AHFS Class:

• HIV Protease Inhibitors 8:18.08.08

Generic Name(s):

• Lopinavir and Ritonavir

Lopinavir and ritonavir (lopinavir/ritonavir) is a fixed combination of 2 human immunodeficiency virus (HIV) protease inhibitors (PIs);1,6,34 ritonavir, a potent inhibitor of hepatic cytochrome P-450 (CYP) 3A isoenzyme, decreases metabolism and increases plasma concentrations of lopinavir.1,5,6,34

Treatment of HIV Infection

The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 14 days of age and older.1

Genotypic or phenotypic testing and/or treatment history should be used to guide the use of lopinavir/ritonavir.1 The number of baseline lopinavir resistance-associated substitutions affects virologic response to lopinavir/ritonavir.1

Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200

Clinical Experience

Antiretroviral-naïve Adults

Results of a study in treatment-naïve adults indicate that a regimen of lopinavir/ritonavir administered once daily in conjunction with 2 NRTIs (tenofovir DF and emtricitabine) is at least as effective as a regimen of lopinavir/ritonavir administered twice daily in conjunction with 2 NRTIs (tenofovir DF and emtricitabine) for initial treatment.1,300 In this randomized, open-label, multicenter study (Study 730), 664 antiretroviral-naïve adults were randomized in a 1:1 ratio to receive a once-daily regimen of lopinavir/ritonavir (lopinavir 800 mg/ritonavir 200 mg once daily) in conjunction with tenofovir DF (300 mg once daily) and emtricitabine (200 mg once daily) or a twice-daily regimen of lopinavir/ritonavir (400/100 mg twice daily) in conjunction with tenofovir DF (300 mg once daily) and emtricitabine (200 mg once daily).1 The primary outcome was viral response as the proportion of patients achieving an HIV-1 RNA level of <50 copies/mL at 48 weeks.300

Enrolled patients had a mean age of 39 years, with a mean baseline HIV-1 RNA level of 5.0 log₁₀ copies/mL and a mean CD4⁺ T-cell count of 216 cells/mm³.1 Through 48 weeks, 78% of those receiving the once-daily lopinavir/ritonavir regimen and 77% of those receiving the twice-daily lopinavir/ritonavir regimen achieved and maintained plasma HIV-1 RNA levels <50 copies/mL.1 At 48 weeks, the mean increase in CD4⁺ T-cell count from baseline was 186 cells/mm³ in those receiving the once-daily regimen and 198 cells/mm³ in those receiving the twice-daily regimen.1

Results at 96 weeks showed no differences between the treatment groups, with 64.9 and 69.2% of patients in the once-daily and twice-daily lopinavir/ritonavir regimens achieving a viral response (HIV-1 RNA <50 copies/mL), respectively.301 Viral suppression was maintained at 96 weeks in 85.0 and 80.7% of patients in the once-daily and twice-daily lopinavir/ritonavir regimens, respectively.301 Mean increases in CD4⁺ T-cell count from baseline to 96 weeks were similar between groups (238.4 and 254.0 cells/mm³ in the once-daily and twice-daily lopinavir/ritonavir regimens, respectively).301

A second study in 653 treatment-naïve adults, Study 863, was a randomized (1:1 ratio), double-blind, multicenter trial comparing lopinavir/ritonavir (400/100 mg twice daily) plus stavudine and lamivudine to nelfinavir (750 mg 3 times daily) plus stavudine and lamivudine.1,302 The primary outcome was virologic response, as the proportion of patients achieving an HIV-RNA level <400 copies/mL at week 24 and the loss of virologic response at week 48.302

Enrolled patients had a mean age of 38 years, with a mean baseline HIV-1 RNA level of 4.9 log₁₀ copies/mL and a mean CD4⁺ T-cell count of 259 cells/mm³.1 Through 24 weeks, 79% of patients given lopinavir/ritonavir achieved a virologic response compared with 71% of those given nelfinavir.302 At 48 weeks, corresponding response rates were 75 and 62%.1 An HIV-1 RNA level <50 copies/mL was observed in 67 and 52% of those receiving lopinavir/ritonavir and those receiving nelfinavir, respectively.1 For durability of virologic response, 84% of patients given lopinavir/ritonavir and 66% of patients given nelfinavir had a response that persisted through week 48.302 Mean increases from baseline to 48 weeks in CD4⁺ T-cell count were 207 and 195 cells/mm³ for the lopinavir/ritonavir and nelfinavir regimens, respectively.1

A third clinical trial, Study 720, was a randomized, double-blind trial evaluating 3 dosing levels of lopinavir/ritonavir: 200/100 mg twice daily, 400/100 mg twice daily, and 400/200 mg twice daily.1,304 Standard doses of stavudine and lamivudine were also added to the regimen.303 After 48 weeks, all patients were switched to lopinavir/ritonavir at a dose of 400/100 mg twice daily.1,304 The primary outcome was virologic response, as the proportion of patients achieving an HIV-1 RNA level <400 copies/mL.303

Enrolled patients (N=100) had a mean age of 35 years, with a mean baseline HIV-1 RNA level of 4.9 log₁₀ copies/mL and a mean CD4⁺ T-cell count of 338 cells/mm³.1 At week 48, 85% of patients achieved an HIV-1 RNA level <400 copies/mL; 78% of patients had an HIV-1 RNA level <50 copies/mL.303 At week 204, HIV-1 RNA levels of <400 copies/mL were seen in 71% of patients and levels <50 copies/mL in 70%.304 Through 360 weeks, 61% of patients had an HIV-1 RNA level <400 copies/mL.1

Antiretroviral-experienced Adults

Lopinavir/ritonavir has been evaluated for use in HIV-infected adults who were antiretroviral-experienced.1 In a randomized, open-label, multicenter study (Study 888), 288 HIV-infected adults who had previously received a PI-containing regimen were randomized to receive either lopinavir/ritonavir (lopinavir 400/100 mg twice daily) in conjunction with nevirapine and NRTIs or an investigator-selected PI in conjunction with nevirapine and NRTIs.1

Enrolled patients had a mean age of 40 years, with a mean baseline plasma HIV-1 RNA level of 4.1 log₁₀ copies/mL and a mean baseline CD4⁺ T-cell count of 322 cells/mm³.1 Through 48 weeks, 57% of those receiving the twice-daily lopinavir/ritonavir regimen and 33% of those receiving the investigator-selected PI regimen had plasma HIV-1 RNA levels <400 copies/mL.1 In addition, the mean increase in CD4⁺ T-cell count from baseline was 111 cells/mm³ in those receiving the lopinavir/ritonavir regimen and 112 cells/mm³ in those receiving the investigator-selected PI regimen.1

A once-daily lopinavir/ritonavir regimen (800/200 mg once daily) was compared with a twice-daily regimen (400/100 mg twice daily) in a randomized (1:1 ratio), open-label study (Study 802) that included 599 HIV-infected adults who had detectable virologic loads while receiving their current antiretroviral regimen.1 All patients received at least 2 NRTIs in conjunction with lopinavir/ritonavir.1

Enrolled patients had a mean age of 41 years, with a mean baseline plasma HIV-1 RNA level of 4.3 log₁₀ copies/mL and a mean baseline CD4⁺ T-cell count of 254 cells/mm³; 55% of patients had not previously received a PI.1 Through 48 weeks, the mean increase in CD4⁺ T-cell count from baseline was 135 cells/mm³ in patients receiving the once-daily lopinavir/ritonavir regimen and 122 cells/mm³ in those receiving the twice-daily lopinavir/ritonavir regimen.1 Virologic success (HIV-1 RNA level <50 copies/mL) was observed in 57% of patients treated with lopinavir/ritonavir once daily and in 54% of patients treated with lopinavir/ritonavir twice daily.1

Study 765 was a randomized, double-blind, multicenter trial comparing 2 doses of lopinavir/ritonavir: 400/100 mg twice daily and 400/200 mg twice daily.305 Treatment regimens also included 1 PI and 1 or 2 NRTIs.305 The primary outcome was virologic response, as the proportion of patients achieving an HIV-1 RNA level <400 copies/mL.305

Seventy patients were enrolled, with a mean age of 40 years, median baseline plasma HIV-1 RNA level of 4.0 log₁₀ copies/mL and a mean baseline CD4⁺ T-cell count of 372 cells/mm³.1 305 No significant difference was observed between lopinavir/ritonavir dosing regimens.305 At 144 weeks of treatment, HIV-1 RNA levels <400 and <50 copies/mL were seen in 54 and 50% of patients, respectively, with a mean increase in CD4⁺ T-cell count of 212 cells/mm³.1

