Drug Interactions between ombitasvir / paritaprevir / ritonavir and upadacitinib

Consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit should be avoided during treatment with upadacitinib as they may increase the blood levels of upadacitinib, which may increase the risk and/or severity of side effects such as low blood cell counts, anemia, serious infections, and elevated blood lipid levels. Contact your doctor if you develop symptoms such as paleness, fatigue, dizziness, fainting, fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, or pain or burning during urination.

Smoking during treatment with upadacitinib may increase your risk of serious cardiovascular events and of developing malignancies. Tell your doctor if you are a current or past smoker. Talk to your doctor if you have any questions or concerns. Get emergency help right away if you develop any symptoms of a heart attack or stroke during treatment with upadacitinib, including severe tightness, pain, pressure, or heaviness in your chest, neck, or jaw; weakness in one side of your body; slurred speech; shortness of breath or feeling lightheaded. 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.

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

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.

Serious and sometimes fatal infections, including opportunistic and reactivation of infections have been reported in patients receiving upadacitinib treatment. It is recommended to avoid the use of upadacitinib in patients with an active, serious infection, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with upadacitinib. Interrupt therapy if a patient develops a new infection or an opportunistic infection and appropriate antimicrobial therapy should be initiated. Treatment with upadacitinib may be resumed once the infection is controlled.

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).

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

Malignancies (including lymphomas and solid tumors) have been reported in patients treated with tofacitinib, baricitinib, upadacitinib, deuruxolitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients who are current or past smokers are at additional increased risk of malignancies. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, pacritinib, and fedratinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), patients who develop a malignancy during therapy, and patients who are current or past smokers. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Thrombosis (including deep venous thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and arterial thrombosis) has occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including baricitinib, tofacitinib, deuruxolitinib and upadacitinib. Many of these adverse events were serious and some resulted in death. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, fedratinib, and pacritinib. In general, JAK inhibitors should be avoided in patients who may be at increased risk of thrombosis. Tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response when treating ulcerative colitis. If symptoms of thrombosis occur in any patients receiving JAK inhibitors, treatment should be discontinued and patients should be evaluated promptly and treated appropriately.

Serious and sometimes fatal infections, including opportunistic and reactivation of infections have been reported in patients receiving upadacitinib treatment. It is recommended to avoid the use of upadacitinib in patients with an active, serious infection, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with upadacitinib. Interrupt therapy if a patient develops a new infection or an opportunistic infection and appropriate antimicrobial therapy should be initiated. Treatment with upadacitinib may be resumed once the infection is controlled.

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.

The use of upadacitinib is associated with an increase incidence of neutropenia, lymphopenia, and anemia. Avoid initiation or interrupt treatment with upadacitinib in patients with low neutrophil counts (i.e., ANC less than 1000 cells/mm3), lymphocyte counts (i.e., less than 500 cells/mm3) and low hemoglobin levels (i.e., less than 8 g/dL). It is recommended to evaluate patients for abnormal blood cell counts at baseline and thereafter according to routine patient management.

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.

Gastrointestinal perforation has been reported with the use of upadacitinib. This agent should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). It is recommended to monitor for new onset abdominal symptoms for early identification of gastrointestinal perforation.

Gastrointestinal perforation has been reported with the use of upadacitinib. This agent should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). It is recommended to monitor for new onset abdominal symptoms for early identification of gastrointestinal perforation.

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 upadacitinib is associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Care should be exercised when using this agent in patients with hyperlipidemia. It is recommended to monitor patients after initiation of treatment, and thereafter according to the clinical guidelines and to manage patients accordingly.

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 upadacitinib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Treatment with upadacitinib is associated with increased incidence of liver enzyme elevation. Evaluate baseline liver function and thereafter according to routine patient management. Treatment should be interrupted if drug-induced liver injury is suspected.

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.

Use of live, attenuated vaccines during, or immediately prior to, upadacitinib therapy is not recommended. Prior to initiating treatment with upadacitinib, it is recommended that patients be brought up to date with all immunizations, including prophylactic zoster vaccinations, in agreement with current immunization guidelines.