:
• Vitamin K Intake: The efficacy of phenprocoumon is directly antagonized by vitamin K. Therefore, a patient's dietary intake of vitamin K can significantly influence their INR. Foods rich in vitamin K include leafy green vegetables (spinach, kale, broccoli, cabbage) and green tea.[2] Patients are not advised to avoid these foods, but rather to maintain a consistent and stable daily intake to avoid large fluctuations in their INR.
• Alcohol: The interaction with alcohol can be complex. Acute binge drinking may inhibit phenprocoumon metabolism and increase the INR, whereas chronic heavy alcohol consumption may induce liver enzymes and decrease the INR.[47]
• Herbal and Dietary Supplements: Numerous supplements can interact. In addition to St. John's Wort, supplements with intrinsic antiplatelet or anticoagulant properties, such as fish oil, garlic, ginkgo, and high-dose Vitamin E, can increase the risk of bleeding.[49]

The following table categorizes key drug interactions by their underlying mechanism to provide a clinical framework for risk assessment.

Table 3: Clinically Significant Drug-Drug Interactions with Phenprocoumon, Categorized by Mechanism
Interacting Agent/Class	Mechanism of Interaction	Effect on INR	Clinical Recommendation
Aspirin, Clopidogrel	Additive antiplatelet effect (Pharmacodynamic)	No direct effect	Increased bleeding risk. Co-administration requires careful risk-benefit assessment.
NSAIDs (e.g., Ibuprofen)	Antiplatelet effect; Protein-binding displacement	May increase	Increased bleeding risk. Avoid routine use; if necessary, monitor INR closely.
SSRIs (e.g., Citalopram)	Impaired platelet aggregation (Pharmacodynamic)	No direct effect	Increased bleeding risk. Monitor for signs of bleeding.
Amiodarone, Fluconazole	Inhibition of CYP2C9/CYP3A4 (Pharmacokinetic)	Increase	Potent interaction. Requires proactive phenprocoumon dose reduction and frequent INR monitoring.
Macrolides (e.g., Clarithromycin)	Inhibition of CYP3A4 (Pharmacokinetic)	Increase	Requires dose reduction and close INR monitoring during antibiotic course.
Allopurinol	Likely inhibition of metabolism (Pharmacokinetic)	Increase	Monitor INR closely when initiating or stopping allopurinol.
St. John's Wort	Induction of CYP3A4 (Pharmacokinetic)	Decrease	Avoid co-administration due to unpredictable and significant reduction in anticoagulant effect.

6.4. Toxicity and Overdose Management

Overdose with phenprocoumon, whether intentional or accidental, is a serious medical condition that can lead to life-threatening hemorrhage. Management is guided by the patient's INR level and the clinical presence and severity of bleeding.

• Symptoms of Overdose: The clinical presentation of toxicity is manifested as signs of abnormal bleeding. This can include the appearance of blood in the stool (melena) or urine (hematuria), excessive menstrual bleeding, petechiae, extensive bruising, or persistent oozing from superficial injuries.[5]
• Management Strategy:
• Asymptomatic Supratherapeutic INR: For patients with a highly elevated INR (e.g., ≥8.0) but no active bleeding, the primary intervention is to withhold one or more doses of phenprocoumon and reduce the subsequent maintenance dose. A small dose of oral vitamin K (phytomenadione, 1-5 mg) may be considered to facilitate a more rapid reduction of the INR.[50]
• Minor Bleeding: For patients with non-life-threatening bleeding, phenprocoumon should be withheld, and a small dose of intravenous vitamin K is typically administered to begin reversing the anticoagulation.[50]
• Major or Life-Threatening Bleeding: This constitutes a medical emergency requiring immediate and aggressive intervention. The strategy involves a two-pronged approach to achieve both rapid and sustained reversal:

