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Jantoven (Warfarin Sodium) - Warnings and Precautions

 
 



BOXED WARNING

  • Warfarin Sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1) ].
  • Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1) ].
  • Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin Sodium therapy [see Drug Interactions (7) ].
  • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

 

WARNINGS AND PRECAUTIONS

  • Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue JANTOVEN and consider alternative anticoagulants if necessary. (5.2)
  • Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue JANTOVEN if such emboli occur. (5.3)
  • Heparin-induced thrombocytopenia (HIT): Initial therapy with Warfarin Sodium in HIT has resulted in cases of amputation and death. Warfarin Sodium may be considered after platelet count has normalized. (5.4)
  • Pregnant women with mechanical heart valves: Warfarin Sodium may cause fetal harm; however, the benefits may outweigh the risks. (5.5)

JANTOVEN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with JANTOVEN therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

 

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of JANTOVEN therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue JANTOVEN therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

 

Anticoagulation therapy with JANTOVEN may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as "purple toes syndrome." Discontinue JANTOVEN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

 

Do not use JANTOVEN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with JANTOVEN may be considered after the platelet count has normalized.

 

JANTOVEN can cause fetal harm when administered to a pregnant woman. While JANTOVEN is contraindicated during pregnancy, the potential benefits of using JANTOVEN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue JANTOVEN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient's medical situation, as well as the most current medical guidelines. JANTOVEN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

 

JANTOVEN exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on JANTOVEN therapy [see Contraindications (4) and Use in Specific Populations (8.8) ].

 

In the following clinical settings, the risks of JANTOVEN therapy may be increased:

  • Moderate to severe hepatic impairment
  • Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
  • Use of an indwelling catheter
  • Severe to moderate hypertension
  • Deficiency in protein C-mediated anticoagulant response: JANTOVEN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with JANTOVEN may minimize the incidence of tissue necrosis in these patients.
  • Eye surgery: In cataract surgery, JANTOVEN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As JANTOVEN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue JANTOVEN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
  • Polycythemia vera
  • Vasculitis
  • Diabetes mellitus

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

 

USE IN SPECIFIC POPULATIONS

  • Nursing mothers: Use with caution in a nursing woman. Monitor breast-feeding infants for bruising or bleeding. (8.3)

Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions (5.5) ] and Pregnancy Category X for other pregnant populations [see Contraindications (4) ].

JANTOVEN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of JANTOVEN may outweigh the risks. JANTOVEN can cause fetal harm when administered to a pregnant woman. JANTOVEN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of warfarin sodium have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) and Warnings and Precautions (5.6) ].

 

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when JANTOVEN is administered to a nursing woman.

 

Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered JANTOVEN should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

 

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3) ]. JANTOVEN is contraindicated in any unsupervised patient with senility. Observe caution with administration of JANTOVEN to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of JANTOVEN in elderly patients [see Dosage and Administration (2.2, 2.3) ].

 

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment.

 

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using JANTOVEN in these patients.

 

JANTOVEN exposure during pregnancy can cause spontaneous abortion, birth defects, or fetal death. Females of reproductive potential who are candidates for JANTOVEN therapy should be counseled regarding the benefits of therapy and potential reproductive risks. Discuss pregnancy planning with females of reproductive potential who are on JANTOVEN therapy. If the patient becomes pregnant while taking JANTOVEN, she should be apprised of the potential risks to the fetus.

 

Page last updated: 2013-03-27

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