warnings and cautions
5 WARNINGS AND PRECAUTIONS INVIRASE must be used in combination with ritonavir. Cobicistat is not interchangeable with ritonavir and is not recommended for use in combination with INVIRASE. ( 5.1 ) The concomitant use of INVIRASE/ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.2 , 7.3 ) QT and PR interval prolongations have been observed in a healthy volunteer study. Use with caution in patients with preexisting conduction system abnormalities and certain heart diseases. ( 5.3 , 5.4 , 12.2 ) Patients on INVIRASE therapy may develop new onset or exacerbations of diabetes mellitus ( 5.5 ), hyperglycemia ( 5.5 ), elevated cholesterol and/or triglyceride concentrations ( 5.6 ), redistribution/accumulation of body fat ( 5.10 ), and immune reconstitution syndrome ( 5.11 ). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. ( 5.8 ) In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease. ( 5.6 ) Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. ( 5.7 ) Each tablet contains lactose monohydrate. INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. ( 5.9 ) Various degrees of cross-resistance have been observed. ( 5.12 ) 5.1 Importance of Co-administration with Ritonavir INVIRASE must be used in combination with ritonavir . Refer to the ritonavir full prescribing information for additional precautionary measures. INVIRASE is not recommended for use in combination with cobicistat. Dosing recommendations for this combination have not been established. Cobicistat is also not recommended in combination with regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Refer to the cobicistat full prescribing information for additional precautionary measures. 5.2 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving INVIRASE/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of INVIRASE/ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of INVIRASE/ritonavir. Loss of therapeutic effect of INVIRASE/ritonavir and possible development of resistance. See Table 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during INVIRASE/ritonavir therapy; review concomitant medications during INVIRASE/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. For concomitantly used drugs including antiretroviral agents used in combination with INVIRASE/ritonavir, prescribers should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions. 5.3 PR Interval Prolongation INVIRASE/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre-existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients [see Warnings and Precautions (5.4) ] . Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occur. The impact on the PR interval of coadministration of INVIRASE/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, coadministration of INVIRASE/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2) ] . For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions. 5.4 QT Interval Prolongation INVIRASE/ritonavir causes dose-dependent QT prolongation. Torsade de pointes has been reported rarely post-marketing. Avoid INVIRASE/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating INVIRASE/ritonavir and monitor these electrolytes periodically during therapy. Do not use in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval (see Table 2 ) [see Clinical Pharmacology (12.2) ] . For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions [see Contraindications (4) and Drug Interactions (7) ]. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occurs. Patients initiating therapy with INVIRASE/ritonavir: An ECG should be performed prior to initiation of treatment. Patients with a QT interval ≥ 450 msec should not initiate treatment with INVIRASE/ritonavir. Treatment-naïve patients initiating treatment with INVIRASE/ritonavir should receive a reduced starting dose of INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment followed by INVIRASE/ritonavir 1000/100 mg twice daily due to potential for an increased risk of PR and QT interval prolongation with the standard 1000/100 mg twice daily dose [see Clinical Pharmacology (12.2) ] . For patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy. Discontinue INVIRASE/ritonavir in patients with a QT interval prolongation > 20 msec over pre-treatment. Patients requiring treatment with medications with the potential to increase the QT interval and concomitant INVIRASE/ritonavir: Such combinations should only be used where no alternative therapy is available, and the potential benefits outweigh the potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECG should be performed after 3–4 days of therapy. For patients demonstrating a subsequent increase in QT interval by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either INVIRASE/ritonavir or the concomitant therapy or both. A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment. 5.5 Diabetes Mellitus/Hyperglycemia New onset of diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established. 5.6 Hepatotoxicity In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism or other underlying liver abnormalities, there have been reports of worsening of the underlying liver disease and development of portal hypertension after starting INVIRASE/ritonavir. Jaundice and exacerbation of chronic liver disease with grade 4 elevated liver function tests were also observed. No dosage adjustment is necessary for patients with mild or moderate hepatic impairment based on limited data [see Clinical Pharmacology (12.3) ] . INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment [see Contraindications (4) ] . If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. 5.7 Hemophilia There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In the majority of reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established. 5.8 Hyperlipidemia Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of INVIRASE/ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate. 5.9 Lactose Intolerance Each tablet contains lactose (monohydrate) 38.5 mg. INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder). 5.10 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial wasting, peripheral wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.11 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE/ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 5.12 Resistance/Cross-resistance Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of INVIRASE/ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4) ] .