Ritonavir Disease Interactions

There have been postmarketing reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in types A and B hemophiliac patients 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 following an interruption. Hemophiliacs and patients with other coagulation defects should be monitored closely for bleeding during protease inhibitor therapy.

Hepatotoxicity, including jaundice, hepatitis and hepatic transaminase elevations exceeding five times the upper limit of normal, has been reported in patients receiving ritonavir alone and in combination with nucleoside reverse transcriptase inhibitors or other protease inhibitors. In addition, ritonavir is primarily metabolized by the liver and may accumulate in patients with hepatic impairment. Therapy with ritonavir should be administered cautiously in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis. Ritonavir is not recommended for patients with severe hepatic impairment.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, glucose intolerance, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors (PIs). In some cases, glucose abnormalities/hyperglycemia persisted despite discontinuation of PI therapy. Frequently, insulin resistance may accompany fat redistribution and serum lipid elevations in what is collectively termed the HIV-associated lipodystrophy syndrome. Although a causal relationship has not been established, these metabolic disturbances have most often occurred in HIV-infected patients during treatment with potent antiretroviral regimens containing PIs. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during PI therapy. Dosage adjustments in insulin or oral hypoglycemic medications may be necessary in patients with diabetes.

Hyperlipidemia has been observed in 10% of patients receiving ritonavir during clinical trials. Increases of 30% to 40% from baseline have been reported for total cholesterol and 200% to 300% or more for triglycerides. These effects have also been reported during postmarketing experience with other protease inhibitors (PIs) but may be the most dramatic with ritonavir. The clinical significance of these elevations is unclear. Severe hyperlipidemia is known to sometimes cause pancreatitis. In addition, some patients have reportedly developed symptomatic atherosclerosis and coronary artery disease after initiating PI treatment. Patients with preexisting hyperlipidemia may require closer monitoring during PI therapy, and adjustments made accordingly in their lipid-lowering regimen. PI therapy should be administered cautiously in patients with coronary artery disease or a history of ischemic heart disease.

Ritonavir may prolong the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported. Ritonavir should be administered cautiously 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.