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  • CLASSES

    Protease Inhibitor Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    A protease inhibitor (PI)
    Indicated to treat HIV-1 infection when used in combination with other antiretroviral agents
    Available as an oral solution and as full-strength and half-strength tablets

    COMMON BRAND NAMES

    Kaletra

    HOW SUPPLIED

    Kaletra Oral Tab: 100-25mg, 200-50mg
    Kaletra/Lopinavir, Ritonavir Oral Sol: 1mL, 80-20mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    NOTE: The following abbreviations are used: nucleoside reverse transcriptase inhibitors (NRTIs); nonnucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs).
    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 (tablets)
    Adults

    400 mg/100 mg PO twice daily. Alternatively, 800 mg/200 mg PO once daily may be administered to patients with less than 3 lopinavir resistance-associated substitutions. NOTE: See dosing below for concomitant efavirenz, nelfinavir, nevirapine, carbamazepine, phenobarbital, or phenytoin therapy.

    Adult pregnant females

    400 mg/100 mg PO twice daily in patients with no documented lopinavir resistance-associated substitutions; there are insufficient data to recommend dosing in pregnant women with any lopinavir resistance-associated substitutions. HIV guidelines suggest increasing dose to 500 mg/125 mg or 600 mg/150 mg PO twice daily may be necessary in the 2nd and 3rd trimesters, especially for PI-experienced women and women with baseline viral loads more than 50 copies/mL. Once daily dosing is NOT recommended.

    Children and Adolescents weighing more than 35 kg

    400 mg/100 mg PO twice daily (for a BSA target of 300 mg/75 mg per m2/dose or 230 mg/57.5 mg per m2/dose). NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Children and Adolescents weighing 31 to 35 kg

    400 mg/100 mg PO twice daily (for a BSA target of 300 mg/75 mg per m2/dose) or 300 mg/75 mg PO twice daily (for a BSA target of 230 mg/57.5 mg per m2/dose). NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Children weighing 26 to 30 kg

    300 mg/75 mg PO twice daily (for a BSA target of 300 mg/75 mg per m2/dose or 230 mg/57.5 mg per m2/dose). NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Children weighing 21 to 25 kg

    300 mg/75 mg PO twice daily (for a BSA target of 300 mg/75 mg per m2/dose) or 200 mg/50 mg PO twice daily (for a BSA target of 230 mg/57.5 mg per m2/dose). NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine

    Children weighing 15 to 20 kg

    200 mg/50 mg PO twice daily (for a BSA target of 300 mg/75 mg per m2/dose or 230 mg/57.5 mg per m2/dose). NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Adults receiving concomitant carbamazepine, phenobarbital, or phenytoin

    400 mg/100 mg PO twice daily. Do NOT administer once daily dosing.

    Adults receiving concomitant efavirenz, nelfinavir, or nevirapine

    500 mg/125 mg PO twice daily. Some experts would use 600 mg/150 mg PO twice daily for ease of tablet dosing.

    Children and Adolescents weighing more than 45 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    500 mg/125 mg PO twice daily. Some experts would use 600 mg/150 mg PO twice daily for ease of tablet dosing.

    Children and Adolescents weighing 31 to 45 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    400 mg/100 mg PO twice daily.

    Children weighing 21 to 30 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    300 mg/75 mg PO twice daily.

    Children weighing 15 to 20 kg oreceiving concomitant efavirenz, nelfinavir, or nevirapine

    200 mg/50 mg PO twice daily.

    Oral dosage (oral solution)
    Adults

    400 mg/100 mg PO twice daily. Alternatively, 800 mg/200 mg PO once daily may be administered to patients with less than 3 lopinavir resistance-associated substitutions. The oral solution should be avoided during pregnancy due to the alcohol content. NOTE: See dosing below for concomitant efavirenz, nelfinavir, nevirapine, carbamazepine, phenobarbital, or phenytoin therapy.