1. Immediate Cessation: Discontinue phenprocoumon immediately.[50]
2. Rapid Reversal with Factor Replacement: The most effective method for rapid reversal is the administration of a 4-factor Prothrombin Complex Concentrate (PCC). PCCs (e.g., Beriplex, Kcentra) contain a concentrated mixture of the vitamin K-dependent clotting factors (II, VII, IX, X) and rapidly restore hemostatic capacity.[50] Fresh Frozen Plasma (FFP) is a less desirable alternative due to the large volumes required and slower correction.[50]
3. Sustained Reversal with Vitamin K: Concurrently, a dose of intravenous vitamin K (e.g., 5-10 mg) must be administered. Vitamin K allows the liver to resume the de novo synthesis of functional, carboxylated clotting factors.[50] Critically, due to the extremely long half-life of phenprocoumon, a single dose of vitamin K is insufficient. The underlying inhibition of VKORC1 will persist for days. Therefore, repeated doses of vitamin K are often required over several days to counteract the ongoing effect of the drug and prevent the dangerous phenomenon of INR rebound.[8]

• Management of Acute Ingestion: In cases of a known acute oral overdose, administration of activated charcoal may be considered if the patient presents within a short time frame (e.g., 1-2 hours) after ingestion to limit further absorption of the drug from the gastrointestinal tract.[53]

Section 7: Comparative Analysis with Other Anticoagulants

To fully appreciate the clinical profile of phenprocoumon, it is essential to compare it with its main therapeutic alternatives: its closest VKA relative, warfarin, and the newer class of Direct Oral Anticoagulants (DOACs). These comparisons highlight the unique pharmacokinetic and clinical characteristics that define phenprocoumon's role in modern antithrombotic therapy.

7.1. Phenprocoumon vs. Warfarin

While often grouped together as coumarin-derived VKAs, phenprocoumon and warfarin exhibit critical differences in their pharmacokinetics that translate into distinct clinical management considerations.

• Fundamental Similarities: Both agents share the same fundamental mechanism of action (inhibition of VKORC1), leading to similar therapeutic indications, a shared primary side effect of bleeding, and the universal requirement for routine INR monitoring. Both are also administered as racemic mixtures, with their respective S(-)-enantiomers being significantly more potent than their R(+)-enantiomers.[2]
• Key Pharmacokinetic Differences:
• Elimination Half-Life: The most profound distinction lies in their elimination half-lives. Phenprocoumon possesses an exceptionally long half-life of approximately 150 hours, which is nearly four times longer than the average half-life of warfarin, which is around 40 hours.[2] This difference is the primary driver of their divergent clinical behaviors. The longer half-life of phenprocoumon is theorized to result in more stable plasma concentrations and, consequently, more stable INR values over time.[37]
• Metabolism and Elimination: The metabolic pathways also differ significantly. While CYP2C9 is a key enzyme for both drugs, its role in the overall clearance of warfarin is predominant. In contrast, for phenprocoumon, the enzyme CYP3A4 plays a much more substantial role in metabolism. Furthermore, a significant portion of phenprocoumon is eliminated unchanged through renal and biliary excretion, whereas the elimination of warfarin is almost entirely dependent on hepatic metabolism.[2]
• Clinical and Pharmacogenomic Implications:
• The differential reliance on metabolic pathways has direct consequences for the impact of genetic polymorphisms. The influence of common CYP2C9 genetic variants (which reduce enzyme function) on the pharmacokinetics and anticoagulant response is significantly less pronounced for phenprocoumon compared to warfarin.[32] Because phenprocoumon has robust alternative clearance pathways (CYP3A4 and direct excretion), the impact of a poorly functioning CYP2C9 enzyme is blunted.
• These pharmacokinetic and pharmacogenomic differences support the clinical observation that patients treated with phenprocoumon often exhibit more stable INR values, remaining within the therapeutic range more consistently and requiring fewer monitoring visits and dose adjustments compared to patients on warfarin.[36] This has led some experts to conclude that, in the absence of routine pharmacogenetic testing, phenprocoumon may be a preferable VKA for long-term anticoagulation due to its greater intrinsic stability.[36]

7.2. Phenprocoumon vs. Direct Oral Anticoagulants (DOACs)

The introduction of DOACs (e.g., apixaban, dabigatran, rivaroxaban, edoxaban) has transformed the landscape of oral anticoagulation. However, the comparative evidence base for these agents against phenprocoumon is notably different from that against warfarin.

