Phenprocoumon

280.323

280.32

207-108-9

DTXSID5023459

FINE WHITE CRYSTALLINE POWDER|Crystals or prisms from dilute methanol

B01AA04|B - Blood and blood forming organs

2932209090

46.5

4.4

Solid

1.3±0.1 g/cm3

179-180 °C

463.2±45.0 °C at 760 mmHg

195.7±21.5 °C

1.638

4.86e-02 g/L

ODORLESS OR HAS SLIGHT ODOR

160 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

III

6.1(b)

UN 2811

P201, P202, P260, P261, P263, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P307+P311, P308+P313, P311, P312, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, P501

H301

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently discontinued drug products, incl phenprocoumon, on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Schardein JL; Drugs affecting blood. Chemically Induced Birth Defects 2: 106-25 (1993). Review of the fetal toxicity of anticoagulants.|Freedman MD, Olatidoye AG; Drug Saf 10 (5): 381-94 (1994). Oral anticoagulants include coumarin derivatives (dicoumarol, phenprocoumon and acenocoumarol. ... The oral anticoagulants, and warfarin in particular are highly interactive with other drugs. Mechanisms of those interactions include both pharmacokinetic and pharmacodynamic mechanisms and may result in either hyperprothrombinemia or hypoprothrombinemia.

50=500 mg/kg. Symptoms of overdose includes suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries).

Like other drugs of this class, effective dose & duration of action are affected by a number of factors, including dietary intake and enteric bacterial synthesis of vitamin k, and concurrent drugs which affect hepatic "microsomal" drug metabolism system. .../its/ interactions are those of dicumarol.|Dicumarol increases serum half-life of tolbutamide and may cause symptoms of hypoglycemia. ... Of coumarin anticoagulants, phenprocoumon interacts with tolbutamide in animals.|Oxyphenbutazone, a metabolite of phenylbutazone, also interacted with coumarin anticoagulants in 2 humans. /coumarins/|High serum levels of heparin prolong prothrombin time and prevent proper interpretation of test as guide to oral anticoagulant dosage. ... It has been advocated that 1 day of heparin therapy be omitted so that prothrombin time totally uninfluenced by heparin may be obtained. /oral anticoagulants/|For more Interactions (Complete) data for PHENPROCOUMON (19 total), please visit the HSDB record page.

SRP: Persons with bleeding disorders or who are taking anticoagulants should be protected from exposure.

99%

Used for the prevention and treatment of thromboembolic disease including venous thrombosis, thromboembolism, and pulmonary embolism as well as for the prevention of ischemic stroke in patients with atrial fibrillation (AF).

Anticoagulants|A prothrombopenic anticoagulant with actions and uses similar to those of dicumarol. Its onset of action is 48-72 hr, and its duration of action may be as long as 7 days. ...|Anticoagulants are indicated in the treatment of patients with recent deep vein thrombosis or thrombophlebitis to prevent extension and embolization of the thrombus and to reduce the risk of pulmonary embolism or recurrent thrombus formation. In acute pulmonary embolism or venous thrombosis, anticoagulants are indicated following initial thrombolytic and/or heparin therapy to decrease the risk of extension, recurrence, or death. /Anticoagulants/|Anticoagulants may prevent the formation of mural thrombi in the heart, which may lead to systemic thromboembolism in patients with chronic atrial fibrillation, especially those with rheumatic mitral stenosis, prosthetic heart valves, left atrial enlargement, or cardiomyopathy. In these patients, anticoagulants may decrease the risk of arterial embolism, pulmonary embolism, or subsequent stroke. /Anticoagulants/|For more Therapeutic Uses (Complete) data for PHENPROCOUMON (8 total), please visit the HSDB record page.

