KALETRA (Brand for LOPINAVIR-RITONAVIR)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Tablets: May be taken with or without food. Administer whole; do not crush, break, or chew.

Oral Liquid Formulations
Oral solution
-Administer with food to enhance absorption.
-Always administer using a calibrated oral dosing syringe or the provided dosing cup. The oral solution is highly concentrated and contains lopinavir 80 mg/ritonavir 20 mg per mL. Pay close attention to dosage of the oral solution, especially in pediatric patients, to ensure appropriate administration and to avoid overdosage.
-The oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol; caution is advised when administering to patients 14 days to 6 months of age.
-The poor palatability of the oral solution may be difficult to overcome. Options to improve tolerability include numbing the taste buds with ice chips prior to administration, masking the taste by administering with sweet or tangy foods, chocolate syrup, or peanut butter, or flavoring the solution by the pharmacist prior to dispensing.
-Because the oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC), can be used for administration of lopinavir; ritonavir oral solution. Follow instructions for use of the feeding tube to administer the medication.

The adverse reaction profile for lopinavir; ritonavir was similar in pediatric patients as compared to adults during clinical trials.

Pancreatitis, in some cases fatal, has been observed in patients receiving treatment with lopinavir; ritonavir. Pancreatitis has been reported in pediatric patients, including reactions of moderate to severe intensity; it was reported in approximately 2% of adult patients in clinical trials. Marked triglyceride elevations with the development of pancreatitis have occurred with lopinavir; ritonavir. Patients with advanced HIV 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. If clinical symptoms (nausea/vomiting, abdominal pain) or lab abnormalities (hyperamylasemia or increased serum lipase) suggestive of pancreatitis occur, evaluate the patient and hold lopinavir; ritonavir and/or other antiretroviral therapy as clinically appropriate. In clinical trials of pediatric patients, hyperamylasemia (more than 2.5 times the upper limit of normal) was reported in 7% of patients. Elevated lipase (more than 2 times the upper limit of normal) was reported in 1% to 5% of adult patients.

Hyperlipidemia, with large increases in total cholesterol and triglyceride concentrations, has been reported during treatment with lopinavir; ritonavir. In clinical trials of pediatric patients who received the oral solution, hypercholesterolemia (more than 300 mg/dL) was reported in 3% of patients. Also, in adults, hypertriglyceridemia (more than 750 mg/dL) was reported in 3% to 36% of patients. Marked triglyceride elevations are a risk factor for development of pancreatitis; marked triglyceride elevations with the development of pancreatitis have occurred with lopinavir; ritonavir. Lipid disorders should be managed as clinically appropriate, taking potential drug interactions into account.

Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy including lopinavir; ritonavir. In adult trials, once daily dosing was associated with a higher incidence of diarrhea compared to twice daily dosing; however, pediatric patients should only receive twice daily dosage regimens. A total of 8 patients experienced an adverse reaction of moderate to severe intensity, which included vomiting, constipation, and dysgeusia. Nausea and abdominal pain were reported in approximately 5% to 10% of adult patients during clinical trials and gastroenteritis, colitis, and dyspepsia were reported in approximately 2% to 3% of patients. Other GI adverse reactions occurring in less than 2% of lopinavir; ritonavir-treated adults included abdominal distention, ageusia, constipation, duodenitis, fecal incontinence, flatulence, gastric or peptic ulcer, gastritis, gastroesophageal reflux disease, hemorrhoids, oral ulceration, rectal hemorrhage, stomatitis, and xerostomia.

Elevated hepatic enzymes have been reported during clinical trials of lopinavir; ritonavir, with elevations in SGOT/AST (8%) and SGPT/ALT (7%) reported in pediatric patients. Hyperbilirubinemia was reported in 3% of pediatric patients in trials. Hepatomegaly and jaundice have also occurred in pediatric patients. Additionally, in adults, hepatitis (3.5%), cholangitis (less than 1%), and hepatic steatosis (less than 1%) have been reported. Patients with underlying hepatitis B or C or marked transaminase elevations prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. There have been postmarketing reports of hepatic dysfunction, including some fatalities, which have generally occurred in patients with advanced HIV disease taking multiple concomitant medications and who have underlying chronic hepatitis or cirrhosis. However, elevated hepatic enzymes (with or without elevated bilirubin), leading to serious hepatic dysfunction in some cases, have been reported in patients without hepatitis.