• The Evidence Gap: A recurring and critical theme in the literature is the absence of large-scale, prospective, randomized controlled trials (RCTs) that directly compare any of the DOACs against phenprocoumon.[58] The landmark pivotal trials that led to the approval of DOACs for indications like atrial fibrillation and VTE all used warfarin as the VKA comparator.[19]
• Reliance on Real-World Evidence: In the absence of RCTs, the comparative effectiveness and safety of DOACs versus phenprocoumon must be inferred from real-world observational studies, primarily conducted using large healthcare claims databases from Germany, where phenprocoumon is the standard VKA.[19] The findings from these studies suggest:
• Effectiveness (Stroke/Thromboembolism Prevention): Some large observational studies have found that DOACs, as a class or individually, are associated with a significantly lower risk of ischemic stroke or systemic embolism compared to phenprocoumon in patients with atrial fibrillation.[60] A study focused on patients undergoing catheter ablation also found a lower risk of thromboembolic events with DOACs.[58]
• Safety (Bleeding Risk): The comparative safety data on bleeding are more nuanced but generally favor some of the DOACs. Apixaban and dabigatran have been associated with a significantly lower risk of major bleeding compared to phenprocoumon, whereas the risk with rivaroxaban has been found to be similar.[60] A consistent finding across studies is that all three of these DOACs are associated with a significantly reduced risk of the most feared complication, intracranial hemorrhage, when compared to phenprocoumon.[60]
• Interpretation and Context: The prevailing interpretation of this real-world evidence is that the modest superiority or non-inferiority of DOACs over warfarin, as demonstrated in the highly controlled environment of RCTs, may not directly translate into the same magnitude of clinical advantage when compared to phenprocoumon in a real-world setting.[60] This is because the quality of VKA control in the warfarin arms of the pivotal trials was often suboptimal, whereas phenprocoumon, due to its long half-life, may achieve more stable and effective anticoagulation in routine clinical practice.

The global landscape of pharmaceutical research and development, which is heavily influenced by the regulatory and market dynamics of the United States, has inadvertently created this significant evidence gap. Because warfarin has long been the standard-of-care VKA in the U.S., it was the logical and necessary comparator for the pivotal trials designed to gain regulatory approval for the novel DOACs in this major market.[19] However, this has left clinicians and healthcare systems in countries where phenprocoumon is the predominant VKA, such as Germany, in a challenging position.[3] They cannot reliably extrapolate the results of the warfarin-controlled trials to their patient populations, given the known pharmacokinetic and clinical differences between the two VKAs.[58] As a result, critical therapeutic decisions for millions of patients must be made based on observational, real-world data, which is susceptible to confounding and bias, rather than on the gold-standard evidence derived from RCTs. This situation highlights how historical, regional variations in prescribing practices can have a lasting impact on the generation of global clinical evidence and create significant uncertainty in contemporary therapeutic decision-making.

The following table provides a direct comparison of the key distinguishing features of phenprocoumon and warfarin.

Table 4: Comparative Profile of Phenprocoumon and Warfarin
Parameter	Phenprocoumon
Elimination Half-Life	~150 hours (very long) 2
Primary Metabolizing Enzymes	CYP2C9 and CYP3A4 2
Impact of CYP2C9 Polymorphisms	Less pronounced effect on dose/response 32
Other Elimination Pathways	Significant renal/biliary excretion of unchanged drug 32
Reported INR Stability	Generally more stable; requires fewer monitoring visits 36

Section 8: Regulatory Status and Special Populations

The final section of this monograph addresses the global regulatory standing of phenprocoumon and provides specific guidance regarding its use in key patient subpopulations where safety and efficacy considerations may differ from the general adult population.

8.1. Global Regulatory Landscape

The regulatory approval and clinical use of phenprocoumon exhibit a distinct geographical pattern, highlighting significant differences in standard anticoagulant care between North America and parts of Europe.

• Use in Europe: Phenprocoumon is an established and widely prescribed VKA in several continental European countries. It is the dominant oral anticoagulant of its class in Germany and is also commonly used in countries such as Austria, Belgium, Denmark, Luxembourg, Brazil, and the Netherlands.[3] Its long history of use in these regions means that there is extensive clinical experience with its management, albeit a relative scarcity of modern, comparative RCT data.
• United States FDA Status: A critical regulatory fact is that phenprocoumon is not approved for marketing or clinical use by the U.S. Food and Drug Administration (FDA).[13] While the substance is cataloged in the FDA's Global Substance Registration System (GSRS) under the UNII code Q08SIO485D, it does not appear in the official FDA databases of approved drug products, such as the "Orange Book" or "Drugs@FDA".[1] This lack of approval explains its complete absence from the U.S. healthcare market and is the primary reason why warfarin, not phenprocoumon, has served as the standard VKA comparator in clinical trials conducted for U.S. regulatory submission.