Pediatric Patients

Lopinavir/ritonavir has been studied in both treatment-experienced and treatment-naïve pediatric patients.1 Study 1030 evaluated the efficacy of lopinavir/ritonavir oral solution (starting dose of 300 mg/75 mg per m²) in combination with 2 NRTIs in pediatric patients ≥14 days to 6 months of age and weighing ≥2.5 kg.1,306,307 Patients treated with lopinavir/ritonavir and/or concurrent NNRTI or PIs were excluded.306 Virologic outcomes included HIV-1 RNA levels and reduction in log₁₀copies/mL in HIV-1 RNA.306 Ten infants ≥14 days to <6 weeks of age were enrolled (median age, 5.7 weeks).1 By week 24, 7 of 10 infants achieved an HIV-RNA of <400 copies/mL.1 Median log₁₀ copies/mL reduction in HIV-1 RNA was 3.61 at 24 weeks.307 Among 21 patients 6 weeks to 6 months of age (median age, 14.7 weeks), 10 achieved an HIV-RNA level <400 copies/mL at week 24, with a median reduction of 3.33 log₁₀ copies/mL.1,306

Study 940 was an open-label, multicenter trial enrolling 100 patients (44% treatment-naïve) 6 months to 12 years of age (mean age, 5 years).1 Patients were randomized to 1 of 2 doses of lopinavir/ritonavir (230/57.5 mg per m²or 300/75 mg per m²) for 3 weeks, then all patients received lopinavir/ritonavir 300/75 mg per m².1 Nevirapine and up to 2 NRTIs were added to the regimen for treatment-experienced patients; lamivudine and stavudine were added for treatment-naïve patients.1 At 48 weeks, a virologic response (HIV-1 RNA <400 copies/mL) was seen in 71% of treatment-experienced patients and in 80% of treatment-naïve patients.1 Corresponding increases in CD4⁺ T-cell counts were 284 and 404 cells/mm³, respectively.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of their viral load or CD4⁺ counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

In the 2023 HHS adult and adolescent HIV treatment guideline, lopinavir/ritonavir is not recommended as part of an initial regimen due to a higher pill burden and higher ritonavir dose compared to other PI-based regimens.200

In the 2023 HHS pediatric HIV treatment guideline, lopinavir/ritonavir is included in various antiretroviral regimens.201 Lopinavir/ritonavir is recommended as the preferred PI-based regimen for infants with a postmenstrual age ≥42 weeks and postnatal age ≥14 days to <4 weeks; and as an alternative PI-based regimen for children ≥4 weeks of age.201 Its use is supported as a preferred PI-based regimen for children up to 3 years of age.201 Once-daily dosing in children is not supported.201

In the 2023 HHS perinatal HIV treatment guideline, lopinavir/ritonavir is included in various antiretroviral regimens.202 Lopinavir/ritonavir plus a preferred dual-NRTI “backbone” is not recommended for initial use during pregnancy except under special circumstances.202 Lopinavir/ritonavir can be continued if pregnancy occurs when part of a fully suppressive, well-tolerated regimen.202 Additionally, lopinavir/ritonavir can be used as an alterative regimen for infant prophylaxis during breastfeeding.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Lopinavir/ritonavir is used as an alternative regimen in conjunction with other antiretrovirals (NNRTIs/NRTIs) for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals.199

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 These experts also state that lopinavir/ritonavir and 2 NRTIs is one of several alternative agents that may be used in PEP regimens.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Lopinavir/ritonavir is used in conjunction with other antiretrovirals as an alterative regimen for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) after sexual, injection drug use, or other nonoccupational exposures.198

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 Lopinavir/ritonavir is included as an alternative agent in conjunction with other antiretroviral agents in certain pediatric patients.198

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• Perform genotypic or phenotypic testing and collect treatment history to guide the use of lopinavir/ritonavir.1
• Monitor liver function prior to initiation of lopinavir/ritonavir, especially in patients with underlying hepatic disease, including hepatitis B virus (HBV) and hepatitis C virus (HCV), or with marked transaminase elevations.1
• Monitor cholesterol and triglycerides prior to initiation of lopinavir/ritonavir.1

Patient Monitoring

• Monitor liver function closely during treatment with lopinavir/ritonavir, especially in patients with underlying hepatic disease, including HBV and HCV, or with marked transaminase elevations.1
• Monitor cholesterol and triglycerides at periodic intervals during treatment with lopinavir/ritonavir.1
• Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus during treatment with lopinavir/ritonavir.1

Administration

The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) is administered orally once or twice daily.1

Not recommended as a once-daily regimen of lopinavir/ritonavir in adults infected with HIV-1 strains with 3 or more of the following mutations associated with lopinavir resistance: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, or I84V.1 Such patients should receive a twice-daily regimen of lopinavir/ritonavir.1

Not recommended as a once-daily regimen of lopinavir/ritonavir in patients younger than 18 years of age.1

Not recommended as a once-daily regimen of lopinavir/ritonavir in pregnant women.1

Not recommended as a once-daily regimen of lopinavir/ritonavir in patients receiving concomitant therapy with efavirenz, nelfinavir, or nevirapine or in those receiving certain anticonvulsants (carbamazepine, phenobarbital, phenytoin).1

Tablets

Lopinavir/ritonavir film-coated tablets can be taken without regard to food.1

Swallow tablets whole and do not chew, break, or crush.1

Children who can reliably swallow an intact tablet may receive lopinavir/ritonavir tablets.1

Store the tablets at 20-25°C (excursions permitted between 15-30°C).1 Dispense in the original container or United States Pharmacopeia (USP) equivalent tight container.1 Patients should be advised that exposure to high humidity outside the original container or USP equivalent tight container for >2 weeks is not recommended.1

Oral Solution

Lopinavir/ritonavir oral solution should be taken with food.1

Administer the oral solution using a calibrated cup (supplied) or an oral dosing syringe.1

Lopinavir/ritonavir oral solution can be used in adults and pediatric patients unable to swallow tablets.1 However, the oral solution contains approximately 42% (v/v) alcohol and approximately 15% (w/v) propylene glycol and should not be used in neonates with a postnatal age less than 14 days or a postmenstrual age less than 42 weeks (i.e., time elapsed since first day of mother's last menstrual period to birth plus time elapsed after birth).1

Avoid lopinavir/ritonavir oral solution in pregnant women since it contains alcohol and propylene glycol.1

Because the oral solution contains ethanol and propylene glycol, do not use the solution with polyurethane feeding tubes due to potential incompatibility.1 Use feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride feeding tubes.1 Follow instructions for use of the feeding tube to administer the oral solution.1

Store the oral solution at 2-8°C until dispensed; avoid exposure to excessive heat.1 Patients should be advised that solution that is stored under refrigeration at 2-8°C is stable until the expiration date.1 If stored at room temperature (≤25°C), use within 2 months.1

Dosage

Lopinavir/ritonavir is commercially available as film-coated tablets containing 100 mg of lopinavir and 25 mg of ritonavir (100 mg of lopinavir/25 mg of ritonavir) or 200 mg of lopinavir and 50 mg of ritonavir (200 mg of lopinavir/50 mg of ritonavir).1

Lopinavir/ritonavir is also commercially available as an oral solution containing 80 mg of lopinavir per mL and 20 mg of ritonavir per mL (80 mg of lopinavir/20 mg of ritonavir per mL).1

Dosage is expressed in terms of both lopinavir and ritonavir.1

Adult Dosage

Treatment of HIV Infection in Adults Not Receiving Efavirenz, Nelfinavir, or Nevirapine

For the treatment of HIV-1 infection in adults who are not receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the usual dosage of the fixed combination of lopinavir/ritonavir is lopinavir 800 mg/ritonavir 200 mg once daily (given as 4 tablets containing 200 mg of lopinavir/50 mg of ritonavir once daily) or lopinavir 400 mg/ritonavir 100 mg twice daily (given as 2 tablets containing 200 mg of lopinavir/50 mg of ritonavir twice daily).1 Alternatively, if the oral solution containing 80 mg of lopinavir/20 mg of ritonavir per mL is used, adults should receive 10 mL (800 mg of lopinavir/200 mg of ritonavir) once daily or 5 mL (400 mg of lopinavir/100 mg of ritonavir) twice daily.1

