Coumafene

Coumafene - General Information

An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Coumafene is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Coumafene is also used as a rodenticide. [PubChem]

 

Pharmacology of Coumafene

Coumafene, a coumarin anticoagulant, is a racemic mixture of two active isomers. It is used in 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).

 

Coumafene for patients

 

Coumafene Interactions

Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with COUMADIN are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response

ENDOGENOUS FACTORS

blood dyscrasias —	diarrhea	hyperthyroidism
see CONTRAINDICATIONS	elevated temperature	poor nutritional state
cancer	hepatic disorders	steatorrhea
collagen vascular disease	infectious hepatitis	vitamin K deficiency
congestive heart failure	jaundice

EXOGENOUS FACTORS

Potential drug interactions with COUMADIN are listed below by drug class and by specific drugs.

Classes of Drugs
5-lipoxygenase Inhibitor	Antiparasitic/Antimicrobials	HMG-CoA Reductase
Adrenergic Stimulants, Central	Antiplatelet Drugs/Effects	Inhibitors†
Alcohol Abuse Reduction	Antithyroid Drugs†	Leukotriene Receptor Antagonist
Preparations	Beta-Adrenergic Blockers	Monoamine Oxidase Inhibitors
Analgesics	Cholelitholytic Agents	Narcotics,prolonged
Anesthetics, Inhalation	Diabetes Agents, Oral	Nonsteroidal Anti-Inflammatory
Antiandrogen	Diuretics†	Agents
Antiarrhythmics†	Fungal Medications, Intravaginal,	Psychostimulants
Antibiotics†	Systemic†	Pyrazolones
Aminoglycosides (oral)	Gastric Acidity and Peptic	Salicylates
Cephalosporins, parenteral	Ulcer Agents†	Selective Serotonin
Macrolides	Gastrointestinal	Reuptake Inhibitors
Miscellaneous	Prokinetic Agents	Steroids, Adrenocortical†
Penicillins, intravenous,	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
high dose	Gout Treatment Agents	Testosterone Derivatives)
Quinolones (fluoroquinolones)	Hemorrheologic Agents	Thrombolytics
Sulfonamides, long acting	Hepatotoxic Drugs	Thyroid Drugs
Tetracyclines	Hyperglycemic Agents	Tuberculosis Agents†
Anticoagulants	Hypertensive Emergency Agents	Uricosuric Agents
Anticonvulsants†	Hypnotics†	Vaccines
Antidepressants†	Hypolipidemics†	Vitamins†
Antimalarial Agents	Bile Acid-Binding Resins†
Antineoplastics†	Fibric Acid Derivatives

Specific Drugs Reported
acetaminophen	fluconazole	penicillin G,intravenous
alcohol†	fluorouracil	pentoxifylline
allopurinol	fluoxetine	phenylbutazone
aminosalicylic acid	flutamide	phenytoin†
amiodarone HCl	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atorvastatin†	gemfibrozil	pravastatin†
azithromycin	glucagon	prednisone†
capecitabine	halothane	propafenone
cefamandole	heparin	propoxyphene
cefazolin	ibuprofen	propranolol
cefoperazone	ifosfamide	propylthiouracil†
cefotetan	indomethacin	quinidine
cefoxitin	influenza virus vaccine	quinine
ceftriaxone	itraconazole	ranitidine†
celecoxib	ketoprofen	rofecoxib
cerivastatin	ketorolac	sertraline
chenodiol	levamisole	simvastatin
chloramphenicol	levofloxacin	stanozolol
chloral hydrate†	levothyroxine	streptokinase
chlorpropamide	liothyronine	sulfamethizole
cholestyramine†	lovastatin	sulfamethoxazole
cimetidine	mefenamic acid	sulfinpyrazone
ciprofloxacin	methimazole†	sulfisoxazole
cisapride	methyldopa	sulindac
clarithromycin	methylphenidate	tamoxifen
clofibrate	methylsalicylate ointment	tetracycline
COUMADIN overdose	(topical)	thyroid
cyclophosphamide†	metronidazole	ticarcillin
danazol	miconazole	ticlopidine
dextran	(intravaginal,systemic)	tissue plasminogen
dextrothyroxine	moricizine hydrochloride†	activator (t-PA)
diazoxide	nalidixic acid	tolbutamide
diclofenac	naproxen	tramadol
dicumarol	neomycin	trimethoprim/sulfamethoxazole
diflunisal	norfloxacin	urokinase
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
ethacrynic acid	oxaprozin	zileuton
fenofibrate	oxymetholone
fenoprofen	paroxetine

