Drug Interactions between ombitasvir / paritaprevir / ritonavir and tenofovir alafenamide

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.

Information for this minor interaction is available on the professional version.

Hepatotoxicity including lactic acidosis, severe hepatomegaly with steatosis, fulminant hepatitis, and hepatic failure has been associated with the use of some nucleoside reverse transcriptase inhibitors (NRTIs) alone or in combination with other antiretroviral agents. Therapy with NRTIs should be administered cautiously in patients with preexisting liver disease, a history of alcohol abuse, or hepatitis. Therapy should be suspended if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. The use of abacavir is contraindicated in patients with moderate to severe liver dysfunction as its safety and efficacy have not been established in these patients.

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.

Severe acute exacerbations of HBV have been reported in HIV-1/HBV-coinfected patients who have discontinued products containing emtricitabine, lamivudine, and/or tenofovir disoproxil fumarate (DF) and may occur with discontinuation of tenofovir alafenamide-containing products. It is recommended that all patients with HIV-1 infection be tested for the presence of HBV before or when initiating products containing emtricitabine, lamivudine, tenofovir DF, or tenofovir alafenamide. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HIV-1/HBV-coinfected patients who discontinue products (including fixed-dose combination products) that contain emtricitabine, lamivudine, tenofovir DF, or tenofovir alafenamide. If appropriate, initiation or resumption of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

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.

Hepatotoxicity including lactic acidosis, severe hepatomegaly with steatosis, fulminant hepatitis, and hepatic failure has been associated with the use of some nucleoside reverse transcriptase inhibitors (NRTIs) alone or in combination with other antiretroviral agents. Therapy with NRTIs should be administered cautiously in patients with preexisting liver disease, a history of alcohol abuse, or hepatitis. Therapy should be suspended if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. The use of abacavir is contraindicated in patients with moderate to severe liver dysfunction as its safety and efficacy have not been established in these patients.

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).

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.

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.

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.

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.

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.

Tenofovir alafenamide (as a single ingredient product) is not recommended in patients with decompensated liver dysfunction (Child-Pugh B or C); safety and efficacy have not been established in these patients. No dose adjustment of tenofovir alafenamide is required in patients with mild liver dysfunction (Child-Pugh A).
-Combination products containing tenofovir alafenamide have not been studied in patients with severe liver dysfunction; some of these products are not recommended for use in such patients. No dose adjustment of tenofovir alafenamide-containing products is required in patients with mild or moderate liver dysfunction (Child-Pugh A or B).

The pharmacokinetics of tenofovir after a single 300 mg dose of tenofovir disoproxil fumarate (DF) have been studied in non-HIV infected subjects with moderate to severe liver dysfunction. There were no significant changes in tenofovir pharmacokinetics in subjects with liver dysfunction compared to those with normal liver function. No adjustment in tenofovir DF dosing is required in patients with liver dysfunction.

In clinical trials, tenofovir disoproxil fumarate (DF) was associated with slightly greater reductions in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk have not been established. Calcium and vitamin D supplementation may be beneficial; however, the effect of such supplementation was not studied. Assessment of BMD should be considered for patients with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, appropriate consultation should be obtained.

Tenofovir is primarily eliminated by the kidneys via glomerular filtration and active tubular secretion. Serum creatinine, estimated CrCl, urine glucose, and urine protein should be assessed in all patients before/when starting tenofovir (alafenamide or disoproxil fumarate [DF]) and during therapy when clinically appropriate. Serum phosphorus should also be assessed in patients with chronic kidney disease.

Postmarketing cases of renal impairment (including acute renal failure, proximal renal tubulopathy, and Fanconi syndrome) have been reported with tenofovir alafenamide-containing products; most cases had potential confounders that may have contributed to the reported renal events and may have predisposed patients to tenofovir-related side effects. Tenofovir alafenamide should be discontinued in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Renal impairment (including acute renal failure and Fanconi syndrome) has been reported with tenofovir DF. Close monitoring of renal function and dosing interval adjustment are recommended for all patients with CrCl less than 50 mL/min. Creatinine clearance should be calculated in all patients before starting tenofovir treatment and during treatment when clinically appropriate. Routine monitoring of serum creatinine and phosphorus is recommended for patients at risk of or with a history of renal dysfunction. Safety and efficacy have not been evaluated in patients with renal dysfunction using dose adjustments; therefore, the benefit of tenofovir DF treatment should be weighed against the risk of renal toxicity. Renal function should be evaluated in patients at risk of renal dysfunction who have persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness (may be indicators of proximal renal tubulopathy).

In clinical trials, tenofovir disoproxil fumarate (DF) was associated with slightly greater reductions in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk have not been established. Calcium and vitamin D supplementation may be beneficial; however, the effect of such supplementation was not studied. Assessment of BMD should be considered for patients with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected, appropriate consultation should be obtained.