Contraindications to oral anticoagulants include pre-existing or coexisting abnormalities of blood coagulation, active bleeding, recent or imminent surgery of the central nervous system or eye, diagnostic or therapeutic procedures with potential for uncontrollable bleeding including lumbar puncture, malignant hypertension, peptic ulceration, pregnancy, threatened abortion, intrauterine device, cerebrovascular hemorrhage, and bacterial endocarditis. Relative contraindications include thrombocytopenia, pericarditis, pericardial effusions, and unreliability of the patient or of patient supervision. /Oral anticoagulants/|Most commonly, oral anticoagulant-induced bleeding is minor and consists of bruising, hematuria, epistaxis, conjunctival hemorrhage, minor gastrointestinal bleeding, bleeding from wounds and sites of trauma, and vaginal bleeding. More serious major or fatal bleeding is most commonly gastrointestinal, intracranial, vaginal, retroperitoneal, or related to a wound or site of trauma, although a large variety of other sites of bleeding have been reported. Intracranial bleeding occurs most frequently in patients receiving oral anticoagulants for cerebrovascular disease and most commonly presents as a subdural hematoma, often unassociated with head trauma. Fatal gastrointestinal bleeding is most commonly from a peptic ulcer, although any gastrointestinal lesion may be a potential source of major bleeding. Overall, a bleeding lesion can be identified in about two thirds of cases of oral anticoagulants-related hemorrhage. /Oral anticoagulants/|Overall, the bleeding rate of oral anticoagulant therapy is influenced by several factors: the intensity of anticoagulation, either intentionally or inadvertent; the underlying clinical disorder for which anticoagulant therapy is used (with bleeding occurring most frequently in ischemic cerebrovascular disease and venous thromboembolism; and, with bleeding occurring most commonly in the elderly; the presence of adverse drug interactions or comorbid factors such as clinical states potentiating warfarin action, pre-existing hemorrhagic diathesis, malignancy, recent surgery, trauma, or pre-existing potential bleeding sites (e.g., surgical wound, peptic ulcer, recent cerebral hemorrhage, carcinoma of colon); the simultaneous use of aspirin (but not of dipyridamole); and patient reliability (e.g., increased bleeding in alcoholics not due to ethanol-warfarin drug interaction but rather to unreliability of drug intake). /Oral anticoagulants/|It is inadvisable to carry out long-term therapy in chronic alcoholic, in individual who may require intensive salicylate therapy, or in cases of malignant hypertension and active tuberculosis. Oral anticoagulant therapy during pregnancy carries significant hemorrhagic risk for fetus. /oral anticoagulants/|For more Drug Warnings (Complete) data for PHENPROCOUMON (21 total), please visit the HSDB record page.

Phenprocoumon, a coumarin anticoagulant, thins the blood by antagonizing vitamin K which is required for the production of clotting factors in the liver. Anticoagulants such as phenprocoumon have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage (damage caused by an inadequate blood supply to an organ or part of the body). However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.

Agents that prevent BLOOD CLOTTING. (See all compounds classified as Anticoagulants.)

Bioavailability is close to 100%|Coumarin anticoagulants pass placental barrier. /coumarin anticoagulants/|The disposition of phenprocoumon differed between male and female rats, with a substantially lower apparent volume of distribution and clearance in female rats. Although female rats had a lower sensitivity to the drug, the differences in kinetics caused an apparent equal response to the same doses and a longer duration of effect.|Samples of urine and feces were collected daily from a normal human volunteer who had received a dose of pseudoracemic phenprocoumon ...containing a tracer dose of 10 microCi of (14C)phenprocoumon... . After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). ...The urinary excretion pattern was also confirmed in four additional healthy male subjects who received a single oral dose of pseudoracemic phenprocoumon... . All the drug-related materials (both hydroxylated metabolites and parent compound) that were excreted into the urine were extensively conjugated.|...A study was conducted in 24 healthy volunteers, ages 23-28 yr, who received an oral and an IV dose of phenprocoumon 9 mg at 3 wk intervals. The following mean data were obtained after IV injection: half-life alpha 0.432 hr, half-life beta 128 hr, initial blood level 0.651 ug/ml, volume of distribution 14.41, area under the concn curve (AUC) 121 ugxhr/ml. After oral intake the following mean values were measured: Tmax 2.25 hr, Cmax 1.01 ug/ml, absorption half-life 0.553 hr, initial blood level 0.865 ug/ml, half-life beta 132 hr, AUC 164 ugxhr/ml. A total mean clearance of 20.0 (IV) and 15.1 (oral) ml/hr was calculated within the first 8 hr post dose, while values measured did not differ between 8 and 48 hr post dose. ...

Phenprocoumon is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites. Cytochrome P450 2C9 is the principal form of human liver P-450 responsible for metabolism.|Pooled plasma from patients receiving phenprocoumon anticoagulant therapy was extracted and the following substances were characterized: phenprocoumon, and its 7-hydroxy,4'-hydroxy and 6-hydroxy derivatives; they were identified by HPLC and after methylation by quartz capillary GC-MS using the electron impact and selective ion monitoring modes. This is the first occasion when phenprocoumon metabolites have been identified in plasma; they were unconjugated and in much lower concentrations (43.2 and 2 ng/ml for the 7,4' and 6-hydroxy derivatives, respectively) than the original compound (2000 ng/ml).|...The metabolites of /pseudoracemic phenprocoumon/ were identified as the 4'-, 6-, and 7-hydroxy analogues of phenprocoumon. Virtually all of the recovered radioactivity could be accounted for by the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of both 4'-(8.1% of administered dose) and 7- (33.4% of administered dose) hydroxyphenprocoumon was highly stereoselective, giving S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of administered dose) hydroxyphenprocoumon showed little stereoselectivity (S/R ratio equal to 0.85).