also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations

^† increased and decreased PT/INR responses have been reported.

The following factors, alone or in combination, may be responsible for DECREASED PT/INR response

ENDOGENOUS FACTORS

edema	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia

EXOGENOUS FACTORS

Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs.

Classes of Drugs
Adrenal Cortical Steroid Inhibitors	Antithyroid Drugs†	HMG-CoA Reductase Inhibitors†
Antacids	Barbiturates	Immunosuppressives
Antianxiety Agents	Diuretics†	Oral Contraceptives,
Antiarrhythmics†	Enteral Nutritional Supplements	Estrogen Containing
Antibiotics†	Fungal Medications, Systemic†	Selective Estrogen Receptor
Anticonvulsants†	Gastric Acidity and	Modulators
Antidepressants†	Peptic Ulcer Agents†	Steroids, Adrenocortical†
Antihistamines	Hypnotics†	Tuberculosis Agents†
Antineoplastics†	Hypolipidemics†	Vitamins†
Antipsychotic Medications	Bile Acid-Binding Resins†

Specific Drugs Reported
alcohol†	COUMADIN underdosage	phenytoin†
aminoglutethimide	cyclophosphamide†	pravastatin†
amobarbital	dicloxacillin	prednisone†
atorvastatin†	ethchlorvynol	primidone
azathioprine	glutethimide	propylthiouracil†
butabarbital	griseofulvin	raloxifene
butalbital	haloperidol	ranitidine†
carbamazepine	meprobamate	rifampin
chloral hydrate†	6-mercaptopurine	secobarbital
chlordiazepoxide	methimazole†	spironolactone
chlorthalidone	moricizine hydrochloride†	sucralfate
cholestyramine†	nafcillin	trazodone
clozapine	paraldehyde	vitamin C (high dose)
corticotropin	pentobarbital	vitamin K
cortisone	phenobarbital

also: diet high in vitamin K unreliable PT/INR determinations

^†Increased and decreased PT/INR responses have been reported.

Because a patient may be exposed to a combination of the above factors, the net effect of COUMADIN on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.

It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.

Botanical (Herbal) Medicines

Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals.

Specific botanicals reported to affect COUMADIN therapy include the following:

• Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, and ginseng are associated most often with an INCREASE in the effects of COUMADIN.

• Coenzyme Q₁₀ (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of COUMADIN.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anti-coagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of COUMADIN.

Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.

Botanticals that contain coumarins with potential anticoagulant effects:
Alfalfa	Celery	Parsley
Angelica (Dong Quai)	Chamomile	Passion Flower
Aniseed	(German and Roman)	Prickly Ash (Northern)
Arnica	Dandelion3	Quassia
Asa Foetida	Fenugreek	Red Clover
Bogbean1	Horse Chestnut	Sweet Clover
Boldo	Horseradish	Sweet Woodruff
Buchu	Licorice3	Tonka Beans
Capsicum2	Meadowsweet1	Wild Carrot
Cassia3	Nettle	Wild Lettuce

Miscellaneous botanticals with anticoagulant properties:
Bladder Wrack (Fucus)	Pau d’arco