    Children and Adolescents

    300 mg/75 mg per m2/dose PO twice daily is routinely used by many clinicians, especially for treatment-experienced patients; however, 230 mg/57.5 mg per m2/dose PO twice daily can be used for antiretroviral-naive patients. The manufacturer recommends 230 mg/57.5 mg per m2/dose PO twice daily. Alternatively, a weight based dose of 12 mg/3 mg per kg/dose PO twice daily for patients weighing less than 15 kg or 10 mg/2.5 mg per kg/dose PO twice daily for patients weighing 15 kg or more may be used. The maximum recommended dose is 400 mg/100 mg per dose. NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Infants 7 to 11 months

    300 mg/75 mg per m2/dose PO twice daily is recommended by the HIV guidelines. The manufacturer, however, recommends 230 mg/57.5 mg per m2/dose PO twice daily. Alternatively, a weight based dose of 12 mg/3 mg per kg/dose PO twice daily for patients weighing less than 15 kg or 10 mg/2.5 mg per kg/dose PO twice daily for patients weighing 15 kg or more may be used. Adjust doses frequently to accommodate growth. NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Neonates 14 to 29 days postnatal age and 42 weeks postmenstrual age or older and Infants 1 to 6 months

    300 mg/75 mg per m2/dose PO twice daily. Alternatively, a weight-based dose of 16 mg/4 mg per kg/dose PO twice daily may also be used. Adjust doses frequently to accommodate growth. Be aware of alcohol and propylene glycol intake; oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. NOTE: See dosing below for concomitant efavirenz, nelfinavir, or nevirapine therapy.

    Adults receiving concomitant carbamazepine, phenobarbital, or phenytoin

    400 mg/100 mg PO twice daily. Do NOT administer once daily dosing.

    Adults receiving concomitant efavirenz, nelfinavir, or nevirapine

    520 mg/130 mg PO twice daily.

    Children and Adolescents weighing more than 45 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    520 mg/130 mg PO twice daily.

    Infants 7 to 11 months, Children, and Adolescents weighing 15 to 45 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    11 mg/2.75 mg per kg/dose (or 300 mg/75 mg per m2/dose) PO twice daily.[28341]

    Infants 7 to 11 months and Children weighing less than 15 kg receiving concomitant efavirenz, nelfinavir, or nevirapine

    13 mg/3.25 mg per kg/dose (or 300 mg/75 mg per m2/dose) PO twice daily.

    Neonates 14 to 29 days postnatal age and 42 weeks postmenstrual age or older and Infants 1 to 6 months receiving concomitant efavirenz, nelfinavir, or nevirapine

    Lopinavir; ritonavir is not recommended in combination with these drugs.

    For human immunodeficiency virus (HIV) prophylaxis†.
    For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure.
    Oral dosage
    Adults

    The World Health Organization (WHO) recommends lopinavir; ritonavir 400 mg/100 mg PO twice daily in combination with tenofovir and either emtricitabine or lamivudine as preferred HIV post-exposure prophylaxis (PEP) regimens. Alternative lopinavir; ritonavir dosing is 800 mg/200 mg PO once daily. The US Public Health Service guidelines and the New York State Department of Health AIDS Institute (NYSDOH AI) recommend lopinavir; ritonavir with either tenofovir or zidovudine and either emtricitabine or lamivudine as alternative PEP regimens. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    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.
    Oral dosage (solution)
    Children weighing more than 40 kg

    400 mg/100 mg PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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 years and older weighing 15 to 40 kg

    10 mg/2.5 mg per kg/dose PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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 years and older weighing less than 15 kg

    12 mg/3 mg per kg/dose PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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.

    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 for 28 days in combination with zidovudine and lamivudine 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.

    Oral dosage (tablets)
    Children weighing more than 35 kg

    400 mg/100 mg PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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 weighing 26 to 35 kg

    300 mg/75 mg PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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 years and older weighing 15 to 25 kg

    200 mg/50 mg PO twice daily for 28 days in combination with tenofovir and emtricitabine or zidovudine and lamivudine 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.

    INVESTIGATIONAL USE: For the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection†, the virus that causes coronavirus disease 2019 (COVID-19)†.
    Oral dosage
    Adults

    Due to unfavorable pharmacodynamics and negative clinical trial data, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend against the use of lopinavir; ritonavir in hospitalized and non-hospitalized patients. Studies have evaluated the use of lopinavir 400 mg/ritonavir 100 mg PO twice daily for 10 to 14 days based on retrospective cohorts, historically controlled studies, case reports, and case series for other coronavirus infections, including the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Some low-level evidence suggests use may reduce the incidence of mortality associated with acute respiratory distress syndrome (ARDS).[65116] [65117] [65118] [65123] However, in a retrospective cohort study of hospitalized patients, no difference was noted in the duration of viral shedding after treatment with lopinavir; ritonavir (n = 29).[65146] Additionally, data from randomized trials involving hospitalized patients have found no clinical benefit with lopinavir; ritonavir as compared to usual standard of care alone. 