8.2. Use in Special Populations

The administration of phenprocoumon in certain patient populations requires special consideration due to altered physiology, increased risk of adverse events, or a lack of comprehensive safety data.

• Pregnancy: The use of phenprocoumon during pregnancy is contraindicated. The drug is known to cross the placental barrier and has been identified as a teratogen, capable of causing developmental toxicity, including a characteristic pattern of birth defects known as fetal warfarin syndrome.[1]
• Lactation: Data on the use of phenprocoumon during breastfeeding are limited. The available evidence indicates that the drug is excreted into breast milk, but at low levels.[13] One study found milk concentrations ranging from 26 to 76 mcg/L in a mother on a stable therapeutic dose.[13] Despite these low levels, significant concern remains due to the drug's extremely long half-life and the theoretical potential for accumulation in the infant. Therefore, shorter-acting anticoagulants, such as warfarin (for which more extensive safety data in lactation exist), are generally preferred, particularly if the infant is younger than two months of age.[13]
• Geriatric Population: While phenprocoumon is frequently used in older adults, particular caution is warranted. Elderly patients may exhibit altered pharmacokinetics, are often more sensitive to the anticoagulant effects of the drug, and are at a higher baseline risk of bleeding complications.[47] Furthermore, they are more likely to have multiple comorbidities and be on multiple medications (polypharmacy), which significantly increases the potential for clinically important drug-drug interactions.[46]
• Renal and Hepatic Impairment: Phenprocoumon is contraindicated in patients with severe hepatic or severe renal insufficiency due to the increased risk of bleeding and unpredictable drug handling.[47] Although one source notes that renal insufficiency does not have a significant impact on the drug's elimination half-life (likely because metabolism is the primary clearance route), the overall risk profile in patients with significant organ dysfunction precludes its use.[7]

Conclusion

Phenprocoumon is a potent, long-acting vitamin K antagonist that holds a significant place in the history and current practice of anticoagulation, particularly within several European nations. Its identity as a 4-hydroxycoumarin derivative is defined by its molecular structure and physicochemical properties, which facilitate its complete oral absorption and high degree of plasma protein binding. The core of its therapeutic action lies in the targeted inhibition of VKORC1, a mechanism that effectively creates a functional vitamin K deficiency, leading to the impaired synthesis of active coagulation factors and the prevention of thrombosis.

The single most important feature governing the clinical profile of phenprocoumon is its exceptionally long elimination half-life of 6-7 days. This pharmacokinetic property is a double-edged sword: it promotes stable plasma concentrations that may lead to more consistent INR control and less frequent monitoring compared to warfarin, but it also imparts a profound clinical inflexibility. The slow onset of action, the prolonged time required to reach steady state, and the persistent anticoagulant effect long after discontinuation necessitate meticulous, individualized management and present significant challenges in acute situations, such as major bleeding or the need for emergency surgery. The risk of INR rebound following acute reversal underscores the complexities introduced by this long half-life.

Clinically, phenprocoumon is an effective agent for the long-term prevention and treatment of major thromboembolic disorders. However, its use is inextricably linked to the primary and substantial risk of hemorrhage, which requires lifelong, vigilant INR monitoring to keep patients within a narrow therapeutic window. The drug is subject to a multitude of interactions with other medications, foods, and supplements, demanding comprehensive patient education and careful review of concomitant therapies.

Finally, the regulatory and research landscape surrounding phenprocoumon is unique. Its non-approval in the United States has resulted in a global "evidence gap," where the vast body of modern comparative data for novel anticoagulants has been generated against warfarin, an agent with demonstrably different pharmacokinetic and pharmacogenomic properties. Consequently, the optimal positioning of phenprocoumon relative to DOACs remains a subject of debate, reliant on real-world evidence rather than gold-standard randomized controlled trials. In conclusion, phenprocoumon remains a valuable but demanding therapeutic tool. Its effective and safe use is a testament to the importance of deep pharmacological understanding and expert clinical management in the art of anticoagulation.

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