Dicumarol
Indications: Embolism, pulmonary; Embolism, pulmonary, prevention; Fibrillation, atrial, adjunct; Occlusion, coronary, adjunct; Thrombosis; Thrombosis, prevention
DESCRIPTION:
Dicumarol is a coumarin anticoagulant, chemically designated as 3,3-methylenebis (4-hydroxycoumarin).
Inactive Ingredients: Corn starch, lactose, magnesium stearate and talc.
CLINICAL PHARMACOLOGY:
Dicumarol and other coumarin anticoagulants act by depressing synthesis in the liver of several factors which are known to be active in the coagulation mechanisms in a variety of diseases characterized by thromboembolic phenomena. The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II. The degree of depression is dependent upon the dosage administered. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombosis has occurred, anticoagulant treatment aims to prevent further extension of the formed clot and prevents secondary thromboembolic complications which may result in serious and possible fatal sequelae.
Maximal plasma concentrations are reached in 1 to 9 hours. Approximately 97% is bound to albumin within the plasma. Dicumarol usually induces hypoprothrombinemia in 36 to 48 hours, and its duration of action may persist for 5 to 6 days, thus producing a smooth, long lasting response curve. Little is known of the metabolic pathways involved in the biotransformation of oral anticoagulants in man. However, their metabolites appear to be eliminated principally in the urine.
INDICATIONS AND USAGE:
Dicumarol is indicated for the prophylaxis and treatment of venous thrombosis and its extension, the treatment of atrial fibrillation with embolization, the prophylaxis and treatment of pulmonary embolism, and as an adjunct in the treatment of coronary occlusion.
CONTRAINDICATIONS:
Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than its potential clinical benefits, such as:
Pregnancy: Dicumarol is contraindicated in pregnancy 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 dicumarol during pregnancy. 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 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.
Threatened Abortion: Eclampsia and preeclampsia. Inadequate laboratory facilitiesor unsupervised senility, alcoholism, psychosis; or lack of patient cooperation.
Spinal Puncture: and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.
Miscellaneous: Major regional, lumbar block anesthesia, severe uncontrolled and/or malignant hypertension, subacute bacterial endocarditis, open wounds, visceral carcinoma, vitamin K deficiency, and severe liver or kidney disease.
WARNINGS:
The most serious risks associated with anticoagulant therapy with dicumarol are hemorrhage in any tissue or organ and, less frequently, necrosis and/or gangrene of skin and other tissues. The risk of hemorrhage is related to the level of intensity and the duration of anticoagulant therapy. Hemorrhage and necrosis have in some cases been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Dicumarol therapy should be discontinued when dicumarol is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases.
Dicumarol is a potent drug with a half-life of 1 to 2 days; therefore its effects may become more pronounced as daily maintenance doses overlap. It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Dosage should be controlled by periodic determinations of prothrombin time or other suitable coagulation tests. Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage prothrombin time. Therefore, to obtain a valid prothrombin time when heparin and dicumarol are given together, a period of at least 5 hours should elapse after the last intravenous dose and 24 hours after the last subcutaneous dose of heparin, before blood is drawn.
Caution should be observed when dicumarol is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage or necrosis is present.
Administration of anticoagulants in the following conditions will be based upon clinical judgement in which the risks of anticoagulant therapy are weighed against the risk of thrombosis or embolization in untreated cases. The following may be associated with these increased risks:
Lactation: Coumarins may pass into the milk of mothers and cause a prothrombinopenic state in the nursing infant.
Mild to Moderate Hepatic or Renal Insufficiency
Infectious Diseases or Disturbances of Intestinal Flora: Sprue, antibiotic therapy.
Trauma: Which may result in internal bleeding.
Surgery or Trauma: Resulting in large exposed raw surfaces.
Indwelling Catheters and/or Drainage Tubes in any Orifice
Mild to Moderate Hypertension
Known or Suspected Hereditary, Familial or Clinical Deficiency in Protein C: This condition, which should be suspected if there is a history of recurrent episodes of thromboembolic disorders in the patient or in the family, has been associated with an increased risk of developing necrosis following dicumarol administration. Skin necrosis may occur in the absence of protein C deficiency. It has been reported that initiation of anticoagulation therapy with heparin for 4 to 5 days before initiation of therapy with dicumarol may minimize the incidence of this reaction. Dicumarol therapy should be discontinued when dicumarol is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.
Miscellaneous: Polycythemia vera, vasculitis, severe diabetes, severe allergic and anaphylactic disorders, active tuberculosis, history of ulcerative disease of the gastrointestinal tract and during the postpartum period.