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: The following maximum dosage limits apply for typical lopinavir; ritonavir use; maximum dosage limits may be altered based on certain individual patient circumstances, such as in the case of specific drug interactions.

    Adults

    800 mg/200 mg per day PO.

    Geriatric

    800 mg/200 mg per day PO.

    Adolescents

    more than 40 kg: 800 mg/200 mg per day.
    36 to 40 kg: 800 mg/200 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 (Max: 800 mg/200 mg per day) is recommended in the HIV guidelines.
    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 in the HIV guidelines.

    Children

    more than 40 kg: 800 mg/200 mg per day PO.
    36 to 40 kg: 800 mg/200 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 (Max: 800 mg/200 mg per day) is recommended in the HIV guidelines.
    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 in the HIV guidelines.
    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 in the HIV guidelines.
    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 in the HIV guidelines.
    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 in the HIV guidelines.
    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 in the HIV guidelines. Safety and efficacy of the tablet formulation have not been established.

    Infants

    older than 6 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 in the HIV guidelines. Safety and efficacy of the tablet formulation have not been established.
    6 months or younger: 32 mg/8 mg per kg/day PO or 600 mg/150 mg per m2/day PO for oral solution. Safety and efficacy of the tablet formulation have not been established.

    Neonates

    14 days postnatal age or older and 42 weeks postmenstrual age or older: 32 mg/8 mg per kg/day PO or 600 mg/150 mg per m2/day PO for oral solution. Safety and efficacy of other formulations have not been established.
    younger than 14 days or postmenstrual age younger than 42 weeks: Not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Lopinavir is metabolized by the liver. Use caution and close monitoring when administering to patients with mild to moderate hepatic impairment (Child-Pugh A and B), as increased drug concentrations may occur. Use in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent Hemodialysis
    Avoid once-daily dosing in patients on hemodialysis.

    ADMINISTRATION

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

    Oral Administration
    Oral Solid Formulations

    Tablets: May be taken with or without food. Administered 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 approximately 42% (v/v) alcohol and 15% (w/v) propylene glycol; caution is advised when administering to patients 14 days to 6 months of age. Additionally, the oral solution should be avoided during pregnancy due to the alcohol content.[42452]
    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.[42452]
    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.[28341]

    STORAGE

    Kaletra:
    - Avoid excessive heat (above 104 degrees F)
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Store and dispense in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake, severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, 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 ranges 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 the patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

    Hepatitis, hepatitis B and HIV coinfection

    Lopinavir; ritonavir should be used with caution in patients with pre-existing hepatitis. Patients with underlying hepatitis prior to treatment may be at increased risk for developing further enzyme elevations or hepatic decompensation. All patients presenting with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide with emtricitabine or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Alcoholism, hepatic disease, jaundice

    Lopinavir; ritonavir should be used with caution in patients with pre-existing hepatic disease (e.g., alcoholism), liver enzyme abnormalities (e.g., jaundice), 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 case, have been reported in patients without underlying hepatitis as early as 7 days after the initiation of lopinavir; ritonavir. Of note, lopinavir; ritonavir was initiated with other antiretrovirals. A causal relationship has not been established. Increased monitoring of LFTs should be considered in these patients, especially during the first several months of treatment.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, pancreatitis

    Patients with advanced acquired immunodeficiency syndrome (AIDS) may be at increased risk for developing hypertriglyceridemia and pancreatitis. Patients who exhibit signs or symptoms of pancreatitis (nausea, vomiting, abdominal pain, abnormal serum lipase or amylase concentrations) should discontinue treatment with lopinavir; ritonavir. Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of protease inhibitors. Triglyceride and cholesterol testing should be performed prior to beginning lopinavir; ritonavir and at regular intervals during treatment. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during treatment with a protease inhibitor, possible interventions include dietary modification, use of lipid lowering agents, or discontinuation of the protease inhibitor. Clinicians should be aware of the potential drug interaction between certain cholesterol-lowering agents and the lopinavir; ritonavir combination.

