Lopinavir and Ritonavir (Monograph)

Brand name: Kaletra
Drug class: HIV Protease Inhibitors
- Protease Inhibitors
VA class: AM800
Chemical name: [1S-[R*(R*),3R*,4R*]]-N-[4-[[2,6-Dimethylphenoxy)-acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide
Molecular formula: C₃₇H₄₈N₄O₅C₃₇H₄₈N₆O₅S₂
CAS number: 192725-17-0

Medically reviewed by Drugs.com on Apr 21, 2023. Written by ASHP.

Introduction

Antiretroviral; fixed combination of 2 HIV protease inhibitors (PIs): lopinavir and ritonavir (lopinavir/ritonavir). Ritonavir, a CYP3A inhibitor, is included in the fixed combination to increase plasma concentrations of lopinavir.

Uses for Lopinavir and Ritonavir

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥14 days of age; used in conjunction with other antiretrovirals.

Usually used in PI-based regimens that include an HIV PI and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

For initial treatment in antiretroviral-naive adults and adolescents, experts state that lopinavir/ritonavir in conjunction with 2 NRTIs is not recommended because of GI intolerance and higher ritonavir dose and higher pill burden than other PI-based regimens. Lopinavir/ritonavir (twice daily) with lamivudine (or emtricitabine) may be considered for initial treatment when the recommended or alternative regimens cannot be used, but use only when tenofovir alafenamide, tenofovir disoproxil fumarate (tenofovir DF), or abacavir cannot be used.

For initial treatment in antiretroviral-naive pediatric patients, experts state that lopinavir/ritonavir (twice daily) with 2 NRTIs is the preferred antiretroviral regimen for neonates ≥14 days of age with postmenstrual age ≥42 weeks (i.e., time elapsed since first day of mother’s last menstrual period to birth plus time elapsed after birth) and for infants <2 years of age. In addition, lopinavir/ritonavir (twice daily) with 2 NRTIs is a preferred regimen for initial treatment in children 2 years to <3 years of age and is one of several preferred PI-based regimens for children 3 years to <12 years of age.

For initial treatment in antiretroviral-naive pregnant women, lopinavir/ritonavir (twice daily) with 2 NRTIs is a preferred PI-based regimen; do not use once-daily lopinavir/ritonavir during pregnancy.

Consider the following factors when initiating lopinavir/ritonavir therapy: Use with other active antiretrovirals is associated with greater likelihood of treatment response; genotypic or phenotypic viral resistance testing and/or treatment history should guide therapy; number of baseline lopinavir resistance-associated mutations affects virologic response to the drug; twice-daily lopinavir/ritonavir must be used in those with HIV-1 strains with ≥3 viral mutations associated with lopinavir resistance; once-daily lopinavir/ritonavir not recommended in pediatric patients, pregnant women, or patients receiving concomitant therapy with certain drugs. (See Dosage under Dosage and Administration.)

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

USPHS recommends a 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV. Lopinavir/ritonavir and 2 NRTIs is one of several alternative regimens. Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF; alternatives are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure^{† [off-label]} (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada); recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.

CDC states that lopinavir/ritonavir is an option that can be considered for use in nPEP regimens in adults and adolescents and is a preferred or alternative option for use in nPEP regimens in certain pediatric patients ≥4 weeks of age; however, expert consultation recommended.

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

Lopinavir and Ritonavir Dosage and Administration

Administration

Oral Administration

Film-coated Tablets

Administer orally without regard to food.

Swallow whole; do not chew, break, or crush.

Oral Solution

Administer orally with food.

Use calibrated dosing syringe.

Can be used in adults and pediatric patients unable to swallow tablets, including children with a body surface area <0.6 m².

Contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol; do not use in neonates with postnatal age <14 days or postmenstrual age <42 weeks. (See Pediatric Use under Cautions.) Avoid use in pregnant women. (See Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution under Cautions.)

Highly concentrated (contains 80 mg of lopinavir and 20 mg of ritonavir per mL). One death has occurred as a result of inadvertent overdosage of lopinavir/ritonavir oral solution. To avoid medication errors and overdosage, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.

Dosage

Available as fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir); dosage expressed in terms of both drugs.

Must be given in conjunction with other antiretrovirals. If used with efavirenz, nelfinavir, or nevirapine, dosage adjustments recommended. (See Specific Drugs under Interactions.)

