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Anisindione should be reserved for patients who cannot tolerate the coumarins.
Oral anticoagulants are potent drugs with prolonged and cumulative effects. Treatment must be individualized according to patient response, and the benefit expected from anticoagulant therapy should be weighed against the possible hazards associated with the use of these drugs.
Because agranulocytosis and hepatitis have been associated with the use of anisindione, liver function and blood studies should be performed periodically. Patients should be instructed to report to the physician symptoms such as marked fatigue, chills, fever, or sore throat; the drug should be discontinued promptly since these symptoms may signal the onset of severe toxicity. If leuko-penia or evidence of hypersensitivity occurs, the drug should be discontinued. Because of the possibility of renal damage associated with the use of phenindione, the urine should be tested periodically for albumin whenever phenindione or any indanedione anticoagulant is used.
Relatively minor bleeding episodes and hemorrhage occur in 2% to 10% of patients treated with oral anticoagulants. Bleeding will vary in intensity, and may be related to the quality of patient monitoring, compliance on the part of the patient, the incidence of potentially hemorrhagic lesions, or the extent of anticoagulation induced. Severe and moderate hypertension, severe to moderate hepatic and renal insufficiency, and infectious diseases or disturbances of intestinal flora as in sprue, or with antibiotic therapy may increase the risks associated with anticoagulant therapy.
Occasionally, fatal hemorrhages can occur. Massive hemorrhage from organ systems may involve cerebral, pericardial, pulmonary, adrenal, hepatic, spinal, gastrointestinal, or genitourinary sites. Gastrointestinal hemorrhage may be secondary to peptic ulceration or silent neoplasm and is responsible for 25% of all deaths due to oral anticoagulant therapy. Bleeding complications in the genitourinary tract may range in severity from microscopic hematuria to gross hematuria to extensive uterine hemorrhage.
Hemorrhagic necrosis and/or gangrene of the skin and subcutaneous tissue, petechial and purpuric hemorrhage, ecchymosis, epistaxis, hematemesis, or hemoptysis, may also occur. 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. MIRADON therapy should be discontinued when anisindione 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.) The risks of anticoagulant therapy may be increased in patients with 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 warfarin administration, and may be expected following anisin-dione therapy. 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 anisindione may minimize the incidence of this reaction. Anisindione therapy should be discontinued when it is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.
Concurrent use of anticoagulants with strepto-kinase, urokinase, or alteplase (recombinant tissue plasminogen activator) is not recommended and may be hazardous. (Consult the product information accompanying those preparations.) Abrupt cessation of anticoagulant therapy is not generally recommended; if possible, taper the dose gradually over 3 to 4 weeks.
General: Periodic determination of prothrombin time or other suitable coagulation test is essential. The availability of suitable laboratory facilities to monitor therapy accurately with oral anticoagulants is mandatory, both to assure adequate anticoagulation and to avoid toxicity due to overdosage. The dosage of oral anticoagulants depends on the clinical response as monitored by prothrombin time determinations (see DOSAGE AND ADMINISTRATION). Since heparin prolongs the one-stage prothrombin time, a period of at least 5 hours should elapse after the last intravenous dose and after the last subcutaneous dose of heparin before drawing blood to determine the prothrombin time when heparin and anisindione have been given together. In addition to adequate laboratory facilities, a supply of oral or parenteral phytonadione (vitamin K1) and a source of whole blood or plasma should be available when emergency treatment of acute overdosage is required (see OVERDOSAGE).
A number of factors including environmental, mental, medical, and nutritional states may affect an individual's response to anticoagulant therapy. Factors which increase sensitivity to the drug and lengthen prothrombin time include:initial hypo-prothrombinemia, increased age, poor nutritional status, vitamin K deficiency or malabsorption, congestive heart failure or vascular damage, hepatic disorders including hepatitis or obstructive jaundice, biliary fistula, febrile states, hyperthyroidism, preparatory bowel sterilization, recent surgery, and X-ray therapy.
Factors which may decrease the response to oral anticoagulants and shorten the prothrombin time include: pregnancy, diabetes mellitus, hyper-lipidemia, hypothyroidism, hypercholesterolemia, and hereditary or acquired resistance.
Laboratory Tests: The need for careful control of the degree of anticoagulation, as determined by changes in prothrombin activity, cannot be overemphasized. It should be noted, however, that bleeding during anticoagulant therapy may not always correlate with prothrombin activity.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term dosing studies to determine the carcinogenic potential of oral anticoagulants, including anisindione, have not been done. Information on mutagenesis is unknown.
Labor and Delivery: Anisindione is contraindicated in pregnancy. If oral anticoagulants are used in pregnant women, they should not be administered during the first trimester, and should be discontinued prior to labor and delivery.
Some clinicians suggest the replacement of oral anticoagulants with heparin therapy before term. Heparin is withheld during early labor and reinstituted 6 hours postpartum. After 5 to 7 days, therapy with oral anticoagulants may be resumed if indicated.
See CONTRAINDICATIONS for the use of oral anticoagulants in pregnancy.
Nursing Mothers: Oral anticoagulants or their metabolites are excreted in the milk of nursing mothers, possibly in amounts sufficient to cause a prothrombopenic state and bleeding in the newborn. As a general rule, nursing should not be undertaken while a patient is receiving an oral anticoagulant.
Pediatric Use: The use of oral anticoagulants in pediatric patients is not well documented. However, they may be beneficial in pediatric patients with rare thromboembolic disorder secondary to other disease states such as the nephrotic syndrome or congenital heart lesions. Heparin is probably the initial anticoagulant of choice because of its immediate onset of action.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/8/2004
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