The twice-daily regimen (not the once-daily regimen) is recommended to be used in adults infected with HIV-1 strains with 3 or more specific mutations associated with lopinavir resistance (i.e., L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, I84V).1

Treatment of HIV Infection in Adults Receiving Efavirenz, Nelfinavir, or Nevirapine

For the treatment of HIV-1 infection in adults receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the usual dosage of the fixed combination of lopinavir/ritonavir is lopinavir 500 mg/ritonavir 125 mg twice daily (given as 2 tablets containing 200 mg of lopinavir/50 mg of ritonavir and 1 tablet containing 100 mg of lopinavir/25 mg of ritonavir twice daily).1 Alternatively, if the oral solution containing 80 mg of lopinavir/20 mg of ritonavir per mL is used, adults should receive lopinavir 520 mg/ritonavir 130 mg twice daily (6.5 mL twice daily).1

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of the fixed combination of lopinavir/ritonavir is lopinavir 400 mg/ritonavir 100 mg twice daily (given as 2 tablets containing 200 mg of lopinavir/50 mg of ritonavir twice daily).199 Alternatively, lopinavir 800 mg/ritonavir 200 mg once daily (given as 4 tablets containing 200 mg of lopinavir/50 mg of ritonavir once daily) can be used.199 Lopinavir/ritonavir is used for PEP in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).199

Initiate the PEP regimen as soon as possible following occupational exposure to HIV (preferably within hours) and continue for 4 weeks, if tolerated.199

Pediatric Dosage

Dosage of lopinavir/ritonavir in children is based on body surface area or body weight.1 Pediatric dosage should not exceed adult dosage.1

A once-daily regimen of lopinavir/ritonavir is not recommended in pediatric patients younger than 18 years of age.1

Treatment of HIV Infection in Pediatric Patients Not Receiving Efavirenz, Nelfinavir, or Nevirapine

For pediatric patients 14 days to <18 years of age not receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the recommended daily dosage of lopinavir/ritonavir oral solution based on body weight or body surface area is outlined in Table 1.1 Total dosage should not exceed the recommended adult daily dose of lopinavir 400 mg/ritonavir 100 mg (5 mL) twice daily.1

For pediatric patients >6 months to <18 years of age not receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the recommended daily dosage of lopinavir/ritonavir tablets based on body weight or body surface area is outlined in Table 2.1

Treatment of HIV Infection in Pediatric Patients Receiving Efavirenz, Nelfinavir, or Nevirapine

Do not use lopinavir/ritonavir in conjunction with efavirenz, nelfinavir, or nevirapine in children younger than 6 months of age.1

For pediatric patients >6 months to <18 years of age receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the recommended daily dosage of lopinavir/ritonavir oral solution based on body weight or body surface area is outlined in Table 3.1

For pediatric patients >6 months to <18 years of age receiving concurrent therapy with efavirenz, nelfinavir, or nevirapine, the recommended daily dosage of lopinavir/ritonavir tablets based on body weight or body surface area is outlined in Table 4.1

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in pediatric patients 14 days to 12 months of age, the recommended dosage of lopinavir/ritonavir oral suspension is lopinavir 16 mg/kg and ritonavir 4 mg/kg (based on body weight) or lopinavir 300 mg/m² and ritonavir 75 mg/m² twice daily (based on body surface area).198

198 For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in pediatric patients >12 months to 18 years of age, the recommended dosage of lopinavir/ritonavir 100/25 mg tablets based on body weight is 2 tablets twice daily for patients weighing 15-25 kg, 3 tablets twice daily for patients weighing >25 to 35 kg, or 4 tablets twice daily for patients weighing >35 kg.198 Alternatively, 2 tablets of lopinavir/ritonavir 200/50 mg can be used in patients weighing >35 kg.

Initiate the nPEP regimen within 72 hours of exposure and continue for 28 days; use in combination with other antiretroviral agents.198

Special Populations

Renal Impairment

Pharmacokinetics of lopinavir have not been studied in patients with renal impairment, but renal clearance of the drug is negligible and a decrease in total body clearance is not expected in patients with impaired renal function.1

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Hepatic Impairment

Limited pharmacokinetic data are available in patients with mild to moderate hepatic impairment; pharmacokinetics have not been studied in patients with severe hepatic impairment.1

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1 However, use lopinavir/ritonavir with caution in patients with hepatic impairment since the drug is principally metabolized by the liver and lopinavir concentrations may be increased.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Pregnancy

For the treatment of HIV-1 infection in pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations, a dosage of lopinavir 400 mg/ritonavir 100 mg twice daily is recommended.1 Data are insufficient to make dosage recommendations for pregnant women infected with HIV-1 strains with lopinavir-associated resistance mutations.1

Dosage adjustments are not needed in postpartum women.1

A once-daily lopinavir/ritonavir regimen is not recommended during pregnancy.1

Avoid lopinavir/ritonavir oral solution in pregnant women since it contains alcohol and propylene glycol.1

Contraindications

• History of clinically important hypersensitivity reaction (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to lopinavir, ritonavir, or any other ingredient in the formulation.1
• Concomitant use of lopinavir/ritonavir with drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events: alfuzosin, cisapride, colchicine, dronedarone, fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir), ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), lomitapide, lovastatin, lurasidone, oral midazolam, pimozide, ranolazine, simvastatin, sildenafil used for treatment of pulmonary arterial hypertension, triazolam.1
• Concomitant use of lopinavir/ritonavir with drugs that are potent inducers of CYP3A: apalutamide, rifampin, St. John's wort ( Hypericum perforatum ); such use is expected to result in significantly reduced lopinavir plasma concentrations and may be associated with loss of virologic response and development of resistance and cross-resistance.1

Warnings/Precautions

Drug Interactions

Lopinavir/ritonavir inhibits CYP3A and may increase plasma concentrations of drugs that are metabolized by CYP3A.1 Clinically important drug interactions, some leading to serious and/or life-threatening adverse effects, may occur due to higher exposures of certain drugs if used concomitantly with lopinavir/ritonavir.1

Initiation of drugs that inhibit or induce CYP3A may increase or decrease concentrations of lopinavir/ritonavir, respectively.1 Clinically important adverse reactions may occur due to higher exposures of lopinavir/ritonavir.1 Loss of virologic effect and possible development of resistance can occur if lopinavir/ritonavir is used concomitantly with certain drugs.1

Consider the potential for drug interactions prior to and during lopinavir/ritonavir therapy.1 Clinicians should review all drugs the patient is receiving and monitor for adverse effects during lopinavir/ritonavir therapy.1

Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution

Lopinavir/ritonavir oral solution contains approximately 42% (v/v) alcohol and approximately 15% (w/v) propylene glycol.1 When administered concomitantly with propylene glycol, ethanol competitively inhibits metabolism of propylene glycol, which may lead to elevated propylene glycol concentrations.1 Preterm neonates† may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.

Life-threatening cardiac toxicity (including complete atrioventricular [AV] block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported in postmarketing experience, predominantly in preterm neonates† receiving lopinavir/ritonavir oral solution.1

Do not use lopinavir/ritonavir oral solution in preterm neonates in the immediate postnatal period because of possible toxicities; a safe and effective dose has not been established in this patient population.1 However, if benefits of using lopinavir/ritonavir oral solution to treat human immunodeficiency virus (HIV) infection in infants immediately after birth outweigh the potential risks, closely monitor infants for increases in serum osmolality and serum creatinine, and for lopinavir/ritonavir-related toxicity (e.g., hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression, seizures, hypotonia, cardiac arrhythmias, ECG changes, hemolysis).1 Consider total amounts of ethanol and propylene glycol from all drugs administered to infants 14 days to 6 months of age in order to avoid toxicity from these excipients.1

Pancreatitis

Pancreatitis (with or without marked elevations in triglycerides) has occurred in patients receiving lopinavir/ritonavir and has been fatal in some patients.1 Although a causal relationship to lopinavir/ritonavir has not been established, marked triglyceride elevations are a risk factor for pancreatitis.1

Patients with advanced HIV type 1 (HIV-1) may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during lopinavir/ritonavir therapy.1 Consider the possibility of pancreatitis in a patient who develops abdominal pain, nausea and vomiting, or elevated biochemical markers (e.g., increased serum amylase or lipase concentration), and suspend therapy with lopinavir/ritonavir, as well as other antiretroviral therapy, if clinically appropriate.1

Hepatic Effects

Cases of hepatic dysfunction, including some fatalities, have been reported during postmarketing experience; a causal relationship to lopinavir/ritonavir has not been established.1 Hepatic dysfunction generally has occurred in patients with advanced HIV-1 infection receiving multiple concomitant drugs in the setting of chronic hepatitis or cirrhosis.1