Do not use once-daily lopinavir/ritonavir in adults infected with HIV-1 strains with ≥3 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. Use twice-daily lopinavir/ritonavir in such patients.

Do not use once-daily lopinavir/ritonavir in patients receiving efavirenz, nelfinavir, or nevirapine or in those receiving certain anticonvulsants (carbamazepine, phenobarbital, phenytoin). (See Specific Drugs under Interactions.)

Pediatric Patients

Treatment of HIV Infection

Dosage based on body weight or body surface area. To avoid medication errors and minimize risk for overdosage, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.

Do not use once-daily lopinavir/ritonavir in pediatric patients.

Children 14 Days to 18 Years of Age Not Receiving Efavirenz, Nelfinavir, or Nevirapine

Oral

Infants 14 days to 6 months of age (oral solution): Recommended dosage based on body surface area is lopinavir 300 mg/m² and ritonavir 75 mg/m² twice daily. Alternatively, recommended dosage based on body weight is lopinavir 16 mg/kg and ritonavir 4 mg/kg twice daily. Do not use concomitantly with efavirenz, nelfinavir, or nevirapine.

Children 6 months to 18 years of age (oral solution): Recommended dosage based on body surface area is lopinavir 230 mg/m² and ritonavir 57.5 mg/m² twice daily. Alternatively, recommended dosage based on body weight is lopinavir 12 mg/kg and ritonavir 3 mg/kg twice daily for those who weigh <15 kg and lopinavir 10 mg/kg and ritonavir 2.5 mg/kg twice daily for those who weigh ≥15–40 kg.

Children 6 months to 18 years of age (tablets): See Table 1.

Two lopinavir/ritonavir tablets containing 200 mg of lopinavir and 50 mg of ritonavir twice daily can be used instead of 4 tablets containing 100 mg of lopinavir and 25 mg of ritonavir twice daily.

Table 1. Dosage of Lopinavir/Ritonavir Tablets for Treatment of HIV Infection in Children 6 Months to 18 Years of Age Not Receiving Efavirenz, Nelfinavir, or Nevirapine1
Weight (kg)	Body Surface Area (m²)	Number of Lopinavir/Ritonavir Tablets Containing 100 mg of Lopinavir and 25 mg of Ritonavir
15 to 25	≥0.6 to <0.9	2 tablets twice daily
>25 to 35	≥0.9 to <1.4	3 tablets twice daily
>35	≥1.4	4 tablets twice daily

Children 6 Months to 18 Years of Age Receiving Efavirenz, Nelfinavir, or Nevirapine

Oral

Children 6 months to 18 years of age (oral solution): Recommended dosage based on body surface area is lopinavir 300 mg/m² and ritonavir 75 mg/m² twice daily. Alternatively, recommended dosage based on body weight is lopinavir 13 mg/kg and ritonavir 3.25 mg/kg twice daily for those who weigh <15 kg and lopinavir 11 mg/kg and ritonavir 2.75 mg/kg twice daily for those who weigh 15–45 kg.

Children 6 months to 18 years of age (tablets): See Table 2.

Two lopinavir/ritonavir tablets containing 200 mg of lopinavir and 50 mg of ritonavir twice daily can be used instead of 4 tablets containing 100 mg of lopinavir and 25 mg of ritonavir twice daily.

Table 2. Dosage of Lopinavir/Ritonavir Tablets for Treatment of HIV Infection in Children 6 Months to 18 Years of Age Receiving Efavirenz, Nelfinavir, or Nevirapine1
Weight (kg)	Body Surface Area (m²)	Number of Lopinavir/Ritonavir Tablets Containing 100 mg of Lopinavir and 25 mg of Ritonavir
15 to 20	≥0.6 to <0.8	2 tablets twice daily
>20 to 30	≥0.8 to <1.2	3 tablets twice daily
>30 to 45	≥1.2 to <1.7	4 tablets twice daily
>45	≥1.7	5 tablets twice daily

Adults

Treatment of HIV Infection

Adults Not Receiving Efavirenz, Nelfinavir, or Nevirapine

Oral

Lopinavir 400 mg/ritonavir 100 mg (2 tablets containing 200 mg of lopinavir/50 mg of ritonavir or 5 mL of oral solution containing 400 mg of lopinavir/100 mg of ritonavir per 5 mL) twice daily.

