Drug Interactions between ombitasvir / paritaprevir / ritonavir and warfarin

Nutrition and diet can affect your treatment with warfarin. Therefore, it is important to keep your vitamin supplement and food intake steady throughout treatment. For example, increasing vitamin K levels in the body can promote clotting and reduce the effectiveness of warfarin. While there is no need to avoid products that contain vitamin K, you should maintain a consistent level of consumption of these products. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. However, even foods that do not contain much vitamin K may occasionally affect the action of warfarin. There have been reports of patients who experienced bleeding complications and increased INR or bleeding times after consuming large quantities of cranberry juice, mangos, grapefruit, grapefruit juice, grapefruit seed extract, or pomegranate juice. Again, you do not need to avoid these foods completely, but it may be preferable to limit their consumption, or at least maintain the same level of use while you are receiving warfarin. Talk to a healthcare provider if you are uncertain about what foods or medications you take that may interact with warfarin. It is important to tell your doctor about all medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

When warfarin is given with enteral (tube) feedings, you may interrupt the feeding for one hour before and one hour after the warfarin dose to minimize potential for interaction. Feeding formulas containing soy protein should be avoided.

Ritonavir should be taken with food to lessen gastrointestinal side effects. It is important that you take this medication exactly as prescribed by your doctor. Do not change your treatment or stop treatment without first talking to your doctor.

Food significantly increases the absorption of paritaprevir. You should take each dose of paritaprevir with a meal. Taking it on an empty stomach may lead to inadequate blood levels and reduced effectiveness of the medication.

Using warfarin together with ethanol (alcohol) can cause you to bleed more easily. If you take warfarin you should avoid large amounts of alcohol, but moderate consumption (one to two drinks per day) are not likely to affect the response to warfarin if you have normal liver function. You may need a dose adjustment in addition to testing of your prothrombin time or International Normalized Ratio (INR). Call your doctor promptly if you have any unusual bleeding or bruising, vomiting, blood in your urine or stools, headache, dizziness, or weakness. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Rarely, vitamin supplements containing vitamin K may reduce the effectiveness of warfarin. This may be more likely to occur in individuals who have low levels of vitamin K in their blood. Before using any vitamin supplement, you should check the label to make sure it does not contain vitamin K. If it does, let your doctor know before you start using it. You may need more frequent monitoring of your INR after starting the supplement or whenever it is discontinued, and appropriate adjustments made in your dosage if necessary. It is important to tell your doctor about all other medications you use, including other nutritional supplements and herbs. Do not stop using any medications without first talking to your doctor.

As you stop smoking during treatment with nicotine, your dosage requirement of warfarin may need to be changed. Talk to your doctor if you have any questions or concerns. Your doctor may be able to prescribe alternatives that do not interact, or you may need a dose adjustment or more frequent monitoring by your doctor to safely use both medications. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

Therapy with oral anticoagulants should be administered cautiously in patients with severe diabetes because they may be at increased risk for hemorrhage. The INR should be monitored closely, and patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with malignant or severe, uncontrolled hypertension. These patients may be at increased risk for cerebral hemorrhage. Therapy with oral anticoagulants should be administered cautiously in patients with moderate hypertension.

HBV reactivation has been reported during or after completion of HCV direct-acting antiviral therapy in HCV/HBV-coinfected patients who were not receiving HBV antiviral therapy; some cases resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in hepatitis B surface antigen (HBsAg)-positive patients and patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and hepatitis B core antibody [anti-HBc] positive). HBV reactivation has also been reported in patients using certain immunosuppressant or chemotherapeutic agents; risk of HBV reactivation associated with HCV direct-acting antiviral therapy may be increased in these patients. All patients should be tested for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before starting HCV direct-acting antiviral therapy. Patients with serologic evidence of current or prior HBV infection should be monitored for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV therapy and posttherapy follow-up; appropriate patient management for HBV infection should be started as clinically indicated.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

HBV reactivation has been reported during or after completion of HCV direct-acting antiviral therapy in HCV/HBV-coinfected patients who were not receiving HBV antiviral therapy; some cases resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in hepatitis B surface antigen (HBsAg)-positive patients and patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and hepatitis B core antibody [anti-HBc] positive). HBV reactivation has also been reported in patients using certain immunosuppressant or chemotherapeutic agents; risk of HBV reactivation associated with HCV direct-acting antiviral therapy may be increased in these patients. All patients should be tested for evidence of current or prior HBV infection by measuring HBsAg and anti-HBc before starting HCV direct-acting antiviral therapy. Patients with serologic evidence of current or prior HBV infection should be monitored for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV therapy and posttherapy follow-up; appropriate patient management for HBV infection should be started as clinically indicated.