Elevated transaminase concentrations, with or without elevated bilirubin concentrations, have been reported in HIV-1 monoinfected patients and uninfected individuals as early as 7 days after initiation of lopinavir/ritonavir therapy in conjunction with other antiretroviral agents.1

HIV-infected patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection or marked elevations in transaminase concentrations prior to lopinavir/ritonavir therapy may be at increased risk for new-onset or worsening transaminase elevations or hepatic decompensation.1

Perform appropriate laboratory tests to evaluate hepatic function prior to initiating lopinavir/ritonavir and periodically during treatment.1 Consider increased AST/ALT monitoring in patients with hepatitis or cirrhosis, especially during the first several months of lopinavir/ritonavir therapy.1

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV protease inhibitors (PIs); diabetic ketoacidosis has occurred.1 It may be necessary to initiate or adjust dosage of antidiabetic therapy (e.g., insulin, oral hypoglycemic agents).1

A causal relationship between HIV PI therapy and these events has not been established.1 Consider monitoring for hyperglycemia, new-onset diabetes mellitus, or exacerbation of diabetes mellitus in patients treated with lopinavir/ritonavir.1

Cardiovascular Effects

Prolongation of the PR interval has occurred in individuals receiving lopinavir/ritonavir; second- or third-degree AV block has been reported.1 Use lopinavir/ritonavir with caution in patients with underlying structural heart disease, cardiac conduction abnormalities, ischemic heart disease, or cardiomyopathies; these individuals may be at increased risk for cardiac conduction abnormalities.1 Caution is advised if lopinavir/ritonavir is used with other drugs that prolong the PR interval (e.g., some β-adrenergic blocking agents, digoxin, calcium-channel blockers, atazanavir), especially drugs metabolized by CYP3A4.1

Prolongation of the QT interval and torsades de pointes have been reported in patients receiving lopinavir/ritonavir during postmarketing experience.1 It is unclear whether these events were related directly to the drug.1 Do not use lopinavir/ritonavir in patients who have or may develop prolongation of the QT interval (e.g., patients with hypokalemia or congenital long QT syndrome; concomitant use of drugs known to prolong QT interval).1

Immune Reconstitution Syndrome

Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]);1 this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance has been reported in patients receiving HIV PIs.1 The mechanism and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1

Lipid Effects

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred during treatment with lopinavir/ritonavir.1 Assess serum triglyceride and cholesterol concentrations before initiating therapy with lopinavir/ritonavir and periodically during therapy with the drug.1 Manage lipid disorders as clinically appropriate and take into account any potential drug-drug interactions with HMG-CoA reductase inhibitors.1

Hemophilia A and B

Increased bleeding, including spontaneous hematomas and hemarthrosis, has been reported in hemophilia A or B patients receiving HIV PIs; a causal relationship has not been established.1

Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1

HIV Resistance

The potential for cross-resistance among HIV PIs has not been fully evaluated in patients receiving lopinavir/ritonavir.1 The possible effect of lopinavir/ritonavir therapy on subsequent therapy with other PIs is unknown.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to lopinavir/ritonavir during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1

Based on prospective reports from the APR that included over 3000 exposures to lopinavir-containing regimens (including over 1000 first trimester exposures), there was no difference in the risk of overall major birth defects for lopinavir compared with the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Similarly, based on prospective reports from the APR that included over 5000 exposures to ritonavir-containing regimens (including over 2000 first trimester exposures), there was no difference in the risk of overall major birth defects for ritonavir compared with the MACDP background rate.1

When lopinavir/ritonavir was administered to pregnant rats or rabbits, no treatment-related malformations were observed; however, embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.1

The US Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that initiation of lopinavir/ritonavir in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) is not recommended, except in special circumstances, for treatment of HIV-1 infection in antiretroviral-naïve or antiretroviral-experienced pregnant women.202

Once-daily lopinavir/ritonavir regimens are not recommended during pregnancy.1 Avoid lopinavir/ritonavir oral solution in pregnant women since it contains alcohol and propylene glycol.1

Trough plasma concentrations of lopinavir were decreased by approximately 40% during the second and third trimesters compared with postpartum in HIV-infected pregnant women treated with lopinavir 400 mg/ritonavir 100 mg twice daily.1 The decrease in lopinavir trough plasma concentrations is not considered clinically important when the usual dosage of lopinavir/ritonavir is used in pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations.1

Lactation

Because of the risk of adverse effects in the infant, the risk of developing viral resistance (in HIV-positive infants), and the risk of HIV transmission (in HIV-negative infants), HIV-infected women should not breast-feed.1

Females and Males of Reproductive Potential

Lopinavir/ritonavir may reduce the efficacy of combined hormonal contraceptives.1 Advise patients of reproductive potential using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method during therapy with lopinavir/ritonavir.1

Pediatric Use

Safety, efficacy, and pharmacokinetic profile of lopinavir/ritonavir have not been established in neonates younger than 14 days of age.1 Because of possible toxicities, do not use lopinavir/ritonavir oral solution in neonates with a postnatal age less than 14 days or a postmenstrual age less than 42 weeks (i.e., time elapsed since first day of mother's last menstrual period to birth plus time elapsed after birth).1

Lopinavir/ritonavir oral solution contains approximately 42% (v/v) alcohol and approximately 15% (w/v) propylene glycol.1 Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in significant toxicity and is potentially lethal.1 There have been postmarketing reports of life-threatening cases of cardiac toxicity, lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution.1 A safe and effective dose of lopinavir/ritonavir oral solution has not been established in this population.1 If the benefits of the oral solution for treatment of HIV infection in an infant immediately after birth are judged to outweigh potential risks, closely monitor the infant for increases in serum osmolality and serum creatinine and other signs of toxicity related to the oral solution.1 These toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias, ECG changes, and hemolysis.1 If lopinavir/ritonavir oral solution is used in preterm neonates or in pediatric patients 14 days to 6 months of age, total amounts of alcohol and propylene glycol from all drugs that the child is receiving should be taken into account to avoid toxicity associated with these excipients.1

Once-daily lopinavir/ritonavir regimens are not recommended in pediatric patients younger than 18 years of age.1

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently from younger adults.1 Use with caution in geriatric individuals because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Pharmacokinetics of lopinavir/ritonavir have not been studied in geriatric patients.1

Hepatic Impairment

Use with caution since lopinavir plasma concentrations may be increased.1 Peak plasma concentrations and AUC of lopinavir increased 20 and 30%, respectively, in patients with mild to moderate hepatic impairment.1 Plasma protein binding decreased in these patients compared with other individuals (99.09 vs 99.31%).1 Pharmacokinetics of lopinavir/ritonavir have not been studied in patients with severe hepatic impairment.1

HIV-infected patients with HBV or HCV coinfection or those with marked increases in transaminases prior to initiation of lopinavir/ritonavir may be at increased risk for further transaminase elevations or hepatic decompensation.1 Carefully monitor liver function in these patients.1

Renal Impairment

The pharmacokinetics of lopinavir have not been studied to date in patients with impaired renal function.1 Renal clearance of lopinavir is negligible; therefore, renal impairment is not expected to have a clinically important effect on the pharmacokinetics of the drug.1

Common Adverse Effects

The most common adverse effects include diarrhea, nausea, vomiting, hypercholesterolemia, and hypertriglyceridemia.1

The following drug interactions are based on studies using lopinavir and/or ritonavir.1 When using the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), consider the drug interactions associated with both agents.