Patients with congestive heart failure may become more sensitive to dicumarol, thereby requiring more frequent laboratory monitoring, and reduced doses of dicumarol.
Use of anticoagulants with streptokinase or urokinase may be hazardous and caution should be exercised when used concomitantly. (Please note recommendations accompanying these preparations.)
Abrupt cessation of anticoagulant therapy is not generally recommended; taper dose gradually over 3 to 4 weeks.
PRECAUTIONS:
Periodic determination of prothrombin time or other suitable coagulation test is essential .
Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state and medication may influence response of the patient to anticoagulants. It is generally good practice to monitor the patient's response with additional prothrombin time determinations in the period immediately after discharge from the hospital, and whenever other medications are initiated, discontinued or taken haphazardly. The following factors are listed for your reference; however, other factors may also affect the prothrombin response.
The Following Factors Alone or in Combination, May be Responsible for Increased Prothrombin Time Response:
Endogenous Factors: Carcinoma; collagen disease; congestive heart failure; diarrhea; elevated temperature; hepatic disorders--infectious hepatitis, hyperthyroidism, jaundice; poor nutritional state; vitamin K deficiency--steatorrhea.
Exogenous Factors: Alcohol; allopurinol; aminosalicylic acid; amiodarone; anabolic steroids; antibiotics; bromelains; chloral hydrate; chloramphenicol; chlorpropamide; chymotrypsin; cimetidine; cinchophen; clofibrate; dicumarol overdosage; dextran; dextrothyroxine; diazoxide; dietary deficiencies; diflunisal; diuretics; disulfiram; drugs affecting blood elements; ethacrynic acid; fenoprofen; glucagon; hepatotoxic drugs; ibuprofen; indomethacin; influenza virus vaccine; inhalation anesthetics; mefenamic acid; methyldopa; methylphenidate; methylthiouracil; metronidazole; miconazole; monoamine oxidase inhibitors; nalidixic acid; naproxen; nortriptyline; oxolinic acid; oxyphenbutazone; pentoxifylline; phenylbutazone; phenyramidol; phenytoin; prolonged hot weather; prolonged narcotics; propylthiouracil; pyrazolones; quinidine; quinine; ranitidine; salicylates; sulfinpyrazone; sulfonamides, long acting; sulindac; thyroid drugs; tolbutamide; triclofos sodium; trimethoprim/sulfamethoxazole; unreliable prothrombin time determinations.
The Following Factors, Alone or in Combination, May be Responsible for Decreased Prothrombin Time Response:
Endogenous Factors: Edema; hereditary resistance to coumarin therapy; hyperlipemia; hypothyroidism.
Exogenous Factors: ACTH steroids; alcohol; antacids; antihistamines; phenobarbital and other barbiturates; carbamazepine; chloral hydrate; chlordiazepoxide; cholestyramine; dicumarol underdosage; diet high in vitamin K; diuretics; ethchlorvynol; glutethimide; griseofulvin; haloperidol; meprobamate; oral contraceptives; paraldehyde; primidone; ranitidine; rifampin; unreliable prothrombin time determinations; vitamin C.
A patient may be exposed to a combination of the above factors, some of which may increase and some decrease his sensitivity to dicumarol. Because the net effect on his prothrombin time response may be unpredictable under these circumstances, more frequent laboratory monitoring is advisable.
Drugs not yet shown to interact or not to interact with coumarins are best regarded with suspicion, and when their administration is started or stopped, the prothrombin time should be determined more often than usual.
Coumarins 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.
ADVERSE REACTIONS:
Potential adverse reactions to dicumarol may include:
Hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs and symptoms will vary according to the location and degree or extent of the bleeding. 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 prothrombin activity. (See OVERDOSAGE.)
Adrenal hemorrhage with resultant acute adrenal insufficiency has occurred during anticoagulant therapy. Anticoagulant therapy should be discontinued in patients who develop signs and symptoms compatible with acute adrenal hemorrhage or insufficiency. Plasma cortisol levels should be measured immediately, and vigorous therapy with intravenous corticosteroids should be instituted promptly. Initiation of therapy should not depend upon laboratory confirmation of the diagnosis, since any delay in an acute situation may result in the patient's death.
Ovarian hemorrhage: Reports indicate that a woman receiving short- or long-term therapy with heparin or warfarin sodium may be at risk of developing ovarian hemorrhage at the time of ovulation. Caution should be observed when dicumarol is administered since these compounds have similar actions.
Paralytic ileus and intestinal obstruction have been reported from submucosal or intramural hemorrhage.
Excessive uterine bleeding has occurred but menstrual flow is usually normal.