Rash has been reported in pediatric patients receiving lopinavir; ritonavir during clinical trials. In 1 study in pediatric patients, the incidence of rash was 12%; however, lopinavir; ritonavir was dosed at higher than recommended doses (400/100 mg/m2 and 480/120 mg/m2). Dry skin (xerosis) and hypersensitivity were also reported in pediatric patients. Maculopapular rash was reported in approximately 4% of adult patients in clinical trials, and hypersensitivity reactions, including urticaria and angioedema, were reported in approximately 3% of patients. Other dermatologic reactions reported in less than 2% of adult patients in clinical trials include alopecia, dermatitis, eczema, night sweats, pruritus, and seborrhea. Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and erythema multiforme have been noted in postmarketing reports.

Fever has been noted in pediatric patients receiving lopinavir; ritonavir in clinical trials. Common musculoskeletal and generalized adverse reactions reported by approximately 5% to 10% of adults during clinical trials included fatigue, asthenia, arthralgia, and back pain. Other adverse reactions reported in less than 2% of adults included myalgia, muscle weakness and spasms (muscle cramps), rhabdomyolysis, and osteonecrosis. Elevated creatine phosphokinase (more than 4 times the upper limits of normal) was noted in 4% to 5% of adults in clinical trials.

Cardiovascular adverse reactions reported in less than 2% of adult patients receiving lopinavir; ritonavir in clinical trials included hypertension, deep vein thrombosis, AV block, myocardial infarction, tricuspid valve incompetence, and capillaritis and vasculitis. QT prolongation was reported in 2 pediatric patients in clinical trials; however, patients were receiving higher than recommended doses (400/100 mg/m2 and 480/120 mg/m2) and both patients had additional risk factors for QT prolongation (i.e., electrolyte abnormalities, concomitant medication, or preexisting cardiac conditions). Bradyarrhythmias (bradycardia), PR prolongation with second and third degree AV block, QT prolongation, and torsade de pointes have also been reported in postmarketing surveillance; however, causality has not been established. The FDA-approved product labeling recommends caution when administering lopinavir; ritonavir in patients with pre-existing structural heart disease and/or receiving other PR prolonging medications. Lopinavir; ritonavir was evaluated for QT prolongation in a randomized, placebo- and moxifloxacin- (400 mg once-daily) controlled, crossover study in 39 healthy adults; QT intervals were measured on the third day. Patients received lopinavir; ritonavir at normal doses (400 mg/100 mg twice daily) and at supratherapeutic doses (800 mg/200 mg twice daily). The maximum mean (95% upper confidence bound) difference in QT interval in patients versus placebo after baseline correction was 5.3 (8.1) milliseconds in patients receiving normal doses of lopinavir; ritonavir and 15.2 (18.0) milliseconds in patients receiving supratherapeutic doses. Lopinavir; ritonavir 800 mg/200 mg twice daily resulted in a Cmax that was 2-fold higher than that observed with approved once and twice daily regimens at steady state.

Headache and migraine, anxiety, insomnia, peripheral neuropathy, and dizziness were reported in approximately 2% to 5% of adult patients receiving lopinavir; ritonavir during clinical trials. Other adverse reactions affecting the nervous system and special senses occurring in less than 1% of adults included abnormal dreams, cerebral vascular event, convulsion or seizures, tinnitus, tremor, vertigo, and visual impairment.

Neutropenia (neutrophil counts less than 0.4 x 109/L) was reported in 2% of pediatric patients who received lopinavir; ritonavir during clinical trials. In a trial of 31 pediatric patients 14 days to 6 months of age, a decreased neutrophil count was noted in 3 patients and anemia was reported in 2 patients. In addition, 4% of pediatric patients reported thrombocytopenia (platelet counts less than 50,000/mm3). Other adverse reactions reported in 2% or less of adults during clinical trials included hemoglobin counts of less than 80 g/L, leukopenia, and lymphadenopathy.