The following list is a guide and is not comprehensive of all drugs that may interact with lopinavir/ritonavir.1 Consider appropriate references for comprehensive information.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Lopinavir/ritonavir inhibits the cytochrome P-450 (CYP) isoenzyme 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.1 Concomitant use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.1 Concomitant use with other drugs that are CYP3A substrates may require dosage adjustment or additional monitoring.1

Lopinavir/ritonavir is a CYP3A substrate; pharmacokinetic interactions may occur with drugs that inhibit or induce CYP3A (increased or decreased lopinavir concentrations, respectively).1

Lopinavir/ritonavir does not inhibit CYP isoenzymes 2D6, 2C9, 2C19, 2E1, 2B6, or 1A2 at clinically relevant concentrations.1

Drugs Metabolized by Glucuronidation

Lopinavir/ritonavir induces glucuronidation and may decrease plasma concentrations of drugs metabolized by glucuronidation.1

Drugs Transported by Organic Anion Transport Protein

Lopinavir inhibits organic anion transport protein (OATP) 1B1 and may increase plasma concentrations of OATP1B1 substrates.1

Alfuzosin

Concomitant use of alfuzosin and lopinavir/ritonavir results in increased alfuzosin plasma concentrations.1 Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated due to potential hypotension.1

Antiarrhythmic Agents

Concomitant use of lopinavir/ritonavir and antiarrhythmic agents (e.g., amiodarone, bepridil [no longer commercially available in the US], systemic lidocaine, quinidine) results in increased plasma concentrations of the antiarrhythmic agent.1 Use lopinavir/ritonavir and antiarrhythmic agents concomitantly with caution and monitor plasma concentrations of the antiarrhythmic agents (if available).1

Concomitant use of dronedarone and lopinavir/ritonavir results in increased dronedarone plasma concentrations.1 Concomitant use of lopinavir/ritonavir and dronedarone is contraindicated due to potential for cardiac arrhthymias.

Anticoagulants

Rivaroxaban: Concomitant use of lopinavir/ritonavir and rivaroxaban results in increased rivaroxaban concentrations and increased risk of bleeding.1 Avoid concomitant use of lopinavir/ritonavir and rivaroxaban.1

Warfarin: Concomitant use of lopinavir/ritonavir and warfarin results in altered (increased or decreased) warfarin plasma concentrations.1 If warfarin is used concomitantly with lopinavir/ritonavir, initial frequent monitoring of the international normalized ratio (INR) is recommended.1

Anticonvulsants

Carbamazepine, Phenobarbital, Phenytoin:Concomitant use of lopinavir/ritonavir and carbamazepine, phenobarbital, or phenytoin may result in decreased lopinavir plasma concentrations, and decreased steady-state phenytoin concentrations.1 Exercise caution if lopinavir/ritonavir is used concomitantly with carbamazepine, phenobarbital, or phenytoin.1 Monitor phenytoin levels when lopinavir/ritonavir and phenytoin are used concomitantly.1 Do not use a once-daily lopinavir/ritonavir regimen in patients receiving carbamazepine, phenobarbital, or phenytoin.1

Lamotrigine:Concomitant use of lopinavir/ritonavir and lamotrigine results in decreased lamotrigine plasma concentrations.1 If lamotrigine is used concomitantly with lopinavir/ritonavir, increased lamotrigine dosage may be needed; therapeutic concentration monitoring of lamotrigine may be indicated, especially during dosage adjustment.1

Valproate:Concomitant use of lopinavir/ritonavir and valproate results in decreased or unchanged valproate concentrations.1 If lopinavir/ritonavir is used concomitantly with valproate, increased dosage of valproate may be needed.1

Antifungal Agents

Fluconazole:Clinically important interactions with fluconazole are not expected.1

Isavuconazonium:Concomitant use of isavuconazonium sulfate (prodrug of isavuconazole) and lopinavir/ritonavir results in increased isavuconazole plasma concentrations.1 Use lopinavir/ritonavir and isavuconazonium concomitantly with caution; consider alternative antifungal therapies.1

Itraconazole:Concomitant use of itraconazole and lopinavir/ritonavir results in increased plasma concentrations of the antifungal agent.1 If used concomitantly, high itraconazole dosage (exceeding 200 mg daily) is not recommended.1

Ketoconazole:Concomitant use of itraconazole and lopinavir/ritonavir results in increased plasma concentrations of the antifungal agent.1 If used concomitantly, high ketoconazole dosage (exceeding 200 mg daily) is not recommended.1

Voriconazole: Concomitant use of voriconazole and lopinavir/ritonavir results in decreased plasma concentrations of voriconazole.1 Do not use voriconazole and lopinavir/ritonavir concomitantly unless potential benefits outweigh risks.1

Antimycobacterial Agents

Bedaquiline:Concomitant use of lopinavir/ritonavir and bedaquiline results in increased plasma bedaquiline concentrations.1 Use bedaquiline and lopinavir/ritonavir concomitantly only if potential benefits outweigh risks.1

Rifabutin:Concomitant use of lopinavir/ritonavir and rifabutin results in increased rifabutin and rifabutin metabolite plasma concentrations.1 If rifabutin is used concomitantly with lopinavir/ritonavir, reduce the dosage of the antimycobacterial agent by at least 75% (i.e., maximum 150 mg every other day or 3 times weekly); increased monitoring for adverse effects is warranted.1 Further dosage reduction of rifabutin may be necessary.1

Rifampin:Concomitant use of lopinavir/ritonavir and rifampin results in decreased lopinavir plasma concentrations.1 Concomitant use of lopinavir/ritonavir and rifampin is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir/ritonavir or other protease inhibitors or concomitantly used antiretroviral agents.1

Antineoplastic Agents

Abemaciclib: Concomitant use of lopinavir/ritonavir and abemaciclib results in increased abemaciclib plasma concentrations.1

Apalutamide: Concomitant use of lopinavir/ritonavir and apalutamide results in decreased lopinavir/ritonavir plasma concentrations.1 Concomitant use is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir/ritonavir or other protease inhibitors.1

Dasatinib or Nilotinib:Concomitant use of lopinavir/ritonavir and dasatinib or nilotinib results in increased dasatinib or nilotinib plasma concentrations.1 A decrease in dosage or adjustment of the dosing interval of dasatinib or nilotinib may be required in patients receiving a potent CYP3A inhibitor, such as lopinavir/ritonavir, concomitantly.1

Encorafenib: Concomitant use of lopinavir/ritonavir and encorafenib results in increased encorafenib plasma concentrations.1 Avoid concomitant use of encorafenib with lopinavir/ritonavir due to potential risk of serious adverse events (e.g., QT prolongation).1 If concomitant use cannot be avoided, modify dosage as recommended in the encorafenib prescribing information.1

Ivosidenib:Concomitant use of lopinavir/ritonavir and ivosidenib results in increased ivosidenib plasma concentrations.1 Avoid concomitant use of ivosidenib with lopinavir/ritonavir due to potential risk of serious adverse events (e.g., QT prolongation).1 If concomitant use cannot be avoided, reduce ivosidenib dosage to 250 mg once daily.1

Neratinib, Venetoclax, or Ibrutinib:Concomitant use of lopinavir/ritonavir and neratinib, venetoclax, or ibrutinib results in increased plasma concentrations of the antineoplastic agent.1 Avoid use of neratinib, venetoclax, or ibrutinib with lopinavir/ritonavir.1

Vincristine or Vinblastine: Concomitant use of vincristine or vinblastine and lopinavir/ritonavir may result in increased plasma concentrations of the vinca alkaloid.1 Consider temporarily withholding ritonavir-containing antiretroviral regimens in patients who develop substantial hematologic or GI toxicity from the vinca alkaloid.1 Alternatively, if the antiretroviral regimen must be withheld for a prolonged period, consider an antiretroviral regimen that does not include agents that inhibit CYP3A or the P-glycoprotein transport system.1

Antipsychotic Agents

Lurasidone:Concomitant use of lurasidone and lopinavir/ritonavir results in increased plasma concentrations of lurasidone.1 Concomitant use of lopinavir/ritonavir and lurasidone is contraindicated due to potential for serious and/or life-threatening adverse effects.1

Pimozide:Concomitant use of pimozide and lopinavir/ritonavir results in increased plasma concentrations of pimozide.1 Concomitant use of lopinavir/ritonavir and pimozide is contraindicated due to potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1

Quetiapine: Concomitant use of quetiapine and lopinavir/ritonavir results in increased quetiapine plasma concentrations.1 Consider alternative antiretroviral therapy in patients receiving quetiapine.1 If lopinavir/ritonavir therapy is necessary in a patient receiving quetiapine, reduce the quetiapine dosage to one-sixth of the original dosage and monitor for quetiapine-related adverse effects.1 If quetiapine is necessary in a patient receiving lopinavir/ritonavir, refer to the quetiapine prescribing information for initial dosage and titration of quetapine.1

Atovaquone

Concomitant use of atovaquone and lopinavir/ritonavir results in decreased plasma atovaquone concentrations; the clinical importance is unknown.1 Increased atovaquone dosage may be needed in patients receiving lopinavir/ritonavir.1

Benzodiazepines

Midazolam:Concomitant use of midazolam and lopinavir/ritonavir results in increased midazolam plasma concentrations.1 Concomitant use of oral midazolam with lopinavir/ritonavir is contraindicated due to potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1 Caution is advised if parenteral midazolam is used with lopinavir/ritonavir; close clinical monitoring for respiratory depression and/or prolonged sedation is recommended.1 In addition, consider dosage adjustment.1