Botanicals that contain salicylate and/or have antiplatelet properties:
Agrimony4	Dandelion3	Meadowsweet1
Aloe Gel	Feverfew	Onion5
Aspen	Garlic5	Policosanol
Black Cohosh	German Sarsaparilla	Poplar
Black Haw	Ginger	Senega
Bogbean1	Ginkgo Biloba	Tamarind
Cassia3	Ginseng (Panax)5	Willow
Clove	Licorice3	Wintergreen

Botanticals with fibrinolytic properties:
Bromelains	Garlic5	Inositol Nicotinate
Capsicum2	Ginseng (Panax)5	Onion5

Botanticals with coagulant properties:
Agrimony4 Mistletoe	Yarrow
Goldenseal
1 Contains coumarins and salicylate.
2 Contains coumarins and has fibrinolytic properties.
3 Contains coumarins and has antiplatelet properties.
4 Contains salicylate and has coagulant properties.
5 Has antiplatelet and fibrinolytic properties.

Effect on Other Drugs

Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.

Special Risk Patients

COUMADIN (Warfarin Sodium) is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients such as the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.

Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.

Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.

Acquired or inherited warfarin resistance should be suspected if large daily doses of COUMADIN are required to maintain a patient’s PT/INR within a normal therapeutic range.

Side Effects

Potential adverse reactions to COUMADIN may include:

• Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscle or other pain; dizziness; shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with PT/INR.

• Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, e.g., tumor, ulcer, etc.

• Necrosis of skin and other tissues.

• Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, vasculitis, edema, fever, rash, dermatitis, including bullous eruptions, urticaria, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills.

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown.

Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.

 

Coumafene Contraindications

Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:

Pregnancy

COUMADIN is contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.

Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness,a nd other central nervous system abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly.

Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.

Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.

Hemorrhagic tendencies or blood dyscrasias.

Recent or contemplated surgery of: (1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces.

Bleeding tendencies associated with active ulceration or overt bleeding of: (1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis.

Threatened abortion, eclampsia and preeclampsia.

Inadequate laboratory facilities.

Unsupervised patients with senility, alcoholism,or psychosis or other lack of patient cooperation.

Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.

Miscellaneous major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product.

 

Additional information about Coumafene

Coumafene Indication: For the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischaemia, arterial embolism and thrombosis.
Mechanism Of Action: Coumafene 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 decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
Drug Interactions: Not Available
Food Interactions: Avoid drastic changes in dietary habit.
Consult your doctor before taking large amounts of Vitamin K (Green leafy vegetables).
Avoid alcohol.
Avoid St.John's Wort.
Limit garlic, ginger, gingko, and horse chestnut.
Generic Name: Warfarin
Synonyms: Warfarin sodium
Drug Category: Rodenticides; Anticoagulants; Coumarin and Indandione Derivatives
Drug Type: Small Molecule; Approved

Other Brand Names containing Warfarin: Athrombin; Athrombin-K; Athrombine-K; Brumolin; Co-Rax; Coumadin; Coumafen; Coumafene; Coumaphen; Coumaphene; Coumarins; Coumefene; D-Con; Dethmor; Dethnel; Dicusat E; Frass-Ratron; Jantoven; Kumader; Kumadu; Kumatox; Kypfarin; Latka 42; Mar-Frin; Marevan; Maveran; Panwarfin; Place-Pax; Prothromadin; RAX; Rosex; Sofarin; Solfarin; Sorexa Plus; Temus W; Tintorane; Tox-Hid; Vampirinip II; Vampirinip III; Waran; Warf 42; Warfarat; Warfarin Plus; Warfarin Q; Warfarine; Warficide; Warfilone; Zoocoumarin;
Absorption: Not Available
Toxicity (Overdose): LD₅₀=374 (orally in mice)
Protein Binding: 99.5%
Biotransformation: Metabolized by hepatic microsomal enzymes.
Half Life: 1 week
Dosage Forms of Coumafene: Tablet Oral
Chemical IUPAC Name: 2-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-4-one
Chemical Formula: C19H16O4
Warfarin on Wikipedia: https://en.wikipedia.org/wiki/Warfarin
Organisms Affected: Humans and other mammals