warnings and cautions
The following have been observed in patients receiving KALETRA: ● Drug Interactions: Consider drug-drug interaction potential to reduce risk of serious or life-threatening adverse reactions. ( 5.1 ) ● Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate. ( 5.2 ) ● Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations. ( 5.3 , 8.6 ) ● PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution in patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval. ( 5.1 , 5.5 , 12.3 ) ● QT interval prolongation and isolated cases of torsade de pointes have been reported although causality could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval. ( 5.1 , 5.6 , 12.3 ) ● Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia ( 5.4 ), immune reconstitution syndrome ( 5.7 ), redistribution/accumulation of body fat. ( 5.8 ) ● Total cholesterol and triglycerides elevations. Monitor prior to therapy and periodically thereafter. ( 5.9 ) ● Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. ( 5.10 ) 5.1 Drug Interactions See Tables 3 and 9 for listing of drugs that are contraindicated for use with KALETRA due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity [see Contraindications ( 4 ) and Drug Interactions ( 7 )] . 5.2 Pancreatitis Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis [see Warnings and Precautions ( 5.9 )] . Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate. 5.3 Hepatotoxicity Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment [see Use In Specific Populations ( 8.6 )]. 5.4 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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 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. 5.5 PR Interval Prolongation Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of co-administration of KALETRA 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, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Clinical Pharmacology ( 12.3 )] . 5.6 QT Interval Prolongation Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval [see Clinical Pharmacology ( 12.3 )] . 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. 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 jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment. 5.8 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial 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. 5.9 Lipid Elevations Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions ( 6.1 )] . Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.3 )]. 5.10 Patients with Hemophilia Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established. 5.11 Resistance/Cross-resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors [see Clinical Pharmacology ( 12.4 )].