Triazolam:Concomitant use of triazolam and lopinavir/ritonavir results in increased triazolam plasma concentrations.1 Concomitant use of triazolam and lopinavir/ritonavir is contraindicated due to potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1

Bosentan

Concomitant use of bosentan and lopinavir/ritonavir results in increased bosentan plasma concentrations.1 In patients who have already been receiving lopinavir/ritonavir for at least 10 days, initiate bosentan at a dosage of 62.5 mg once daily or every other day based on individual tolerability.1 In patients who have already been receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating lopinavir/ritonavir; after at least 10 days of lopinavir/ritonavir therapy, resume bosentan at a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

Bupropion

Concomitant use of bupropion and lopinavir/ritonavir may result in decreased plasma concentrations of bupropion and hydroxybupropion (active metabolite).1 If bupropion and lopinavir/ritonavir are used concomitantly, monitor patients for adequate clinical response to bupropion.1

Calcium Channel Blockers

Concomitant use of lopinavir/ritonavir and dihydropyridine calcium-channel blocking agents (e.g., felodipine, nicardipine, nifedipine) results in increased plasma concentrations of the calcium-channel blocking agent.1 Consider dosage reduction of the dihydropyridine calcium-channel blocking agent; clinical monitoring of the patient recommended.1

Colchicine

Concomitant use of colchicine and lopinavir/ritonavir results in increased colchicine plasma concentrations.1 Concomitant use of colchicine and lopinavir/ritonavir is contraindicated in patients with renal or hepatic impairment due to potential for serious and/or life-threatening adverse effects.1

When colchicine is used for treatment of gout flares in patients (with normal renal or hepatic function) receiving lopinavir/ritonavir, give an initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later; the colchicine dose should be repeated no earlier than 3 days later.1

When colchicine is used for prophylaxis of gout flares in patients (with normal renal or hepatic function) receiving lopinavir/ritonavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1

When colchicine is used for treatment of familial Mediterranean fever in patients (with normal renal or hepatic function) receiving lopinavir/ritonavir, use a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily).1

Corticosteroids

Concomitant use of lopinavir/ritonavir and corticosteroids (systemic, inhaled, nasal, or ophthalmic), such as betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisone, and triamcinolone, may result in increased concentrations of the corticosteroid and reduced concentrations of lopinavir.1

Concomitant use of lopinavir/ritonavir and oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir.1 Consider alternative corticosteroids.1

Concomitant use of lopinavir/ritonavir and corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression.1 Consider alternative corticosteroids (e.g., beclomethasone, prednisolone) whose pharmacokinetics and pharmacodynamics are less impacted by strong CYP3A inhibitors in comparison to other steroids, especially for long-term use.1

Dapsone

Clinically important interactions between dapsone and lopinavir/ritonavir are unlikely.1

Desipramine

Concomitant use of lopinavir/ritonavir and desipramine did not result in clinically important drug interactions between desipramine and lopinavir/ritonavir.1

Disulfiram or Metronidazole

Alcohol contained in lopinavir/ritonavir oral solution may result in disulfiram-like reactions if the oral solution is used concomitantly with disulfiram or other drugs that produce this reaction (e.g., metronidazole).1

Elagolix

Concomitant use of elagolix and lopinavir/ritonavir results in increased elagolix plasma concentrations and decreased lopinavir/ritonavir plasma concentrations.1 Concomitant use of elagolix 200 mg twice daily and lopinavir/ritonavir for more than 1 month is not recommended due to potential risk of adverse events (e.g., bone loss, hepatic transaminase elevations).1 Limit concomitant use of elagolix 150 mg once daily and lopinavir/ritonavir to 6 months.1

Ergot Derivatives

Concomitant use of lopinavir/ritonavir and ergot derivatives (dihydroergotamine, ergotamine, methylergonovine) results in increased plasma concentrations of ergot derivative.1 Due to the potential for serious adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) with ergot alkaloids, concomitant use with lopinavir/ritonavir is contraindicated.1

Ethinyl Estradiol and Norethindrone

Concomitant use of lopinavir/ritonavir and a hormonal contraceptive containing ethinyl estradiol and norethindrone results in decreased ethinyl estradiol plasma concentrations.1 Contraceptive steroid concentrations may be altered when lopinavir/ritonavir is used concomitantly with oral contraceptives or with the contraceptive patch; therefore, use alternative nonhormonal or additional methods of contraception.1

Fostamatinib

Concomitant use of lopinavir/ritonavir and fostamatinib results in increased plasma concentrations of the fostamatinib metabolite R406.1 Monitor for toxicities of fostamatinib metabolite R406 (e.g., hepatotoxicity, neutropenia); fostamatinib dosage reduction may be required.1

GI Drugs

Cisapride:Concomitant use of lopinavir/ritonavir and cisapride results in increased cisapride plasma concentrations.1 Concomitant use is contraindicated due to potential for cardiac arrhythmias.1

Omeprazole: Concomitant use of omeprazole did not have a clinically important effect on plasma concentrations of lopinavir/ritonavir.1

Hepatitis C Virus (HCV) Antivirals

Sofosbuvir, Velpatasvir, and Voxilaprevir:Concomitant use of the fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) with lopinavir/ritonavir results in increased plasma concentrations of sofosbuvir, velpatasvir, and voxilaprevir.1 Concomitant use is not recommended.1

Boceprevir: Concomitant use of lopinavir/ritonavir and boceprevir results in decreased concentrations of boceprevir.1 Concomitant use is not recommended.1

Ombitasvir/paritaprevir/ritonavir and dasabuvir: Concomitant use of lopinavir/ritonavir and the fixed combination of ombitasvir/paritaprevir/ritonavir and dasabuvir results in increased concentrations of ombitasvir, paritaprevir, and ritonavir.1 Concomitant use is not recommended.1

Glecaprevir and Pibrentasvir:Concomitant use of lopinavir/ritonavir and the fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) results in increased concentrations of glecaprevir and pibrentasvir.1 Concomitant use is not recommended.1

Simeprevir:Concomitant use of simeprevir and lopinavir/ritonavir may increase plasma concentrations of simeprevir.1 Concomitant use is not recommended.1

Elbasvir and Grazoprevir:Concomitant use of lopinavir/ritonavir and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) results in increased concentrations of elbasvir/grazoprevir.1 Concomitant use of elbasvir/grazoprevir and lopinavir/ritonavir is contraindicated due to increased risk of ALT elevations.1

HIV Entry and Fusion Inhibitors

Maraviroc: Concomitant use of maraviroc and lopinavir/ritonavir results in increased maraviroc plasma concentrations.1 If maraviroc is used concomitantly with lopinavir/ritonavir, the recommended dosage of maraviroc is 150 mg twice daily.1

HIV Integrase Inhibitors (INSTIs)

Raltegravir:There was no clinically important pharmacokinetic interaction when lopinavir/ritonavir was used concomitantly with raltegravir.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine:Concomitant use of delavirdine and lopinavir/ritonavir may result in increased plasma concentrations of lopinavir.1 Appropriate dosages for concomitant use of lopinavir/ritonavir and delavirdine with respect to safety and efficacy have not been established.1

Efavirenz:Concomitant use of efavirenz and lopinavir/ritonavir results in decreased lopinavir plasma concentrations.1 Do not use a once-daily regimen of lopinavir/ritonavir in patients receiving efavirenz.1 If a twice-daily regimen of lopinavir/ritonavir is used with efavirenz, adults should receive lopinavir 500 mg/ritonavir 125 mg (as tablets) twice daily with the usual dosage of efavirenz.1 Alternatively, adults may receive lopinavir 520 mg/ritonavir 130 mg (as the oral solution) twice daily with the usual dosage of efavirenz.1 Refer to the Pediatric Dosage section for dosage recommendations in pediatric patients receiving lopinavir/ritonavir and efavirenz concomitantly for treatment of HIV infection.1

Etravirine:There was no clinically important pharmacokinetic interaction when lopinavir/ritonavir was used concomitantly with etravirine.1