Oral anticoagulants (coumarin and indandione derivatives) are primarily metabolized by the liver. Patients with hepatic impairment may have a heightened response to these agents due to decreased clearance of the drugs as well as defective hemostasis associated with impaired synthesis of clotting factors by the liver. Therapy with oral anticoagulants should be administered cautiously in patients with severe or moderate liver disease. The INR should be monitored closely, and patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools

The use of drugs containing paritaprevir in combination with ombitasvir and ritonavir is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C). No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh A).

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with malignant or severe, uncontrolled hypertension. These patients may be at increased risk for cerebral hemorrhage. Therapy with oral anticoagulants should be administered cautiously in patients with moderate hypertension.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

Tissue necrosis is a rare complication that develops during the initiation of oral anticoagulant therapy due to thrombotic occlusion of venules in the dermis and subcutaneous tissues. Hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S, may be associated with a hypercoagulable state and an increased risk of the complication. Therapy with oral anticoagulants should be administered cautiously in patients with known or suspected deficiency in protein C-mediated anticoagulant response. Concomitant administration with heparin for the first 5 to 7 days of oral anticoagulant therapy may minimize the risk. If tissue necrosis develops, oral anticoagulant therapy should be discontinued promptly and vitamin K or frozen plasma administered at once. Heparin should then be considered for anticoagulation.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

In general, the use of oral anticoagulants is contraindicated in patients with active bleeding or a hemorrhagic diathesis or other significant risks for bleeding, including hemostatic and/or coagulation defects associated with hemophilia, hypoprothrombinemia, thrombocytopenia, thrombocytopathy, severe hepatic impairment, and myeloproliferative disorders such as leukemia or polycythemia vera. Additionally, oral anticoagulants are usually contraindicated in the presence of any active ulceration of the gastrointestinal, respiratory, or genitourinary tracts; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aortic); pericarditis and pericardial effusions; bacterial endocarditis; and eclampsia, preeclampsia, or threatened abortion. These patients may be at increased risk for uncontrollable hemorrhage or bleeding complications during therapy with oral anticoagulants. Other potential contraindications include diverticulitis, vasculitis, malnutrition, and vitamin C or vitamin K deficiency. The decision to administer anticoagulants must be based upon clinical judgment in which the risks are weighed against the benefits in each patient.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors; however, a causal relationship has not been established. In some patients, additional factor VIII was given. In more than half of the reported cases, protease inhibitor therapy was continued or reintroduced. Patients with hemophilia or other coagulation defects should be monitored closely for bleeding during protease inhibitor therapy.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Patients with edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism, or nephrotic syndrome may exhibit lower than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition.

Ritonavir may prolong the PR interval in some patients. Postmarketing cases of second or third degree atrioventricular block have been reported. Ritonavir should be administered with caution in patients with underlying structural heart disease, preexisting conduction abnormalities, ischemic heart disease, and cardiomyopathies as these patients might be at increased risk for developing cardiac conduction abnormalities.

Patients with edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism, or nephrotic syndrome may exhibit lower than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition.

Treatment with ritonavir alone or in combination with other protease inhibitors (e.g., lopinavir, saquinavir, tipranavir, fosamprenavir) has resulted in substantial increases in the concentration of total cholesterol and triglycerides. These effects have also been reported with other protease inhibitors but may be the most dramatic with ritonavir. The clinical significance of these elevations is unclear. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Triglyceride and cholesterol testing is recommended before starting ritonavir (with or without other protease inhibitors) and periodically during therapy. Lipid disorders should be managed as clinically appropriate.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

Patients with edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism, or nephrotic syndrome may exhibit lower than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition.

Hepatotoxicity (including jaundice, clinical hepatitis, and hepatic transaminase elevations exceeding 5 times the upper limit of normal) has been reported in patients receiving ritonavir alone or in combination with other antiretroviral drugs. Ritonavir should be administered with caution in patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis; increased monitoring of AST/ALT should be considered in these patients, especially during the first 3 months of ritonavir therapy. Ritonavir is not recommended for use in patients with severe liver dysfunction.

Patients with a collagen vascular disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), congestive heart failure (especially decompensated disease), severe or prolonged diarrhea, fever, hyperthyroidism, malabsorption, or steatorrhea may exhibit greater than expected hypoprothrombinemic response to oral anticoagulants. Thus, more frequent laboratory (PT/INR) monitoring and dosage adjustment of anticoagulant may be required based on changes in the patient's condition. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

There is no evidence that hypoprothrombinemic response to oral anticoagulants (coumarin and indandione derivatives) is altered in renal impairment due to decreased plasma protein binding, thus dosage adjustments are generally not necessary. However, patients with renal impairment may demonstrate platelet defects and may be at increased risk for bleeding. Therapy with oral anticoagulants should be administered cautiously in patients with severe or moderate renal dysfunction. The INR should be monitored closely, and patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.