Alternatively, lopinavir 800 mg/ritonavir 200 mg (4 tablets containing 200 mg of lopinavir/50 mg of ritonavir or 10 mL of oral solution containing 400 mg of lopinavir/100 mg of ritonavir per 5 mL) can be given once daily. Do not use once-daily regimen in patients with ≥3 viral 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).

Adults Receiving Efavirenz, Nelfinavir, or Nevirapine

Oral

Lopinavir 500 mg/ritonavir 125 mg (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.

Alternatively, lopinavir 520 mg/ritonavir 130 mg (6.5 mL of oral solution containing 400 mg of lopinavir/100 mg of ritonavir per 5 mL) twice daily.

Do not use once-daily regimen in patients receiving efavirenz, nelfinavir, or nevirapine.

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)† [off-label]

Oral

Lopinavir 400 mg/ritonavir 100 mg twice daily. Alternatively, lopinavir 800 mg/ritonavir 200 mg once daily (given as 4 tablets containing 200 mg of lopinavir/50 mg of ritonavir once daily). Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).

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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

Do not exceed adult dosage.

Special Populations

Hepatic Impairment

Dosage recommendations not available; use with caution. Limited pharmacokinetic data in patients with mild to moderate hepatic impairment; not studied to date in those with severe hepatic impairment. (See Hepatic Impairment under Cautions.)

Renal Impairment

Renal clearance is negligible. Some experts state avoid once-daily regimen in those undergoing hemodialysis.

Pregnant Women

Pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations: Lopinavir 400 mg/ritonavir 100 mg twice daily. Dosage adjustments not needed in postpartum women.

Some experts recommend an increased dosage of lopinavir 600 mg/ritonavir 150 mg twice daily during second and third trimesters, especially in HIV PI-experienced pregnant women and those with baseline plasma HIV-1 RNA levels >50 copies/mL at the time treatment is initiated. If usual dosage used during second and third trimesters, these experts recommend monitoring virologic response and lopinavir plasma concentrations.

Once-daily regimen not recommended during pregnancy. (See Pregnancy under Cautions.)

Manufacturer states data insufficient to make dosage recommendations for pregnant women infected with HIV-1 strains with lopinavir-associated resistance mutations.

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

Cautions for Lopinavir and Ritonavir

Contraindications

History of clinically important hypersensitivity reaction (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to lopinavir, ritonavir, or any ingredient in the formulation.
Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, midazolam, pimozide, triazolam, lovastatin, sildenafil used for treatment of pulmonary arterial hypertension, simvastatin). (See Specific Drugs under Interactions.)
Concomitant use with drugs that are potent inducers of CYP3A (e.g., rifampin, St. John’s wort [Hypericum perforatum]) since such use may result in decreased plasma concentrations of lopinavir with possible loss of virologic response and development of resistance. (See Specific Drugs under Interactions.)

Warnings/Precautions

Interactions

Serious and/or life-threatening drug interactions, clinically important drug interactions, or loss of virologic effect can occur with some drugs. (See Contraindications and see Specific Drugs under Interactions.)

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

Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution

Oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol.

Preterm neonates^{† [off-label]} 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. Neonates, especially those born prematurely, are at risk of lopinavir, ethanol, and/or propylene glycol toxicity if they receive lopinavir/ritonavir oral solution.

Life-threatening cardiac toxicity (including complete AV block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported, predominantly in preterm neonates^{† [off-label]} receiving lopinavir/ritonavir oral solution. (See Pediatric Use under Cautions.)

Pancreatitis

Pancreatitis (sometimes fatal) with or without marked elevations in triglycerides has occurred.

Although causal relationship to lopinavir/ritonavir not established, marked triglyceride elevations are a risk factor for pancreatitis. (See Lipid Effects under Cautions.)

Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis; those with a history of pancreatitis may be at increased risk for recurrence during lopinavir/ritonavir therapy.

Consider pancreatitis in patients who develop abdominal pain, nausea, and vomiting or elevated serum amylase or lipase concentrations. Suspend lopinavir/ritonavir therapy, as well as other antiretroviral therapy, if clinically appropriate.

Hepatic Effects

Hepatic dysfunction (including some fatalities) reported; causal relationship not established. Generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs in the setting of chronic hepatitis or cirrhosis.

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

HIV-infected patients with HBV or 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.