5-6 days|Phenprocoumon (Marcumar) has a longer plasma half-life /of/ 5 days than warfarin, as well as a somewhat slower onset of action and a longer duration of action (7-14 days).|Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12-0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6-7 days after drug administration. The binding of [3H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64 +/- 0.16 ml/h/kg mean +/- SEM) than in the healthy volunteers (0.90 +/- 0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144 +/- 14 ml/h/kg) compared with normal (113 +/- 11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5 +/- 2.9 ml/h/kg) compared with normal (35.6 +/- 3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.|...The following mean data were obtained after IV injection /of phenprocoumon/: half-life alpha 0.432 hr, half-life beta 128 hr... . After oral intake the following mean values were measured: ...absorption half-life 0.553 hr, ...half-life beta 132 hr... .

Phenprocoumon inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decreased prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.|The oral anticoagulants block the regeneration of reduced vitamin K and thereby induce a state of functional vitamin K deficiency. The mechanism of the inhibition of reductase(s) by the coumarin drugs is not known. There exist reductases that are less sensitive to these drugs but that act only at relatively high concentrations of oxidized vitamin K; this property may explain the observation that administration of sufficient vitamin K can counteract even large doses of oral anticoagulants. /Oral Anticoagulants/|The disposition of a single intravenous bolus dose of 10 mg vitamin K1 and vitamin K1-2,3-epoxide were studied in two healthy subjects without and with 12 hr pretreatment dose of phenprocoumon (0.4 mg/kg). For each compound administered alone the plasma concn-time profile was adequately fitted by a biexponential equation, with an avg terminal half-life of 2.0 and 1.15 hr for the administered vitamin K and its 2,3-epoxide respectively. While vitamin K1 was measurable in plasma following admin of vitamin K1-2,3-epoxide, the epoxide was not detectable following admin of vitamin K1. Following pretreatment with phenprocoumon and after iv admin of vitamin K1, both the avg half-life and area under the plasma concn-time profile of vitamin K1 were marginally reduced to 1.5 hr and 1.76 mg/l/hr respectively, while the plasma concn of vitamin K1-2,3-epoxide was readily measurable and its half-life markedly prolonged to 14.7 hr. Following pretreatment with phenprocoumon and after oral administration of vitamin K1-2,3-epoxide, no vitamin K1 was detectable in plasma and the half-life of the epoxide was 13.8 hr. Based on area considerations the data suggest that either phenprocoumon does more than just inhibit the reduction of vitamin K1-2,3-epoxide to vitamin K1, or that the simple model describing the interconversion between vitamin K1 and its epoxide is inadequate. The same conclusion is drawn from the analysis of comparable data in dogs... .|Both 4-hydroxycoumarin derivatives and indandiones (also known as oral anticoagulants) are antagonists of vitamin K. Their use as rodenticides is based on the inhibition of the vitamin K-dependent step in the synthesis of a number of blood coagulation factors. The vitamin K-dependent proteins ...in the coagulation cascade... are the procoagulant factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart-Prower factor), and the coagulation-inhibiting proteins C and S. All these proteins are synthesized in the liver. Before they are released into the circulation the various precursor proteins undergo substantial (intracellular) post-translational modification. Vitamin K functions as a co-enzyme in one of these modifications, namely the carboxylation at well-defined positions of 10-12 glutamate residues into gamma-carboxyglutamate (Gla). The presence of these Gla residues is essential for the procoagulant activity of the various coagulations factors. Vitamin K hydroquinone (KH2) is the active co-enzyme, and its oxidation to vitamin K 2,3-epoxide (KO) provides the energy required for the carboxylation reaction. The epoxide is than recycled in two reduction steps mediated by the enzyme KO reductase... . The latter enzyme is the target enzyme for coumarin anticoagulants. Their blocking of the KO reductase leads to a rapid exhaustion of the supply of KH2, and thus to an effective prevention of the formation of Gla residues. This leads to an accumulation of non-carboxylated coagulation factor precursors in the liver. In some cases these precursors are processed further without being carboxylated, and (depending on the species) may appear in the circulation. At that stage the under-carboxylated proteins are designated as descarboxy coagulation factors. Normal coagulation factors circulate in the form of zymogens, which can only participate in the coagulation cascade after being activated by limited proteolytic degradation. Descarboxy coagulation factors have no procoagulant activity (i.e. they cannot be activated) and neither they can be converted into the active zymogens by vitamin K action. Whereas in anticoagulated humans high levels of circulating descarboxy coagulation factors are detectable, these levels are negligible in warfarin-treated rats and mice. /Anticoagulant rodenticides/

