Drug Interactions between nintedanib and ombitasvir / paritaprevir / ritonavir

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.

Grapefruit juice and Seville orange juice can increase the blood levels of nintedanib. This may increase the risk and/or severity of side effects such as liver problems, diarrhea, nausea, vomiting, stomach or intestinal wall perforation, bleeding, and cardiovascular problems such as heart attack, chest pain, or stroke. It is best to avoid or minimize the consumption of grapefruit, grapefruit juice, Seville orange, or Seville orange juice during treatment. You should take nintedanib with food and swallow it whole with water. Taking nintedanib with food may help with absorption of the medication and reduce gastrointestinal side effects. You may also take it with a small amount (teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, but it must be swallowed whole (unchewed) immediately to ensure the capsule stays intact. 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.

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.

Nintedanib may increase the risk of bleeding. Nintedanib should only be used in patients with known risk of bleeding if the anticipated benefit outweighs the potential risk. Close monitoring is recommended.

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.

Nintedanib may increase the risk of gastrointestinal perforation. Use caution when treating patients who have had recent abdominal surgery or history of diverticular disease. It is recommended to discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Nintedanib should only be used in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. Care and close monitoring is recommended.

Nintedanib may increase the risk of gastrointestinal perforation. Use caution when treating patients who have had recent abdominal surgery or history of diverticular disease. It is recommended to discontinue therapy with nintedanib in patients who develop gastrointestinal perforation. Nintedanib should only be used in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk. Care and close monitoring is recommended.

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.

Arterial thromboembolic events, including myocardial infarction have been reported in patients taking nintedanib. It is recommended to exercise caution when treating patients at higher cardiovascular risk, including known coronary artery disease and to consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

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.

Arterial thromboembolic events, including myocardial infarction have been reported in patients taking nintedanib. It is recommended to exercise caution when treating patients at higher cardiovascular risk, including known coronary artery disease and to consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

The use of nintedanib is associated with elevations of liver enzymes. Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment. Patients with mild hepatic impairment can be treated with a reduced dose of nintedanib. It is recommended to conduct liver function tests prior to treatment with nintedanib and periodically thereafter as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations as clinically indicated and according to medical practices.

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.

Based on a population pharmacokinetics analysis of nintedanib, exposure to nintedanib is not influenced by mild or moderate renal impairment. No dose adjustment is required in patients with mild to moderate renal impairment. Care and close monitoring is recommended when using this agent in patients with severe renal impairment and end-stage renal disease as the safety, efficacy, and, pharmacokinetics of nintedanib have not been studied these patients.

Smoking is associated with decreased exposure to nintedanib. Patients that are smokers might alter the efficacy profile of nintedanib. Encourage patients that are smokers to stop smoking prior to treatment because it might alter the efficacy profile of nintedanib and to avoid smoking while on therapy.

Arterial thromboembolic events, including myocardial infarction have been reported in patients taking nintedanib. It is recommended to exercise caution when treating patients at higher cardiovascular risk, including known coronary artery disease and to consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.