Evaluate hepatic function prior to and during therapy. Consider increased AST/ALT monitoring in patients with hepatitis or cirrhosis, especially during the first several months of therapy.

Hyperglycemic and Diabetogenic Effects

Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.

Cardiovascular Effects

Prolongation of the PR interval reported; second- or third-degree AV block has occurred. Use with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease, or cardiomyopathies; these individuals may be at increased risk for cardiac conduction abnormalities. Caution 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; clinical monitoring recommended. (See Specific Drugs under Interactions.)

Prolongation of the QT interval and torsades de pointes have occurred. Do not use in patients who have or may develop prolongation of the QT interval (e.g., hypokalemia, congenital long QT syndrome, use of drugs known to prolong QT interval).

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who respond 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]); this may necessitate further evaluation and treatment.

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

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.

Mechanism and long-term consequences of adipogenic effects unknown; causal relationship not established.

Lipid Effects

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred. Marked triglyceride elevations are a risk factor for pancreatitis. (See Pancreatitis under Cautions.)

Determine serum triglyceride and cholesterol concentrations prior to initiating therapy and monitor concentrations periodically; manage lipid disorders as clinically appropriate. (See HMG-CoA Reductase Inhibitors under Interactions.)

Hemophilia A and B

Increased bleeding, including spontaneous hematomas and hemarthrosis, reported with HIV PIs; causal relationship not established.

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

HIV Resistance

Potential for cross-resistance among PIs not fully evaluated in patients receiving lopinavir/ritonavir. Possible effect of lopinavir therapy on subsequent therapy with other PIs unknown.

General Precautions

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Kaletra (the fixed combination of lopinavir and ritonavir) and Keppra (levetiracetam) may result in errors.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Available data suggest lopinavir does not increase risk of overall major birth defects compared with background rate for major birth defects.

Experts state that lopinavir/ritonavir (twice daily) with 2 NRTIs is an alternative PI-based regimen for initial treatment of HIV-1 in pregnant women.

Once-daily lopinavir/ritonavir regimens not recommended during pregnancy.

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

Some experts recommend increased lopinavir/ritonavir dosage during second and third trimesters, especially in HIV PI-experienced pregnant women and those with baseline plasma HIV-1 RNA levels >50 copies/mL at the time antiretroviral treatment is initiated. (See Pregnant Women under Dosage and Administration.)

Although plasma concentrations of lopinavir decreased during second and third trimesters and total clearance increased during pregnancy, plasma concentrations of unbound lopinavir not substantially altered. Manufacturer states decreases in lopinavir trough plasma concentrations during second and third trimesters are not clinically important when usual dosage used in pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations.

Lactation

Lopinavir and ritonavir distributed into milk in rats. Lopinavir concentrations in human milk are very low or undetectable.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety, efficacy, and pharmacokinetics not established in neonates <14 days of age.

Because of possible toxicities, do not use oral solution in neonates with postnatal age <14 days or postmenstrual age <42 weeks.

Oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in significant toxicity and is potentially lethal. (See Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution under Cautions.)

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

A safe and effective dose of lopinavir/ritonavir oral solution not established in neonates <14 days of age^† (whether born prematurely or full term). If benefits of the oral solution for treatment of HIV infection in an infant immediately after birth are judged to outweigh potential risks, monitor the infant closely for increases in serum osmolality and serum creatinine and other signs of toxicity related to the oral solution. Possible toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias, ECG changes, and hemolysis.

If oral solution is used in preterm neonates^† or pediatric patients 14 days to 6 months of age, take into account the total amounts of alcohol and propylene glycol from all drugs the child is receiving to avoid toxicity associated with these excipients.

Do not use once-daily regimen in patients <18 years of age.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Use with caution since lopinavir plasma concentrations may be increased. Not evaluated in severe hepatic impairment.

Risk of further transaminase elevations in HIV-infected patients with underlying HBV or HCV coinfection or preexisting transaminase elevations. Carefully monitor liver function in these patients.

Common Adverse Effects

Diarrhea, nausea, vomiting, abdominal pain, fatigue (including asthenia), headache (including migraine), hypercholesterolemia, hypertriglyceridemia, musculoskeletal pain, upper or lower respiratory tract infection. Higher incidence of diarrhea reported with once-daily regimen compared with twice-daily regimen.