    Diabetes mellitus, diabetic ketoacidosis, hyperglycemia

    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. Drug recipients should be monitored closely for new-onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

    Hemophilia

    Protease inhibitors such as lopinavir; ritonavir should be used 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 causal relationship has not been established.

    Human immunodeficiency virus (HIV) infection resistance

    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. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. 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 result kept in the patient's medical record until it becomes 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 following loss of viral suppression may increase the likelihood of antimicrobial resistance to other protease inhibitors.

    Children, infants, neonates

    Administering lopinavir; ritonavir oral solution to neonates with a postnatal age of less than 14 days or a postmenstrual age (first day of the mother's last menstrual period to birth plus the time since birth) of less 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 outweighs 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 approximately 42% (v/v) alcohol and 15% (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 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 patient. In children, lopinavir; ritonavir dosages are either based on weight or body surface area (BSA). Typically, a child younger than 12 years will receive less than 5 mL of solution, unless certain enzyme-inducing drugs are prescribed or the child weighs 40 kg or more; the oral solution is highly concentrated and contains lopinavir 80 mg/ritonavir 20 mg per mL. In infants and children 6 months to 12 years of age, the adverse events reported during clinical trials were similar to adults.

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. Due to an increased risk of preterm birth, which may lead to an increase in infant morbidity and mortality, lopinavir; ritonavir is not recommended for initiation during pregnancy (except in special circumstances). For women who conceive while on a suppressive, well-tolerated lopinavir; ritonavir regimen, treatment should continue; however, lopinavir; ritonavir must be given twice daily during pregnancy. Once daily lopinavir; ritonavir dosing is NOT recommended in pregnancy. No dosing adjustment is required for patients during the postpartum period. Avoid use of lopinavir; ritonavir oral solution during pregnancy due to the alcohol content.[28341] [47165] Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,430 first trimester exposures to lopinavir-containing regimens, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When lopinavir; ritonavir exposures occurred in the first trimester, the prevalence of defects was 2.1% (95% CI: 1.4 to 3.0). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to lopinavir; ritonavir; information about the registry can be obtained at http://www.apregistry.com/ or by calling 1-800-258-4263.[23512] [27468] [28341]

    Breast-feeding

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] There are limited data regarding lopinavir; ritonavir use of during breast-feeding, and excretion into human breast milk is unknown. In 1 study, breast milk from mothers receiving lopinavir; ritonavir were analyzed with high-performance liquid chromatography and tandem mass spectrometry; the analysis failed to detect either drug in any of the 60 samples. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    AV block, cardiac disease, cardiomyopathy

    Ritonavir prolongs the PR interval in some patients, and postmarketing cases of 2nd- or 3rd-degree AV block have been reported. Lopinavir; ritonavir should be used with caution in patients with cardiac disease such as 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 (including calcium channel blockers, beta-adrenergic blockers, digoxin, and atazanavir) 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.

    Apheresis, bradycardia, celiac disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Cases of QT prolongation and torsade de pointes (TdP) have been reported during 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.[28341] [51080] 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.[65170] 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. [28432] [28457] [56592] [65180]