Increased bleeding, including spontaneous skin hematoma and hemarthrosis, has been reported in HIV infected patients with hemophilia (type A and B) being treated with protease inhibitors. The majority of the patients have been able to continue taking their protease inhibitor therapy in spite of the bleeding events; some patients received additional coagulation factor. A causal relationship with lopinavir; ritonavir has not been established. More serious bleeding episodes, such as GI bleeding, were reported in less than 1% of adult patients during clinical trials.

A lipodystrophy syndrome (approximately 2% in adult clinical trials), consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, breast enlargement, gynecomastia, and other cushingoid features, has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes protease inhibitors. This syndrome may be associated with metabolic complications such as insulin resistance and dyslipidemia, but not always. Some studies indicate that up to 5% to 30% of patients receiving protease inhibitors may develop lipodystrophy. The mechanism and long-term consequences are not known. A casual relationship has not been established. Changes in HAART to reverse lipodystrophy should probably be avoided unless the patient finds the changes in body fat intolerable and more conservative interventions fail.

Anorexia or decreased appetite with weight loss was observed in approximately 2% of adult patients during clinical trials. Other metabolic and nutritional disorders reported in less than 1% of adults included appetite stimulation, weight gain, and lactic acidosis.

In clinical trials, hyperglycemia (glucose more than 250 mg/dL) was observed in 1% to 5% and diabetes mellitus was observed in approximately 1% of adult patients receiving lopinavir; ritonavir in combination with other antiretrovirals. New-onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with postmarketing use of protease inhibitors (PI). Diabetic ketoacidosis has also occurred. Initiation or adjustment of hypoglycemic therapy is required in some patients after beginning PI treatment. In some patients who have discontinued PI therapy, hyperglycemia has persisted. A causal relationship with these events has not been established. It should also be noted that many of these patients have confounding medical conditions that require therapy with drugs that have been associated with the development of diabetes mellitus or hyperglycemia.

In clinical trials of pediatric patients who received lopinavir; ritonavir oral solution, hypernatremia (sodium more than 149 mEq/L) and hyponatremia (less than 130 mEq/L) were reported in 3% of patients each. In a trial of 31 patients 14 days to 6 months of age, high potassium (hyperkalemia) and low sodium were each reported in 2 patients. Additional laboratory abnormalities reported during adult clinical trials include hypophosphatemia (2% or less) and hyperuricemia (5% or less).

Viral infection has been reported in pediatric patients during lopinavir; ritonavir clinical trials. Upper or lower respiratory infections were reported in approximately 5% to 15% of adult patients in clinical trials. Skin infections, including cellulitis, folliculitis, and furunculosis, occurred in approximately 3% of patients.

Renal and urinary disorders reported in less than 2% of adult patients in clinical trials included renal failure (unspecified), hematuria, and nephritis. Creatinine clearance of less than 50 mL/minute was noted in 2% to 3% of adult patients in trials. Cases of nephrolithiasis have been reported during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Menstrual disorders, including amenorrhea and menorrhagia, and male gonadal suppression were reported in less than 2% and less than 1%, respectively, of adult patients receiving lopinavir; ritonavir during clinical trials.

Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake, or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable serum concentrations of efavirenz and nevirapine range from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Use lopinavir; ritonavir with caution in patients with pre-existing hepatic disease, liver enzyme abnormalities, or hepatitis. Patients with underlying hepatitis B or C or marked elevations in liver enzymes prior to treatment may be at increased risk for developing further enzyme elevations or hepatic decompensation. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis; however, elevated hepatic enzymes (with or without elevated bilirubin), leading to serious hepatic dysfunction in some cases, have been reported in patients without underlying hepatitis as early as 7 days after the initiation of lopinavir; ritonavir. A causal relationship has not been established. Consider increased monitoring of LFTs in these patients, especially during the first several months of treatment. In addition, screen all patients presenting with HIV infection for hepatitis B and HIV coinfection to assure appropriate treatment. Begin patients who are coinfected with HIV and HBV and require treatment for either infection on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, use another agent with anti-HBV activity in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Hyperlipidemia is a recognized side effect of protease inhibitor-based regimens. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with lopinavir; ritonavir include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.

Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition with lopinavir; ritonavir treatment. In some cases, diabetic ketoacidosis has occurred. Further, reports of new onset diabetes mellitus have been associated with protease inhibitor therapy. Either initiation or dose adjustments of insulin or oral hyperglycemic agents may be required. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

Use protease inhibitors, such as lopinavir; ritonavir, cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A casual relationship has not been established.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of lopinavir; ritonavir after loss of viral suppression may increase the likelihood of resistance to other protease inhibitors.

Administering lopinavir; ritonavir oral solution to neonates with a postnatal age of younger than 14 days and/or a postmenstrual age (first day of the mother's last menstrual period to birth plus the time since birth) of younger than 42 weeks may result in significant alcohol and propylene glycol-related toxicities; use is not recommended. If the benefits of using the oral solution in infants immediately after birth outweigh the potential risk, the manufacturer recommends monitoring for increases in serum osmolarity, serum creatinine, and for adverse events such as hyperosmolarity, lactic acidosis, renal toxicity, CNS depression (stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias (ECG changes), and hemolysis. When dosing and administering the oral solution to any pediatric patient, use caution to avoid an overdosage. The solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol; an accidental overdosage by a young child could result in significant propylene glycol or alcohol-related toxicities including death. For patients between the ages of 14 days and 6 months, health care providers are advised to calculate the total amounts of alcohol and propylene glycol from all medications that are being administered to the patient.

Ritonavir prolongs the PR interval in some patients, and postmarketing cases of second- or third-degree AV block have been reported. Lopinavir; ritonavir should be used with caution in patients with cardiac disease such as congenital heart disease, underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, and cardiomyopathy, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval has not been evaluated; however, concomitant administration with such drugs should be undertaken with caution, particularly with those drugs metabolized by cytochrome P450 3A4 isoenzymes. Clinical monitoring is recommended.