Drug Interactions

Lopinavir metabolized by CYP3A. Fixed combination of lopinavir and ritonavir inhibits CYP3A4. At clinically important concentrations, lopinavir does not inhibit CYP2D6, 2C9, 2C19, 2E1, 2B6, or 1A2.

Fixed-combination of lopinavir and ritonavir induces glucuronidation.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration in metabolism of lopinavir, ritonavir, and/or other drug.

Drugs Metabolized by Glucuronidation

May decrease plasma concentrations of drugs metabolized by glucuronidation.

Specific Drugs

Drug	Interaction	Comments
Abacavir	Possible decreased abacavir concentrations	Clinical importance unknown
Alfuzosin	Increased alfuzosin concentrations; may result in hypotension	Concomitant use contraindicated
Antiarrhythmic agents (amiodarone, dofetilide, dronedarone, flecainide, systemic lidocaine, propafenone, quinidine)	Possible increased antiarrhythmic agent concentrations	Use concomitantly with caution; monitor serum concentrations of antiarrhythmic if possible Dronedarone: Some experts state concomitant use contraindicated
Anticoagulants, oral	Apixaban: Increased apixaban concentrations expected Dabigatran: Possible increased dabigatran concentrations Edoxaban: Increased edoxaban concentrations Rivaroxaban: Increased rivaroxaban concentrations; possible increased risk of bleeding Warfarin: Possible altered warfarin concentrations	Apixaban, edoxaban, rivaroxaban: Avoid concomitant use Dabigatran: Dosage adjustments not needed in patients with Cl_cr >50 mL/minute; avoid concomitant use in patients with Cl_cr <50 mL/minute Warfarin: Monitor INR, especially when initiating or discontinuing lopinavir/ritonavir; adjust warfarin dosage accordingly
Anticonvulsants (carbamazepine, ethosuximide, lamotrigine, phenobarbital, phenytoin, valproic acid)	Carbamazepine: Possible increased carbamazepine concentrations; possible decreased lopinavir concentrations and possible decreased effectiveness of the antiretroviral Ethosuximide: Possible increased ethosuximide concentrations Lamotrigine: Decreased lamotrigine AUC; no clinically important change in lopinavir concentrations Phenobarbital: Possible decreased lopinavir concentrations and decreased effectiveness of the antiretroviral Phenytoin: Decreased phenytoin AUC; decreased lopinavir concentrations and AUC and possible decreased effectiveness of the antiretroviral Valproate or valproic acid: Possible decreased or no change in valproic acid concentrations; increased lopinavir concentrations and AUC	Carbamazepine, phenobarbital, phenytoin: Use concomitantly with caution; do not use once-daily lopinavir/ritonavir; consider alternative anticonvulsant or monitor anticonvulsant and lopinavir concentrations and virologic response Ethosuximide: Monitor for ethosuximide toxicity Lamotrigine: Increased lamotrigine dosage may be needed and lamotrigine concentration monitoring indicated, especially during dosage adjustment; alternatively, consider a different anticonvulsant Valproate or valproic acid: Increased dosage of the anticonvulsant may be needed and anticonvulsant concentration monitoring indicated, especially during dosage adjustment; monitor for virologic response and lopinavir-associated toxicity
Antifungals, azoles	Fluconazole: Clinically important interactions not expected Isavuconazonium (prodrug of isavuconazole): Increased isavuconazole AUC and decreased lopinavir AUC Itraconazole: Increased antifungal concentrations Ketoconazole: Increased antifungal concentrations Voriconazole: Possible decreased antifungal concentrations and AUC	Isavuconazonium: Consider monitoring isavuconazole concentrations and virologic response Itraconazole: High itraconazole dosage (>200 mg daily) not recommended; consider monitoring itraconazole concentrations Ketoconazole: High ketoconazole dosage (>200 mg daily) not recommended Voriconazole: Avoid concomitant use unless benefits outweigh risks; if used concomitantly, some experts recommend monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly
Antimalarial agents	Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Decreased concentrations and AUC of artemether and active metabolite of artemether; increased concentrations and AUC of lumefantrine; clinical importance unknown Fixed combination of artesunate and mefloquine (artesunate/mefloquine; not commercially available in US): Decreased AUC of dihydroartemisinin and mefloquine; no effect on lopinavir concentrations; clinical importance unknown Fixed combination of atovaquone and proguanil (atovaquone/proguanil): Decreased atovaquone and proguanil concentrations	Artemether/lumefantrine: Monitor for antimalarial efficacy and lumefantrine toxicity Artesunate/mefloquine: Monitor for antimalarial efficacy Atovaquone/proguanil: Consider alternative antimalarial, if possible
Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)	Bedaquiline: Increased bedaquiline AUC; clinical importance unknown Rifabutin: Increased rifabutin and rifabutin metabolite concentrations and AUCs Rifampin: Substantially decreased lopinavir concentrations with possible loss of virologic response and increased risk of lopinavir resistance Rifapentine: Possible decreased lopinavir concentrations	Bedaquiline: Use concomitantly with caution and only if potential benefits outweigh risks; monitor for QT_c interval prolongation and liver dysfunction Rifabutin: Use usual lopinavir dosage but reduce rifabutin dosage by at least 75% (i.e., maximum 150 mg every other day or 3 times weekly); monitor closely for adverse effects; some experts recommend rifabutin 150 mg once daily or 300 mg 3 times weekly in addition to monitoring plasma rifabutin concentrations Rifampin: Concomitant use contraindicated Rifapentine: Concomitant use not recommended
Antiplatelet agents (ticagrelor, vorapaxar)	Ticagrelor, vorapaxar: Increased concentrations of the antiplatelet agent expected	Ticagrelor, vorapaxar: Avoid concomitant use
Antipsychotics (lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)	Lurasidone: Risk of serious and/or life-threatening adverse effects Perphenazine, risperidone, thioridazine: Possible increased antipsychotic concentrations Pimozide: Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias) Quetiapine: Increased quetiapine concentrations expected	Lurasidone: Concomitant use contraindicated Perphenazine, risperidone, thioridazine: Initiate antipsychotic at lowest dosage and adjust maintenance dosage; monitor for toxicities associated with the antipsychotic Pimozide: Concomitant use contraindicated Quetiapine: Consider alternative antiretroviral; if lopinavir/ritonavir necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine efficacy and adverse effects; if quetiapine necessary in patient receiving lopinavir/ritonavir, experts state initiate using lowest quetiapine dosage, titrate as needed, and monitor for quetiapine efficacy and adverse effects
Atazanavir	Prolonged PR interval reported with both atazanavir and lopinavir In vitro evidence of additive to synergistic antiretroviral effects; no in vitro evidence of antagonism	Use concomitantly with caution and clinical monitoring
Atovaquone	Atovaquone: Decreased atovaquone concentrations; clinical importance unknown	Atovaquone: Increased atovaquone dosage may be needed
Avanafil	Increased avanafil concentrations and increased risk of avanafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Do not use concomitantly; safe and effective dosages for concomitant use not established
β-adrenergic blocking agents (atenolol, labetalol, metoprolol, nadolol, sotalol, timolol)	Metoprolol, timolol: Possible increased concentrations of the β-blocker	Decreased β-blocker dosage may be needed; adjust based on clinical response; consider use of certain β-blockers not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol)
Benzodiazepines	Midazolam, triazolam: Increased benzodiazepine concentrations; potential for prolonged or increased sedation or respiratory depression; interaction expected to be more substantial with oral midazolam than with parenteral midazolam Alprazolam, clonazepam, diazepam: Possible increased benzodiazepine concentrations	Oral midazolam or triazolam: Concomitant use contraindicated Parenteral midazolam: Some experts state a single parenteral midazolam dose can be given with caution in a monitored situation for procedural sedation in patients receiving lopinavir/ritonavir; manufacturer of lopinavir states use concomitantly only in a monitored setting where respiratory depression and/or prolonged sedation can be managed Alprazolam, clonazepam, diazepam: Consider alternative benzodiazepines with less potential for interaction (e.g., lorazepam, oxazepam, temazepam)
Bosentan	Increased bosentan concentrations	In patients already receiving lopinavir/ritonavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating lopinavir/ritonavir; after ≥10 days of lopinavir/ritonavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability
Buprenorphine	Buprenorphine (sublingual, buccal, or subdermal implant): No clinically important pharmacokinetic interactions	Dosage adjustments not needed; monitor patient clinically; if route of buprenorphine administration changed from transmucosal to subdermal implantation, monitor to ensure effect of buprenorphine is adequate and not excessive
Bupropion	Decreased bupropion and hydroxybupropion (active metabolite) concentrations	Monitor for clinical response to bupropion; titrate bupropion dosage as needed
Buspirone	Increased buspirone concentrations expected	Use low buspirone dosage with caution and titrate based on clinical response