Nevirapine:Concomitant use of nevirapine and lopinavir/ritonavir results in decreased lopinavir plasma concentrations.1 Do not use a once-daily regimen of lopinavir/ritonavir in patients receiving nevirapine.1 If a twice-daily regimen of lopinavir/ritonavir is used with nevirapine, adults should receive lopinavir 500 mg/ritonavir 125 mg (as tablets) twice daily with the usual dosage of nevirapine.1 Alternatively, adults may receive lopinavir 520 mg/ritonavir 130 mg (as the oral solution) twice daily with the usual dosage of nevirapine.1 Refer to the Pediatric Dosage section for dosage recommendations in pediatric patients receiving lopinavir/ritonavir and nevirapine concomitantly for treatment of HIV infection.1

Rilpivirine:There was no clinically important pharmacokinetic interaction when lopinavir/ritonavir was used concomitantly with rilpivirine.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

There were no clinically important pharmacokinetic interactions when lopinavir/ritonavir was used concomitantly with lamivudine.1 Although the clinical importance is unclear, lopinavir induces glucuronidation and has the potential to reduce abacavir or zidovudine plasma concentrations.1

Didanosine:Administer didanosine on an empty stomach 1 hour before or 2 hours after lopinavir/ritonavir oral solution (given with food).1 Lopinavir/ritonavir tablets can be taken at the same time as didanosine without food.1

Tenofovir Disoproxil Fumarate:Concomitant use of tenofovir disoproxil fumarate (tenofovir DF) and lopinavir/ritonavir results in increased tenofovir plasma concentrations.1 Monitor patients receiving lopinavir/ritonavir and tenofovir DF concomitantly for tenofovir toxicity.1

HIV Protease Inhibitors (PIs)

Atazanavir:Concomitant use of lopinavir/ritonavir and other drugs that prolong the PR interval such as atazanavir has not been evaluated.1 Use lopinavir/ritonavir and atazanavir concomitantly with caution; clinical monitoring is recommended.1

Fosamprenavir:Concomitant use of fosamprenavir (with low-dose ritonavir) and lopinavir/ritonavir results in decreased lopinavir and amprenavir (active metabolite of fosamprenavir) plasma concentrations.1 An increased incidence of adverse effects has been reported when the drugs were used concomitantly.1 Appropriate dosages for concomitant use with respect to safety and efficacy have not been established.1

Indinavir: Concomitant use of indinavir and lopinavir/ritonavir results in increased indinavir concentrations.1 Decrease indinavir dose to 600 mg twice daily, when co-administered with lopinavir/ritonavir 400/100 mg twice daily.1 Lopinavir/ritonavir once daily has not been studied in combination with indinavir.1

Nelfinavir:Concomitant use of nelfinavir and lopinavir/ritonavir results in decreased plasma concentrations of lopinavir and increased plasma concentrations of nelfinavir and its metabolite M8.1 If these drugs are used concomitantly, adults should receive lopinavir 500 mg/ritonavir 125 mg (as tablets) twice daily with nelfinavir.1 Alternatively, adults may receive lopinavir 520 mg/ritonavir 130 mg (as the oral solution) twice daily.1 Do not use a once-daily regimen of lopinavir/ritonavir in patients receiving nelfinavir.1 Refer to the Pediatric Dosage section for dosage recommendations in pediatric patients receiving lopinavir/ritonavir and nelfinavir concomitantly for treatment of HIV infection.1

Ritonavir:Concomitant use of lopinavir and ritonavir results in increased plasma concentrations of lopinavir and is used to therapeutic advantage in commercially available fixed-combination lopinavir/ritonavir.1 In patients receiving lopinavir/ritonavir, appropriate dosages of additional ritonavir with respect to safety and efficacy have not been established.1

Saquinavir: Concomitant use of saquinavir and lopinavir/ritonavir results in increased saquinavir concentrations.1 The saquinavir dose is 1000 mg twice daily, when co-administered with lopinavir/ritonavir 400/100 mg twice daily.1 Lopinavir/ritonavir once daily has not been studied in combination with saquinavir.1

Tipranavir:Concomitant use of ritonavir-boosted tipranavir (tipranavir 500 mg twice daily and ritonavir 200 mg twice daily) and lopinavir/ritonavir decreases lopinavir plasma concentrations.1 Concomitant use of lopinavir/ritonavir and ritonavir-boosted tipranavir is not recommended.1

HMG-CoA Reductase Inhibitors

Concomitant use of lopinavir/ritonavir and certain HMG-CoA reductase inhibitors (statins) (e.g., atorvastatin, lovastatin, rosuvastatin, simvastatin) increases plasma concentrations of the statin.1

Atorvastatin:If atorvastatin is used concomitantly with lopinavir/ritonavir, caution is advised; use the lowest necessary atorvastatin dosage.1

Lovastatin:Concomitant use of lovastatin with lopinavir/ritonavir is contraindicated due to potential for myopathy including rhabdomyolysis.1

Pitavastatin:Pharmacokinetic interaction is not considered clinically important.1

Pravastatin:Pharmacokinetic interaction is not considered clinically important.1

Rosuvastatin:If rosuvastatin is used concomitantly with lopinavir/ritonavir, rosuvastatin dosage should not exceed 10 mg daily.1 Carefully titrate rosuvastatin dosage and use the lowest necessary dosage.1

Simvastatin:Concomitant use of simvastatin with lopinavir/ritonavir is contraindicated due to potential for myopathy including rhabdomyolysis.1

Immunosuppressive Agents

Concomitant use of lopinavir/ritonavir and cyclosporine, sirolimus, or tacrolimus results in increased plasma concentrations of the immunosuppressive agent.1 If lopinavir/ritonavir is used concomitantly with cyclosporine, sirolimus, or tacrolimus, monitor plasma concentrations of the immunosuppressive agent.1

Lomitapide

Concomitant use of lomitapide (a sensitive substrate for CYP3A4 metabolism) and lopinavir/ritonavir results in increased concentrations of lomitapide.1 Concomitant use of lomitapide with lopinavir/ritonavir is contraindicated due to potential for hepatotoxicity.1

Macrolides

Clinically important interactions between lopinavir/ritonavir and azithromycin or erythromycin are not expected.1

Clarithromycin:Concomitant use of clarithromycin and lopinavir/ritonavir results in increased plasma concentrations of clarithromycin.1 Modification of the usual dosage of clarithromycin is not necessary in those with normal renal function; however, the clarithromycin dosage should be reduced by 50% in those with creatinine clearances of 30-60 mL/minute and reduced by 75% in those with creatinine clearances less than 30 mL/minute.1

Opiates and Opiate Partial Agonists

Fentanyl:Concomitant use of lopinavir/ritonavir and fentanyl results in increased fentanyl plasma concentrations.1 Careful monitoring for therapeutic and adverse effects (e.g., potentially fatal respiratory depression) is recommended if fentanyl and lopinavir/ritonavir are used concomitantly.1

Methadone:Concomitant use of lopinavir/ritonavir and methadone results in decreased plasma concentrations of methadone.1 If methadone and lopinavir/ritonavir are used concomitantly, increased methadone dosage may be necessary.1

Phosphodiesterase Type 5 Inhibitors

Concomitant use of lopinavir/ritonavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) is expected to result in substantially increased plasma concentrations of the PDE5 inhibitor.1

Avanafil:Do not use avanafil in patients receiving lopinavir/ritonavir; safe and effective dosages for concomitant use have not been established.1

Sildenafil:Concomitant use of lopinavir/ritonavir and sildenafil (Revatio^®) for treatment of pulmonary arterial hypertension (PAH) is contraindicated due to increased risk of sildenafil-related adverse effects (e.g., hypotension, syncope, visual abnormalities, priapism).1 Use sildenafil with caution for treatment of erectile dysfunction in patients receiving lopinavir/ritonavir.1 Sildenafil dosage should not exceed 25 mg once every 48 hours; monitor the patient for sildenafil-related adverse effects.1

Tadalafil:If tadalafil (Adcirca^®) is indicated for treatment of PAH in patients who have been receiving lopinavir/ritonavir for at least 1 week, initiate tadalafil at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1 Do not initiate lopinavir/ritonavir in patients receiving tadalafil for treatment of PAH; discontinue tadalafil for at least 24 hours prior to initiating lopinavir/ritonavir.1 After at least 1 week, tadalafil may be resumed at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1 Use tadalafil with caution for treatment of erectile dysfunction in patients receiving lopinavir/ritonavir; tadalafil dosage should not exceed 10 mg once every 72 hours.1 Monitor the patient for tadalafil-related adverse effects.1

Vardenafil:Use vardenafil with caution for treatment of erectile dysfunction in patients receiving lopinavir/ritonavir.1 Vardenafil dosage should not exceed 2.5 mg once every 72 hours; monitor the patient for vardenafil-related adverse effects.1