Cases of QT prolongation and torsade de pointes (TdP) have been reported with postmarketing surveillance. In general, lopinavir; ritonavir should not be used unmonitored in patients with known QT prolongation, with ongoing proarrhythmic conditions that may increase the risk of developing TdP, or receiving drugs that prolong the QT interval. Obtain a pre-treatment QTc using a standard 12-lead ECG, telemetry, or mobile ECG device. Obtain baseline electrolytes, including calcium, magnesium, and potassium. Determine if the patient is currently on any QT-prolonging medications that can be discontinued. Document high-risk cardiovascular and comorbid conditions. If the baseline QTc is 500 msec or more and/or the patient has an inherent tendency to develop an exaggerated QTc response (i.e., change of 60 msec or more), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and proceed with close QTc surveillance. Obtain an initial on-therapy QTc approximately 2 to 4 hours after the first dose and then again at 48 and 96 hours after treatment initiation. If the baseline QTc is 460 to 499 msec (prepubertal), 470 to 499 msec (postpubertal males), or 480 to 499 msec (postpubertal females), correct contributing electrolyte abnormalities, review and discontinue other unnecessary QTc prolonging medications, and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation. If the baseline QTc is less than 460 msec (prepubertal), less than 470 msec (postpubertal males), or less than 480 msec (postpubertal females), correct electrolyte abnormalities and obtain an initial on-therapy QTc 48 and 96 hours after treatment initiation. Use lopinavir; ritonavir with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia, or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Description: Lopinavir is an antiretroviral protease inhibitor. It is formulated with a small amount of ritonavir to increase and maintain adequate lopinavir concentrations; lopinavir is the active component of the lopinavir; ritonavir formulation. Responses to lopinavir; ritonavir have been reported in treatment-naive patients and in patients who have failed other therapies. Lopinavir; ritonavir is indicated to treat HIV-1 infection in pediatric patients as part of combination therapy. Lopinavir ritonavir is approved for use in neonates at least 14 days old with a postmenstrual age of 42 weeks; the tablets are approved in pediatric patients older than 6 months of age who can swallow the tablets whole.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-For treatment-naive infants (14 days and older and postmenstrual age of 42 weeks or more) and children younger than 3 years, lopinavir boosted with ritonavir in combination with a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option is a recommended protease inhibitor (PI)-based treatment regimen for initial therapy. For treatment-naive children 3 years and older, lopinavir boosted with ritonavir with a 2-NRTI backbone option is an alternative PI-based treatment regimen.
-For treatment-naive adolescents, lopinavir boosted with ritonavir is NOT recommended as initial therapy. Boosted darunavir (generally preferred) or atazanavir is the recommended PI for a PI-based regimen. However, lopinavir; ritonavir in combination with lamivudine or emtricitabine is a regimen that may be used as initial therapy in patients unable to take abacavir or tenofovir.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
NOTE: Lopinavir; ritonavir should not be administered once daily in pediatric patients due to inferior efficacy observed with once daily dosing compared with twice daily dosing.
Oral dosage (solution):
Neonates 42 weeks postmenstrual age and older and 14 to 29 days postnatal age: 300 mg lopinavir; 75 mg ritonavir per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg lopinavir; 4 mg ritonavir per kg/dose PO twice daily may be used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants 1 to 6 months: 300 mg lopinavir; 75 mg ritonavir per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg lopinavir; 4 mg ritonavir per kg/dose PO twice daily may be used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants 7 to 11 months: 300 mg lopinavir; 75 mg ritonavir per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg lopinavir; 4 mg ritonavir per kg/dose PO twice daily may also be used. The FDA-approved dose is 230 mg lopinavir; 57.5 mg ritonavir per m2/dose PO twice daily or a weight based dose of 12 mg lopinavir; 3 mg ritonavir per kg/dose PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children weighing less than 15 kg: 300 mg lopinavir; 75 mg ritonavir per m2/dose (13 mg lopinavir; 3.25 mg ritonavir per kg/dose) PO twice daily. May consider 230 mg lopinavir; 57.5 mg ritonavir per m2/dose (12 mg lopinavir; 3 mg ritonavir per kg/dose) PO twice daily for antiretroviral-naive patients. The FDA-approved dose is 230 mg lopinavir; 57.5 mg ritonavir per m2/dose PO twice daily or a weight-based dose of 12 mg lopinavir; 3 mg ritonavir per kg/dose PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 15 to 45 kg: 300 mg lopinavir; 75 mg ritonavir per m2/dose (11 mg lopinavir; 2.75 mg ritonavir per kg/dose) PO twice daily. May consider 230 mg lopinavir; 57.5 mg ritonavir per m2/dose (10 mg lopinavir; 2.5 mg ritonavir per kg/dose) PO twice daily for antiretroviral-naive patients. The FDA-approved dose is 230 mg lopinavir; 57.5 mg ritonavir per m2/dose PO twice daily or a weight-based dose of 10 mg lopinavir; 2.5 mg ritonavir per kg/dose PO twice daily. Max: 400 mg lopinavir; 100 mg ritonavir per dose. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing more than 45 kg: 400 mg lopinavir; 100 mg ritonavir PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (tablets):
Children weighing 15 to 20 kg: 200 mg lopinavir; 50 mg ritonavir PO twice daily (for a BSA target of 300 mg lopinavir; 75 mg ritonavir per m2/dose or 230 mg lopinavir; 57.5 mg ritonavir per m2/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children weighing 21 to 25 kg: 300 mg lopinavir; 75 mg ritonavir PO twice daily (for a BSA target of 300 mg lopinavir; 75 mg ritonavir per m2/dose) or 200 mg lopinavir; 50 mg ritonavir PO twice daily (for a BSA target of 230 mg lopinavir; 57.5 mg ritonavir per m2/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children weighing 26 to 30 kg: 300 mg lopinavir; 75 mg ritonavir PO twice daily (for a BSA target of 300 mg lopinavir; 75 mg ritonavir per m2/dose or 230 mg lopinavir; 57.5 mg ritonavir per m2/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 31 to 35 kg: 400 mg lopinavir; 100 mg ritonavir PO twice daily (for a BSA target of 300 mg lopinavir; 75 mg ritonavir per m2/dose) or 300 mg lopinavir; 75 mg ritonavir PO twice daily (for a BSA target of 230 mg lopinavir; 57.5 mg ritonavir per m2/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents weighing 36 kg or more: 400 mg lopinavir; 100 mg ritonavir PO twice daily (for a BSA target of 300 mg lopinavir; 75 mg ritonavir per m2/dose or 230 mg lopinavir; 57.5 mg ritonavir per m2/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For human immunodeficiency virus (HIV) prophylaxis*:
-for human immunodeficiency virus (HIV) prophylaxis* to prevent mother-to-child transmission (MTCT) during breastfeeding:
NOTE: Lopinavir; ritonavir is an alternative option for infants who cannot tolerate zidovudine or nevirapine or for breastfeeding parents with viral resistance to nevirapine. For high-risk infants, treatment should start after completion of 6 weeks of presumptive HIV therapy.
Oral dosage (solution):
Neonates 42 weeks postmenstrual age and older and 14 to 29 days postnatal age: 300 mg lopinavir; 75 mg ritonavir per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg lopinavir; 4 mg ritonavir per kg/dose PO twice daily may be used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Optimal treatment duration has not been established. For low-risk infants, some recommend 2 to 6 weeks of treatment while others recommend continuing treatment throughout breastfeeding and 1 to 4 weeks after weaning. For high-risk infants, treatment should continue during breastfeeding and for 1 to 4 weeks after weaning to minimize the risk of transmission.
Infants: 300 mg lopinavir; 75 mg ritonavir per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg lopinavir; 4 mg ritonavir per kg/dose PO twice daily may be used. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Optimal treatment duration has not been established. For low-risk infants, some recommend 2 to 6 weeks of treatment while others recommend continuing treatment throughout breastfeeding and 1 to 4 weeks after weaning. For high-risk infants, treatment should continue during breastfeeding and for 1 to 4 weeks after weaning to minimize the risk of transmission.
-for human immunodeficiency virus (HIV) prophylaxis* after nonoccupational exposure, including sexual assault:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis. Lopinavir; ritonavir is not part of preferred or alternative regimens in adolescents.
Oral dosage (solution):
Infants and Children 4 weeks to 1 year: 300 mg/75 mg per m2/dose or 16 mg/4 mg per kg/dose PO twice daily in combination with zidovudine and lamivudine for 28 days is a preferred HIV post-exposure prophylaxis (PEP) regimen in infants and children younger than 2 years. Lopinavir/ritonavir in combination with zidovudine and emtricitabine is an alternative regimen. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing less than 15 kg: 12 mg/3 mg per kg/dose PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 15 to 40 kg: 10 mg/2.5 mg per kg/dose PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing more than 40 kg: 400 mg/100 mg PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Oral dosage (tablets):
Children 2 to 12 years weighing 15 to 25 kg: 200 mg/50 mg PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing 26 to 35 kg: 300 mg/75 mg PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 2 to 12 years weighing more than 35 kg: 400 mg/100 mg PO twice daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 2 years and older. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 5,500 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs


Maximum Dosage Limits:
-Neonates
younger than 42 weeks postmenstrual age or 0 to 13 days postnatal age: Not recommended.
42 weeks postmenstrual age and older and 14 to 29 days postnatal age: 32 mg/8 mg per kg/day PO or 600 mg/150 mg per m2/day PO for oral solution.
-Infants
1 to 6 months: 32 mg/8 mg per kg/day PO or 600 mg/150 mg per m2/day PO oral solution.
7 to 11 months: 24 mg/6 mg per kg/day PO or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day is recommended by guidelines.
-Children
weight less than 15 kg: 24 mg/6 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day is recommended by guidelines. Safety and efficacy of other formulations have not been established.
weight 15 to 20 kg: 400 mg/100 mg per day PO for tablets; 20 mg/5 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution is recommended by guidelines.
weight 21 to 25 kg: 400 mg/100 mg per day PO for tablets; 20 mg/5 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution or 600 mg/150 mg per day for oral tablets is recommended by guidelines.
weight 26 to 30 kg: 600 mg/150 mg per day PO for tablets; 20 mg/5 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day oral solution is recommended by guidelines.
weight 31 to 35 kg: 600 mg/150 mg per day PO for tablets; 20 mg/5 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution or 800 mg/200 mg per day for oral tablets is recommended by guidelines.
weight 36 to 40 kg: 800 mg/200 mg per day PO for tablets; 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution (Max: 800 mg/200 mg per day) is recommended by guidelines.
weight more than 40 kg: 800 mg/200 mg per day PO for tablets; 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution (Max: 800 mg/200 mg per day) is recommended by guidelines.
-Adolescents
weight 31 to 35 kg: 600 mg/150 mg per day PO for tablets; 20 mg/5 mg per kg/day or 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day oral solution or 800 mg/200 mg per day for oral tablets is recommended by guidelines.
weight 36 to 40 kg: 800 mg/200 mg per day PO for tablets; 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution (Max: 800 mg/200 mg per day) is recommended by guidelines.
weight more than 40 kg: 800 mg/200 mg per day PO for tablets; 460 mg/115 mg per m2/day PO for oral solution is recommended in the FDA-approved labeling; however, up to 600 mg/150 mg per m2/day for oral solution (Max: 800 mg/200 mg per day) is recommended by guidelines.