Human exposure to second-generation and indandione anticoagulants produces symptoms consistent with anticoagulation effects (e.g., hematomas, hematemesis, hematuria, easy bruisability). Treatment of cases of exposure, particularly of substantial and repeated exposure, may require vitamin K1 therapy and monitoring of prothrombin times for periods of many months.

/HUMAN EXPOSURE STUDIES/ Overdose...may cause hemorrhagic diathesis... /phenprocoumon/ may cause diarrhea or other mild GI disturbances, such as anorexia, nausea, vomiting, and dermatitis. leukopenia, urticaria, erythema, or hemorrhagic infarction of skin and digits may occur.|/HUMAN EXPOSURE STUDIES/ Bleeding is the major toxicity of oral anticoagulant drugs. ... Especially serious episodes involve sites where irreversible damage may result from compression of vital structures (e.g., intracranial, pericardial, nerve sheath, or spinal cord) or from massive internal blood loss that may not be diagnosed rapidly (e.g., gastrointestinal, intraperitoneal, retroperitoneal). /Oral Anticoagulants/|/HUMAN EXPOSURE STUDIES/ To measure a possible influence of long term anticoagulant therapy with phenprocoumon on peripheral bone mass, measurements of peripheral bone mineral content (BMC) and serum osteocalcin (OC) levels were performed with single photon absorptiometry in ... 78 patients on anticoagulant treatment, 43 women (mean age 66 years) and 35 men (mean age 65 years) with a median duration of phenprocoumon therapy of 1 year (1-9 years). ... Both in the male and female groups, mean peripheral BMC was significantly decreased (male: p less than 0.01, female: p less than 0.003) when compared with corresponding controls . Serum OC levels measured in 16 patients were also significantly lower than those of the controls (p less than 0.02). Decreased BMC and low serum OC levels indicate reduced bone mass in patients on long term anticoagulant therapy with phenprocoumon.|/HUMAN EXPOSURE STUDIES/ ...Recent retrospective and prospective studies show that the risk of fetal or embryonal teratogenic injury is about 25-30% if coumarol derivatives are given through the 6th to 9th wk of pregnancy.|/CASE REPORTS/ Pneumatosis cystoides intestinalis is a rarely observed disorder on plain abdominal X-ray or colonoscopy examination. Although causing few complaints in adults, it can nevertheless lead to gastrointestinal bleeding. In the reported case, gastrointestinal bleeding was observed with coinciding pneumatosis and phenprocoumon therapy. After stopping anticoagulant therapy, pneumatosis vanished completely, thus suggesting that phenprocoumon is probably a further cause of the cystic disease. In the known list of drugs able to provoke pneumatosis, this case adds a new mechanism of affliction different to either immunosuppression or gas production.

Falithrom

GRUSSNER, BALTHASAR, US PATENT 2,723,276 (1955 TO HOFFMANN-LA ROCHE); JUNEK, ZIEGLER, MONATSH (87) 218, 1956; SCHROEDER, LINK, J AM CHEM SOC (79) 3291, 1957; US PATENT 2,872,457 (1959 TO WISCONSIN ALUMNI RES FOUND); BRITISH PATENT 805,748 (1958 TO GEIGY).

AOAC Official Method 973.72: Acenocoumarol, Dicumarol, Phenprocoumon, Warfarin Potassium, and Warfarin Sodium in Drugs; Automated Spectrophotometric Method.|AOAC Official Method 988.24: Dicumarol, Phenprocoumon, and Warfarin Sodium in Drug Tablets; Liquid Chromatography Method.

PHENPROCOUMON WAS DETERMINED IN RAT SERUM BY HIGH-PRESSURE LIQ CHROMATOGRAPHY AFTER ORAL ADMIN OF SODIUM PHENPROCOUMON. RECOVERY WAS 97-98%, & OTHER SERUM COMPONENTS DID NOT INTERFERE.|LIMIT OF DETECTION IN HUMAN SERUM OR PLASMA WAS APPROX 0.25 MUG PHENPROCOUMON/ML. NO INTERFERENCE FROM OTHER USUAL ORAL ANTICOAGULANT DRUGS.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals