Drug Interactions between ombitasvir / paritaprevir / ritonavir and zanubrutinib

Grapefruit juice and Seville orange juice can increase the blood levels of zanubrutinib. This may increase side effects such as rash, diarrhea, constipation, cough, hemorrhage, development of other cancers, abnormal heart rhythm, and impaired bone marrow function resulting in low numbers of different types of blood cells. You may also be more likely to develop anemia, bleeding problems, or infections due to low blood cell counts. You should avoid the consumption of grapefruit, grapefruit juice, Seville oranges (a citrus relative of the grapefruit), and Seville orange juice during treatment with zanubrutinib. You may need a dose adjustment, interruption, or more frequent monitoring to safely use both medications. Be sure to take the medication at approximately the same time(s) every day to maintain consistent blood levels and effects. Talk to your doctor or pharmacist if you have questions on how to take this or other medications you are prescribed. 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.

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.

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).

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.

Fatal and serious hemorrhage have occurred in patients with hematological malignancies treated with zanubrutinib monotherapy. Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Special care should be taken when this agent is coadministered with antiplatelet or anticoagulant medications as coadministration may further increase the risk of hemorrhage. It is recommended to monitor for signs/symptoms of bleeding and to discontinue zanubrutinib if intracranial hemorrhage of any grade occurs. The benefit-risk of withholding zanubrutinib for 3 to 7 days before and after surgery (depending on the type of surgery and the risk of bleeding) should be considered.

Cytopenias (including neutropenia, thrombocytopenia, and anemia [based on laboratory measurements]) were reported in patients treated with zanubrutinib monotherapy. Care should be taken when using this agent in patients with hematological abnormalities. It is recommended to monitor complete blood counts during therapy and interrupt treatment, reduce the dose, or discontinue zanubrutinib as warranted. Growth factor or transfusions should be used as treatment, as needed.

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.

Serious cardiac arrhythmias have been reported with zanubrutinib. Atrial fibrillation and atrial flutter have occurred in patients treated with zanubrutinib monotherapy. Care should be exercised when using this agent in patients with cardiac risk factors, hypertension, and acute infections as they may be at increased risk of cardiac arrhythmias. It is recommended to monitor for signs/symptoms of cardiac arrhythmias, manage appropriately, and consider the risks and benefits of continued treatment with zanubrutinib.

The effect of dialysis on zanubrutinib pharmacokinetics is unknown. Patients on dialysis should be monitored for zanubrutinib adverse reactions. No dosage modification is recommended in patients with mild, moderate, or severe renal dysfunction (CrCl at least 15 mL/min, estimated by Cockroft-Gault).

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.

Serious cardiac arrhythmias have been reported with zanubrutinib. Atrial fibrillation and atrial flutter have occurred in patients treated with zanubrutinib monotherapy. Care should be exercised when using this agent in patients with cardiac risk factors, hypertension, and acute infections as they may be at increased risk of cardiac arrhythmias. It is recommended to monitor for signs/symptoms of cardiac arrhythmias, manage appropriately, and consider the risks and benefits of continued treatment with zanubrutinib.

Serious cardiac arrhythmias have been reported with zanubrutinib. Atrial fibrillation and atrial flutter have occurred in patients treated with zanubrutinib monotherapy. Care should be exercised when using this agent in patients with cardiac risk factors, hypertension, and acute infections as they may be at increased risk of cardiac arrhythmias. It is recommended to monitor for signs/symptoms of cardiac arrhythmias, manage appropriately, and consider the risks and benefits of continued treatment with zanubrutinib.

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with zanubrutinib monotherapy. Infections due to hepatitis B virus reactivation have occurred. Prophylaxis for herpes simplex virus, Pneumocystis jirovecii pneumonia, and other infections according to standard of care should be considered in patients who are at increased risk for infections. Patients should be monitored and evaluated for fever or other signs/symptoms of infection and treated appropriately.

The safety of zanubrutinib has not been evaluated in patients with severe liver dysfunction (Child-Pugh C); dosage modification of zanubrutinib is recommended in these patients. The recommended dosage for patients with severe liver dysfunction is 80 mg orally twice a day. No dosage modification is recommended in patients with mild to moderate liver dysfunction (Child-Pugh A and B). Patients with liver dysfunction should be monitored for zanubrutinib adverse reactions.

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.

The effect of dialysis on zanubrutinib pharmacokinetics is unknown. Patients on dialysis should be monitored for zanubrutinib adverse reactions. No dosage modification is recommended in patients with mild, moderate, or severe renal dysfunction (CrCl at least 15 mL/min, estimated by Cockroft-Gault).