Patients with Hepatic Impairment Dosing
Dosing in patients with hepatic impairment has not been studied. Since lopinavir is hepatically metabolized, a reduction in dosage may be necessary; however, specific dosing is not available.

Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: In HIV-infected patients, administration of lopinavir 400 mg; ritonavir 100 mg BID yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir, with plasma levels of ritonavir less than 7% of those obtained after administration of ritonavir 600 mg BID. The in vitro antiviral EC50 (the mean 50% effective concentration) of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of lopinavir; ritonavir is due to lopinavir. Lopinavir is a competitive inhibitor of HIV protease, an enzyme involved in the replication of HIV. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages).

Pharmacokinetics: Lopinavir; ritonavir is administered orally. Lopinavir is approximately 98% protein bound to alpha1-acid glycoprotein and albumin, with a greater affinity for alpha1-acid glycoprotein. It undergoes oxidative metabolism via the hepatic cytochrome CYP450 system, almost exclusively by the CYP3A isozyme. Ritonavir inhibits CYP3A, thereby increasing plasma concentrations of lopinavir. At least 13 lopinavir oxidative metabolites have been identified in humans. Ritonavir has been shown to induce its own metabolism. Trough lopinavir concentrations decline with time during multiple dosing stabilizing after approximately 10 to 16 days. The half-life of lopinavir is 6.9 +/- 2.2 hours. The majority of lopinavir is excreted as metabolites in the feces (82%), with about 10% of the dose appearing in the urine.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2B6, Organic Anion Transporting Polypeptide 1B1 (OATP1B1), P-glycoprotein (P-gp), glucuronosyl transferase (UGT)
When given as single agents, lopinavir is a substrate of CYP3A4 and an inhibitor of the drug transporter OATP1B1. Ritonavir is a substrate, inducer, and potent inhibitor of CYP3A4 (in vivo and in vitro), a partial substrate and minor inhibitor of CYP2D6, and a substrate and inhibitor of P-gp. Ritonavir also appears to induce CYP1A2 and UGT. According to the manufacturer, ritonavir may induce CYP2C9, CYP2C19, and CYP2B6. Ritonavir has been associated with many clinically significant drug interactions; however, the magnitude and effect of ritonavir on the pharmacokinetics of coadministered drugs are difficult to predict due to various CYP enzymes that are affected and the potential of ritonavir to induce or inhibit these enzymes. Interactions with drugs that are substrates of multiple CYP enzymes or that have a low intrinsic CYP3A clearance are especially difficult to predict. Drugs metabolized by CYP3A4 are expected to have large (greater than 3-fold) increases in the AUC when coadministered with ritonavir; drugs metabolized by CYP2D6 may display up to a 2-fold increase in AUC when coadministered with treatment doses of ritonavir. However, according to the manufacturer of lopinavir; ritonavir, the booster dose of ritonavir used in the combination product is unlikely to cause inhibition of CYP2D6.