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    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 progressive multifocal leukoencephalopathy (PML), 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.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / 1.7-1.7
    renal failure (unspecified) / Delayed / 1.2-1.2
    rhabdomyolysis / Delayed / 0.7-0.7
    thrombosis / Delayed / 0.7-0.7
    GI bleeding / Delayed / 0.5-0.5
    myocardial infarction / Delayed / 0.4-0.4
    lactic acidosis / Delayed / 0.4-0.4
    seizures / Delayed / 0.3-0.3
    visual impairment / Early / 0.3-0.3
    peptic ulcer / Delayed / 0.2-0.2
    osteonecrosis / Delayed / 0.1-0.1
    vasculitis / Delayed / 0.1-0.1
    AV block / Early / 0.1-0.1
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 3.0-39.0
    hyperlipidemia / Delayed / 3.0-39.0
    hypertriglyceridemia / Delayed / 3.0-36.0
    elevated hepatic enzymes / Delayed / 1.0-11.0
    hyperamylasemia / Delayed / 3.0-8.0
    neutropenia / Delayed / 1.0-5.0
    hyperglycemia / Delayed / 1.0-5.0
    hyperuricemia / Delayed / 0-5.0
    thrombocytopenia / Delayed / 4.0-4.0
    hepatitis / Delayed / 3.5-3.5
    hyperbilirubinemia / Delayed / 1.0-3.0
    hyponatremia / Delayed / 3.0-3.0
    hypernatremia / Delayed / 3.0-3.0
    colitis / Delayed / 2.5-2.5
    lipodystrophy / Delayed / 2.2-2.2
    anemia / Delayed / 2.1-2.1
    peripheral neuropathy / Delayed / 2.0-2.0
    hypophosphatemia / Delayed / 0-2.0
    hypertension / Early / 1.8-1.8
    impotence (erectile dysfunction) / Delayed / 1.7-1.7
    leukopenia / Delayed / 1.7-1.7
    hemorrhoids / Delayed / 1.5-1.5
    lymphadenopathy / Delayed / 1.3-1.3
    diabetes mellitus / Delayed / 1.1-1.1
    constipation / Delayed / 1.0-1.0
    oral ulceration / Delayed / 0.9-0.9
    stomatitis / Delayed / 0.9-0.9
    gastritis / Delayed / 0.8-0.8
    hematuria / Delayed / 0.8-0.8
    fecal incontinence / Early / 0.2-0.2
    hepatomegaly / Delayed / 0.2-0.2
    steatosis / Delayed / 0.1-0.1
    cholangitis / Delayed / 0.1-0.1
    jaundice / Delayed / Incidence not known
    furunculosis / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    PR prolongation / Rapid / Incidence not known
    migraine / Early / Incidence not known
    bleeding / Early / Incidence not known
    hematoma / Early / Incidence not known
    nephrolithiasis / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 22.0-22.0
    vomiting / Early / 6.8-21.0
    diarrhea / Early / 12.0-19.5
    infection / Delayed / 3.3-13.9
    rash / Early / 3.8-12.0
    nausea / Early / 10.3-10.3
    fatigue / Early / 7.6-7.6
    asthenia / Delayed / 7.6-7.6
    back pain / Delayed / 6.4-6.4
    arthralgia / Delayed / 6.4-6.4
    headache / Early / 6.3-6.3
    abdominal pain / Early / 6.1-6.1
    anxiety / Delayed / 3.9-3.9
    insomnia / Early / 3.8-3.8
    weight loss / Delayed / 2.3-2.3
    dyspepsia / Early / 2.0-2.0
    anorexia / Delayed / 2.0-2.0
    seborrhea / Delayed / 1.9-1.9
    myalgia / Early / 1.8-1.8
    amenorrhea / Delayed / 1.7-1.7
    menorrhagia / Delayed / 1.7-1.7
    dizziness / Early / 1.7-1.7
    night sweats / Early / 1.6-1.6
    gastroesophageal reflux / Delayed / 1.5-1.5
    flatulence / Early / 1.4-1.4
    weakness / Early / 1.3-1.3
    pruritus / Rapid / 1.1-1.1
    gonadal suppression / Delayed / 0.8-0.8
    weight gain / Delayed / 0.8-0.8
    libido decrease / Delayed / 0.7-0.7
    alopecia / Delayed / 0.4-0.4
    xerostomia / Early / 0.3-0.3
    tremor / Early / 0.3-0.3
    vertigo / Early / 0.3-0.3
    tinnitus / Delayed / 0.2-0.2
    appetite stimulation / Delayed / 0.2-0.2
    maculopapular rash / Early / Incidence not known
    xerosis / Delayed / Incidence not known
    fever / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    Cushingoid features / Delayed / Incidence not known
    folliculitis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
    Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
    Abacavir; Lamivudine, 3TC: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. (Minor) Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
    Abemaciclib: (Major) If coadministration with ritonavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If ritonavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of ritonavir. Abemaciclib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
    Acebutolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
    Acetaminophen: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Acetaminophen; Butalbital: (Major) Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. (Moderate) Barbiturates may increase the metabolism of lopinavir and lead to decreased antiretroviral efficacy. In addition, coadministration of lopinavir boosted with ritonavir may induce the CYP metabolism of barbiturates, resulting in decreased barbiturate concentrations. Appropriate dose adjustments necessary to ensure optimum levels of both anti-retroviral agent and the barbiturate are unknown; however, once daily lopinavir; ritonavir should not be used. Anticonvulsant serum conce