Drug Interactions between ombitasvir / paritaprevir / ritonavir and tacrolimus

Grapefruit and grapefruit juice may increase the amount of tacrolimus in your body. This can lead to potentially dangerous side effects and should be avoided. If you are already consuming grapefruit products, do not increase or decrease the amount of these products in your diet without first talking to your doctor. You should also avoid the use of alcohol while being treated with tacrolimus to help prevent potentially dangerous side effects. Tacrolimus should be taken on a consistent schedule before or after you eat at the same time(s) each day. Talk to your doctor or pharmacist to make sure you know exactly how and when to take tacrolimus. 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.

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.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

Tacrolimus can induce post-transplant insulin-dependent diabetes mellitus (PTDM). Temporary insulin therapy has been required in some patients, while long-term insulin use has been necessary in others. Reversible insulin dependence has occurred in kidney and liver transplant patients. PTDM has occurred in a greater percentage of tacrolimus-treated (20%) versus cyclosporine-treated (4%) kidney transplant patients. Black and Hispanic patients are at increased risk for PTDM. Therapy with tacrolimus should be administered cautiously in patients with pre-transplant diabetes mellitus.

Tacrolimus may prolong the QT/QTc interval and may cause Torsade de Pointes. It is recommended to avoid tacrolimus in patients with congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia, consider monitoring of tacrolimus whole blood concentrations and obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment.

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.

Due to immunosuppression, patients receiving tacrolimus are at increased risk for infections, including polyoma virus infections, post-transplant lymphoproliferative disorder (PTLD) and CMV viremia and CMV disease. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML). Cases of PML have been reported in patients treated with tacrolimus. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. PTLD associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. Patients that are Epstein-Barr Virus (EBV) seronegative appears to have the greatest risk of developing PTLD. It is recommended to monitor EBV serology during tacrolimus therapy. Caution and patient monitoring is recommended when using this drug in immunosuppressed patients.

Due to immunosuppression, patients receiving tacrolimus are at increased risk for infections, including polyoma virus infections, post-transplant lymphoproliferative disorder (PTLD) and CMV viremia and CMV disease. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated progressive multifocal leukoencephalopathy (PML). Cases of PML have been reported in patients treated with tacrolimus. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. PTLD associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. Patients that are Epstein-Barr Virus (EBV) seronegative appears to have the greatest risk of developing PTLD. It is recommended to monitor EBV serology during tacrolimus therapy. Caution and patient monitoring is recommended when using this drug in immunosuppressed 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.

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).

Tacrolimus undergoes significant hepatic metabolism, primarily by CYP450 3A enzymes. Less than 5% of tacrolimus is eliminated unchanged in the bile and <1% is eliminated unchanged in the urine. Moderate or severe hepatic dysfunction or impaired post-transplant hepatic function may alter the metabolic and therapeutic activity of tacrolimus and increase the whole blood tacrolimus concentration. Therapy with tacrolimus should be administered cautiously and dosage adjustments considered in the presence of moderate or severe hepatic impairment.

Nephrotoxicity has been reported in 52% of kidney and 40% of liver transplant patients. Renal toxicity includes increasing serum creatinine and blood urea nitrogen, and renal failure sometimes requiring hemodialysis. Oliguria and hematuria also have been reported. The mechanism of tacrolimus-induced renal dysfunction is not well established. Renal toxicity appears to be dose-related, although toxicity may still occur even at suggested therapeutic concentrations. Therapy with tacrolimus should be administered cautiously and dosage reductions may be necessary in patients with compromised renal function. Alternative immunosuppressive therapy should be considered in the presence of persistent or worsening renal dysfunction.

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.

The use of tacrolimus has been associated with hyperkalemia. Therapy with tacrolimus should be administered cautiously in patients with elevated serum potassium levels. Close monitoring of potassium levels is recommended. Careful consideration should be given prior to use of other agents also associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) during tacrolimus therapy.

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.

The use of tacrolimus has been associated with hypertension. Therapy with tacrolimus should be administered cautiously in patients with elevated blood pressure. Close monitoring of blood pressure is recommended.

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.