Ranolazine

Concomitant use of ranolazine and lopinavir/ritonavir results in increased ranolazine plasma concentrations.1 Concomitant use of lopinavir/ritonavir and ranolazine is contraindicated due to potential for serious and/or life-threatening adverse effects.1

Salmeterol

Concomitant use of lopinavir/ritonavir and salmeterol results in increased salmeterol plasma concentrations and increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1 Concomitant use of lopinavir/ritonavir and salmeterol is not recommended.1

St. John's Wort ( Hypericum perforatum )

Concomitant use of lopinavir/ritonavir and St. John's wort ( Hypericum perforatum ) results in decreased lopinavir plasma concentrations.1 Concomitant use is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir or other PIs.1

Trazodone

Concomitant use of trazodone and lopinavir/ritonavir results in increased plasma concentrations of trazodone; nausea, dizziness, hypotension, and syncope were observed when trazodone and ritonavir were used concomitantly.1 Consider a lower trazodone dosage.1

Description

Lopinavir and ritonavir (lopinavir/ritonavir) is a fixed combination of 2 human immunodeficiency virus (HIV) protease inhibitors (PIs).1,6,34 Lopinavir is extensively metabolized by the hepatic cytochrome P-450 (CYP) enzyme system, principally the 3A isoenzyme.1,5,6,34 Because ritonavir is a potent inhibitor of CYP3A, concomitant administration of ritonavir and lopinavir results in decreased metabolism and increased plasma concentrations of lopinavir.1,5,6,34 The concentration of ritonavir present in the fixed combination, although sufficient to inhibit CYP3A, is much lower than ritonavir dosages that are used therapeutically.1 Therefore, the antiretroviral activity of lopinavir/ritonavir is due to lopinavir.1,34

Lopinavir inhibits replication of HIV type 1 (HIV-1) by interfering with HIV protease.1 During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes.1 By interfering with the formation of these essential proteins and enzymes, lopinavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions.1 Lopinavir also has some in vitro activity against HIV type 2 (HIV-2).40,200

Strains of HIV-1 resistant to lopinavir can be produced in cell culture, and the presence of ritonavir does not appear to influence selection of lopinavir-resistant HIV-1 in cell culture.1 Strains of HIV-1 resistant to lopinavir have emerged during therapy with the fixed combination of lopinavir and ritonavir.1 Although varying degrees of HIV cross-resistance have been observed among PIs, the potential for cross-resistance in HIV-1 isolates from patients treated with lopinavir/ritonavir remains to be more fully elucidated.1

Following administration of lopinavir/ritonavir tablets, time to peak plasma lopinavir concentrations is 4.4 ± 0.8 hours.1 Administration with a meal increased the AUC of lopinavir by 19 and 130%, respectively, for the tablet and oral solution compared to the fasted state.1 Plasma concentrations of lopinavir following administration of lopinavir/ritonavir tablets were similar to those following administration of lopinavir/ritonavir capsules (no longer commercially available in the US) under fed conditions.1 The tablet formulation was associated with less pharmacokinetic variability than the capsule formulation.1 Lopinavir concentrations were similar following administration of lopinavir/ritonavir capsules and oral solution under fed conditions (500 kcal, 25% from fat).1

Lopinavir is >98% bound to human plasma proteins.1 Lopinavir is metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A4.1 Approximately 10% of an oral dose of lopinavir is excreted in urine and 83% is eliminated in feces.1 Following administration of lopinavir/ritonavir tablet, the plasma elimination half-life of lopinavir is 6.9 ± 2.2 hours.1

In pediatric patients, the 230/57.5 mg/m² twice daily regimen without nevirapine and the 300/75 mg/m² twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine.1

Advice to Patients

• Inform patients of the critical nature of compliance with human immunodeficiency virus (HIV) therapy and importance of remaining under the care of a clinician.1 Advise patients to take the antiretroviral regimen as prescribed, and to not alter or discontinue the regimen without consulting a clinician.1
• Advise patients and caregivers that the oral solution should be administered using the calibrated dosing cup (supplied by the manufacturer) or an oral dosing syringe.1
• Advise caregiver of a pediatric patient to inform their healthcare provider if the child's weight changes in order to make sure that the child's lopinavir/ritonavir dose is adjusted as needed.1
• Advise patients to take lopinavir/ritonavir on a regular schedule and to not miss a dose since this may result in development of resistance.1 If a dose is missed, inform patients to take the dose as soon as it is remembered and take the next dose at the regularly scheduled time; if a dose is skipped, inform patients to not double the next dose.1
• Inform patients that lopinavir/ritonavir tablets may be taken with or without food and to take lopinavir/ritonavir oral solution with food.1
• Inform patients that there may be an increased risk of diarrhea with the once-daily regimen of lopinavir/ritonavir as compared with the twice-daily regimen.1
• Advise patients that mild to severe skin reactions have occurred.1 Inform patients to contact a clinician if rash occurs.1
• Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as lopinavir/ritonavir.1
• Inform patients of the importance of notifying a clinician if manifestations of liver disease occur (e.g., jaundice of skin or eyes, pale stools, itchy skin, loss of appetite, or pain, aching, or sensitivity in right upper quadrant of abdomen).1
• Inform patients to notify a clinician if manifestations of pancreatitis occur (e.g., nausea, vomiting, stomach pain).1
• Advise patients to inform a clinician if signs or symptoms of diabetes (e.g., frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased blood glucose) occur.1
• Advise patients that changes in an electrocardiogram may occur and to inform a clinician if they experience signs or symptoms of cardiac effects (e.g., dizziness, lightheadedness, heart rhythm changes, loss of consciousness).1
• Advise patients that lopinavir/ritonavir therapy can cause substantial increases in total cholesterol and triglyceride concentrations.1
• Advise patients that redistribution or accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1
• Inform caregivers that lopinavir/ritonavir oral solution contains alcohol and propylene glycol, which can cause serious adverse effects in neonates.1 Inform caregivers to immediately inform a clinician if an infant appears too sleepy or if their breathing has changed.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John's wort), as well as any concomitant illnesses.1
• Advise women to inform their clinician if they are or plan to become pregnant.1 Advise women that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to lopinavir/ritonavir during pregnancy.1 Inform patients using hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with lopinavir/ritonavir.1
• Advise women to inform their clinician if they plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1
• Advise patients of other precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. AbbVie Inc. Kaletra^® (lopinavir/ritonavir) film-coated oral tablets and oral solution prescribing information. North Chicago, IL; 2023 Apr.

5. Kumar GN, Dykstra J, Roberts EM et al. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug-drug interaction. Drug Metabol Dispos . 1999; 27:902-8.

6. Sham HL, Kempf DJ, Molla A et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrobial Agents Chemother . 1998; 42:3218-24.

34. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs . 2003; 63:769-802. [PubMed 12662125]

40. Desbois D, Roquebert B, Peytavin G et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob Agents Chemother . 2008; 52:1545-8. [PubMed 18227188]

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From CDC.gov website. [Web]

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov website. [Web]

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HIV.gov website. [Web]

300. Gathe J, da Silva B, Cohen D, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior to twice-daily dosing and results in similar safety and tolerability in antiretroviral-naïve subjects through 48 weeks. J Acquir Defic Syndr. 2009;50:474-481.

301. Gonzalez-Garcia J, Cohen D, Johnson M, et al. Short communication: Comparable safety and efficacy with once-daily versus twice-daily dosing of lopinavir/ritonavir tablets with emtricitabine + tenofovir DF in antiretroviral-naïve, HIV type 1-infected subjects: 96 week final results of the randomized trial M05-730. AIDS Res Hum Retroviruses. 2010;26(8):841-845.

302. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002;346(26):2039-2046.

303. Murphy R, Brun S, Hicks C, et al. ABT-378/ritonavir plus stavudine and lamivudine for the treatment of antiretroviral-naïve adults with HIV-1 infection: 48-week results. AIDS.2001;15:1-9.

304. Hicks C, King M, Gulick R, et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naïve patients: 4 year follow-up study. AIDS. 2004;18:775-779.

305. Benson C, Deeks S, Brun S, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibotor-experienced patients. J Infect Dis. 2002;185:599-607.

306. Chadwick E, Capparelli E, Yogev R, et al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS. 2008;22:249-255.

307. Chadwick E, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age. Pediatr Infect Dis J. 2009;28:215-219.