Bleeding which occurs when the prothrombin time 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. (See WARNINGS.)
Other adverse reactions are infrequent and consist of alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramping, a syndrome called "purple toes," hypersensitivity reactions, leukopenia, and vomiting.
Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.
OVERDOSAGE:
Excessive prothrombinopenia, with or without bleeding, is readily controlled by discontinuing dicumarol, and if necessary, the oral or parenteral administration of vitamin K1. The appearance of microscopic hematuria, excessive menstrual bleeding, melena, petechiae or oozing from nicks made while shaving are early manifestation of hypoprothrombinemia beyond a safe and satisfactory level.
In excessive prothrombinopenia with mild or no bleeding, omission of one or more doses of dicumarol may suffice; and if necessary, small doses of vitamin K1 orally, 2 1/2 to 10 mg, will usually correct the problem.
If minor bleeding persists, or progresses to frank bleeding, vitamin K1 in doses of 5 to 25 mg may be given parenterally. (Please note recommendations accompanying vitamin K preparations prior to use.)
Fresh whole blood transfusions should be considered in cases of severe bleeding or prothrombinopenic states unresponsive to vitamin K1.
Resumption of dicumarol administration reverses the effect of vitamin K1, and a therapeutic hypoprothrombinemia level can again be obtained. A hypercoagulable state has been reported to occur following rapid reversal of a prolonged prothrombin time, therefore, caution must be used in determining the need for this vitamin.
DOSAGE AND ADMINISTRATION:
Dosage and Laboratory Control
The aim of anticoagulant therapy is to impede the coagulation or clotting mechanism to such an extent that avoiding such extensive impairment as might produce spontaneous bleeding. Effective therapeutic levels with minimal complications can best be achieved in cooperative and well-instructed patients, who keep the doctor informed of their status between visits.
The administration and dosage of dicumarol must be individualized for each patient according to the particular patient's sensitivity to the drug as indicated by the prothrombin time. The prothrombin time reflects the depression of vitamin K dependent Factors VII, X and II. These factors, in addition to Factor IX, are affected by coumarin anticoagulants. There are several modifications of the Quick one-stage prothrombin time and the physician should become familiar with the specific method used in his laboratory.
Administration of dicumarol should be gauged according to prothrombin time determinations by a suitable method. The blood prothrombin time should usually be determined daily after the administration of the initial dose until prothrombin time results stabilize in the therapeutic range. Intervals between subsequent prothrombin time determinations should be based upon the physician's judgment of the patient's reliability and response to dicumarol in order to maintain the individual within the therapeutic range. Acceptable intervals for prothrombin time determinations have usually fallen within the range of 1 to 4 weeks. Satisfactory levels for maintenance of therapeutic anticoagulation are 1 1/2 to 2 1/2 times the normal prothrombin time (e.g., 18 to 30 seconds, with a control of 12 seconds).
Induction
The dosage range for the average adult with normal prothrombin activity ranges from 200 to 300 mg the first day.
Maintenance
On subsequent days the dosage ranges from 25 to 200 mg. It is essential that prothrombin time be measured daily while establishing the correct maintenance dose. Once this has been determined, prothrombin times can be checked less frequently. Dicumarol tablets may not be interchangeable with dicumarol capsules. Retitration of the dosage should be considered if the dosage form prescribed is changed.
Duration of Therapy
The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.
Treatment During Dentistry and Surgery
The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists. Interruption of anticoagulant therapy may precipitate thromboembolism, and conversely, if anticoagulants are maintained at full doses, some patients may hemorrhage excessively. If it is elected to administer anticoagulants prior to, during, or immediately following dental or surgical procedures, it is recommended that the dosage of dicumarol be adjusted to maintain the prothrombin time at approximately 1 1/2 to 2 1/2 times the control level. The operative site should be sufficiently limited to permit the effective use of local procedures for hemostasis including absorbable hemostatic agents, sutures, and pressure dressings if necessary. Under these conditions dental and surgical procedures may be performed without undue risk of hemorrhage.
Dicumarol with Heparin
Since a delay intervenes between the administration of the initial dose and the therapeutic prolongation of prothrombin time, it may be advisable in emergency situations to administer sodium heparin initially along with dicumarol.
It should be noted that heparin may affect the prothrombin time, and therefore, when patients are receiving both heparin and dicumarol, the blood sample for prothrombin time determination should be drawn just prior to the next heparin dosage, at least 5 hours after the last intravenous injection or 24 hours after the last subcutaneous injection.
Increased and decreased prothrombin time responses have been reported.
Recommended Storage: Store below 77Β°F (25Β°C).