-Route-Specific Pharmacokinetics
Oral Route
Relative to fasting, administration of the oral solution with a high fat meal increases lopinavir AUC and Cmax by 130% and 56% respectively; when administered with a moderate fat meal, there is an increase in lopinavir AUC and Cmax by 80% and 54% respectively. To enhance bioavailability and minimize pharmacokinetic variability, administer the oral solution with food. Relative to fasting, administration of the tablets with a high fat meal increased lopinavir AUC by 18.9% with no effect on Cmax; when administered with a moderate fat meal there is an increase in lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. These pharmacokinetic alterations were not found to be clinically relevant, and the tablets may be taken with or without food.


-Special Populations
Pediatrics
Neonates and Infants 1 to 5 months
The clearance of lopinavir; ritonavir is dependent on weight and postmenstrual age in neonates and infants and decreases with increasing age. The pharmacokinetics of the oral solution at a dose of approximately 300 mg/75 mg/m2 twice daily have been evaluated in infants 14 days and older to younger than 6 weeks of age (n = 9) and between 6 weeks and 6 months of age (n = 18). The mean steady-state lopinavir AUC, Cmax, and trough were 43.4 +/- 14.8 mcg x hour/mL, 5.2 +/- 1.8 mcg/mL, and 2.5 mcg/mL, respectively, in neonates and infants 14 days and older to younger than 6 weeks of age. The mean half-life was 3.67 +/- 1.46 hours. The mean lopinavir AUC, Cmax, and trough were 74.5 +/- 37.9 mcg x hour/mL, 9.4 +/- 4.9 mcg/mL, and 2.7 mcg/mL, respectively, in infants between 6 weeks and 6 months of age. The mean half-life was 4.24 +/- 2.83 hours.

Infants 6 to 11 months, Children, and Adolescents
The clearance of lopinavir; ritonavir is higher in younger children and decreases with increasing age. Children have a lower drug exposure of lopinavir; ritonavir compared with adults when treated with doses that are directly scaled for body surface areas (BSA). The directly scaled dose of 230 mg/57.5 mg/m2 of lopinavir; ritonavir would be comparable to the adult dose of 400 mg/100 mg; however, younger children have increased lopinavir clearance and higher doses of the drug would be needed to achieve drug exposures similar to adults with standard dosing. The pediatric dose needs to be increased by 30% to achieve similar trough concentrations compared to those observed in adults. In a study of pediatric patients ranging in age from 6 months to 12 years, the mean lopinavir trough concentration was 4.74 +/- 2.93 mcg/mL for doses of 230 mg/57.4 mg/m2 (n = 12), while the mean trough concentration was 7.91 +/- 4.52 mcg/mL for doses of 300 mg/75 mg/m2 (n = 15) compared to the adult value of 7.1 +/- 4.52 mcg/mL. In a study of 23 children, aged 4.8 months to 13 years treated with lopinavir; ritonavir 230 mg/57.5 mg/m2, the mean AUC and Cmin were lower than those observed in adults treated with doses of 400 mg/100 mg. Additionally, a Cmin of less than 1 mg/L was noted in 7 patients (5 patients younger than 2 years and 2 patients older than 2 years, p = 0.011). Lower age was significantly correlated with a lower Cmin (p = 0.003) and AUC (p = 0.009). The mean half-life reported in studies was 5.8 to 7.6 hours.

Hepatic Impairment
Lopinavir is extensively metabolized by the liver; hepatic dysfunction alters the pharmacokinetic parameters of lopinavir; ritonavir. In 1 small study, multiple doses of 400 mg/100 mg lopinavir; ritonavir were given twice daily to HIV and HCV coinfected patients with mild to moderate hepatic impairment (n = 12). An evaluation of the data found the AUC and Cmax of lopinavir to be increased by 30% and 20%, respectively, compared to HIV-infected patients with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was significantly lower in both mild and moderate hepatic impairment compared to controls (99.09% vs. 99.31%, respectively). Lopinavir; ritonavir has not been studied in patients with severe hepatic impairment.

Renal Impairment
Pharmacokinetics of lopinavir; ritonavir are not altered in patients with renal dysfunction. Lopinavir pharmacokinetics have not been studied in patients with renal impairment, although no change in total clearance is expected in patients with renal dysfunction.