Calcium-channel blocking agents	Dihydropyridines (e.g., felodipine, nifedipine, nicardipine): Possible increased concentrations of the calcium-channel blocking agent Diltiazem: Possible increased diltiazem concentrations	Dihydropyridines (e.g., felodipine, nifedipine, nicardipine): Use concomitantly with caution; clinical monitoring recommended Diltiazem: Use concomitantly with caution; adjust diltiazem dosage based on clinical response and toxicity
Cisapride	Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)	Concomitant use contraindicated
Cobicistat		Do not use concomitantly with lopinavir/ritonavir
Colchicine	Increased colchicine concentrations	Patients with renal or hepatic impairment: Concomitant use not recommended Colchicine for treatment of gout flares: In those receiving lopinavir/ritonavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later Colchicine for prophylaxis of gout flares: In those receiving lopinavir/ritonavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving lopinavir/ritonavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)
Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone)	Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected Budesonide or fluticasone (orally inhaled, intranasal): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome Budesonide, dexamethasone, prednisone (systemic): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome	Budesonide or fluticasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects; consider alternative (e.g., beclomethasone) Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir) Budesonide, dexamethasone, prednisone (systemic): Use concomitantly with caution only when potential benefits outweigh risks of systemic corticosteroid adverse effects; Consider alternative to dexamethasone for long-term corticosteroid use
Co-trimoxazole	Clinically important interactions unlikely
Daclatasvir	Decreased daclatasvir concentrations and AUC; not considered clinically important	Dosage adjustments not needed
Dapsone	Clinically important interactions unlikely
Darunavir	Decreased darunavir concentrations; no change in lopinavir concentrations No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended; appropriate dosages with respect to safety and efficacy not established
Dasatinib	Increased dasatinib concentrations and possible increased dasatinib adverse effects	May need to decrease dasatinib dose or adjust dosing interval
Delavirdine	Possible increased lopinavir concentrations	Appropriate dosages for concomitant use with respect to safety and efficacy not established
Didanosine	Lopinavir/ritonavir oral solution: Conflicting administration instructions regarding food	Lopinavir/ritonavir oral solution: Administer didanosine (without food) 1 hour before or 2 hours after lopinavir (given with food) Lopinavir/ritonavir tablets: May be administered at the same time as didanosine
Disulfiram	Lopinavir/ritonavir oral solution: Possible disulfiram-like reaction because of alcohol content
Dolutegravir	No clinically important effect on dolutegravir or lopinavir pharmacokinetics	Dosage adjustments not needed for either drug; once- or twice-daily dosage of lopinavir/ritonavir may be used
Efavirenz	Decreased lopinavir concentrations and AUC In vitro evidence of additive antiretroviral effects	Once-daily lopinavir/ritonavir regimen not recommended with efavirenz If used with efavirenz in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily; alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 520 mg/ritonavir 130 mg twice daily For dosage recommendations in pediatric patients receiving efavirenz, see Pediatric Dosage under Dosage and Administration
Elbasvir and grazoprevir	Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Increased elbasvir concentrations and substantially increased grazoprevir concentrations; increased grazoprevir concentrations may increase risk of ALT elevations	Elbasvir/grazoprevir: Concomitant use contraindicated
Elvitegravir	Cobicistat-boosted elvitegravir: Possible altered concentrations of elvitegravir, cobicistat, and/or lopinavir	Cobicistat-boosted elvitegravir: Do not use concomitantly with lopinavir/ritonavir
Eplerenone	Increased eplerenone concentrations expected	Experts state concomitant use contraindicated
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)	Potential for serious or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)	Concomitant use contraindicated If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving lopinavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible
Estrogens/progestins	Oral hormonal contraceptives containing ethinyl estradiol or norethindrone: Decreased ethinyl estradiol and norethindrone concentrations IM medroxyprogesterone acetate (MPA): Increased peak concentrations and AUC of MPA; no clinically important effects on trough concentrations of MPA Sub-Q etonogestrel implant: Increased trough concentrations and AUC of etonogestrel Transdermal ethinyl estradiol and norelgestromin: Decreased AUC of ethinyl estradiol; increased AUC of norelgestromin	Use alternative or additional nonhormonal contraceptive measures IM MPA: Dosage adjustments not needed Sub-Q etonogestrel implant: Dosage adjustments not needed Transdermal ethinyl estradiol and norelgestromin: Dosage adjustments not needed
Etravirine	Decreased etravirine concentrations and AUC; decreased lopinavir concentrations and AUC No in vitro evidence of antagonistic antiretroviral effects	Because decrease in etravirine systemic exposure in patients receiving concomitant lopinavir/ritonavir is similar to that in patients receiving etravirine and concomitant ritonavir-boosted darunavir (a combination found to be safe and effective), dosage adjustments not needed for either drug
Fentanyl	Increased fentanyl concentrations	Carefully monitor for therapeutic and adverse effects (e.g., respiratory depression)
Flibanserin	Increased flibanserin concentrations expected	Experts state concomitant use contraindicated
Fluvoxamine	Possible altered lopinavir/ritonavir concentrations	Consider alternative therapy
Fosamprenavir	Fosamprenavir: Decreased concentrations and AUC of amprenavir (active metabolite of fosamprenavir); no change in lopinavir concentrations or AUC Ritonavir-boosted fosamprenavir: Decreased amprenavir concentrations and AUC; altered lopinavir concentrations and AUC (increased or decreased) Increased incidence of adverse effects reported In vitro evidence of additive to synergistic antiretroviral effects	Fosamprenavir or ritonavir-boosted fosamprenavir: Concomitant use not recommended; appropriate dosages for concomitant use with respect to safety and efficacy not established
Histamine H₂-receptor antagonists (e.g., ranitidine)	Ranitidine: No clinically important effect on lopinavir/ritonavir concentrations or AUC	Dosage adjustments not necessary when used with a histamine H₂-receptor antagonist
HMG-CoA reductase inhibitors (statins)	Atorvastatin, lovastatin, rosuvastatin, simvastatin: Increased concentrations and AUC of the antilipemic agents; increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis Pitavastatin: Decreased concentrations and AUC of pitavastatin and lopinavir; not considered clinically important Pravastatin: Increased pravastatin concentrations and AUC; not considered clinically important	Atorvastatin: Use concomitantly with caution and use lowest necessary atorvastatin dosage Lovastatin: Concomitant use contraindicated Pitavastatin: Dosage adjustments not necessary Pravastatin: Dosage adjustments not necessary Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily; carefully titrate rosuvastatin dosage and use lowest necessary dosage Simvastatin: Concomitant use contraindicated
Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)	Increased concentrations of the immunosuppressive agent expected	Monitor immunosuppressive agent concentrations; some experts state initiate immunosuppressive agent with adjusted dosage to account for potential increased concentrations, monitor for toxicities, consult a specialist if needed
Indinavir	Increased indinavir concentrations In vitro evidence of additive to synergistic antiretroviral effects	Use indinavir 600 mg twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily; lopinavir once-daily regimen not studied in patients receiving indinavir
Ivabradine	Increased ivabradine concentrations expected	Experts state concomitant use contraindicated
Lamivudine	No clinically important pharmacokinetic interactions
Ledipasvir and sofosbuvir	Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Not expected to result in clinically important pharmacokinetic interactions Concomitant use of ledipasvir/sofosbuvir and HIV antiretroviral regimen that includes lopinavir/ritonavir and tenofovir DF: Possible increased tenofovir concentrations; safety of increased tenofovir concentrations not established	Ledipasvir/sofosbuvir: Dosage adjustments not needed if used with lopinavir/ritonavir Concomitant use of ledipasvir/sofosbuvir and HIV antiretroviral regimen that includes lopinavir/ritonavir and tenofovir DF: Consider alternative HCV treatment or an alternative antiretroviral regimen; if concomitant use necessary, monitor for tenofovir-associated adverse effects
Macrolides (azithromycin, clarithromycin, erythromycin)	Clarithromycin: Increased clarithromycin concentrations Azithromycin or erythromycin: Clinically important interactions not expected	Clarithromycin: If used concomitantly, monitor for clarithromycin adverse effects or consider alternative macrolide (e.g., azithromycin); in patients with renal impairment, reduce clarithromycin dosage by 50% if Cl_cr 30–60 mL/minute or by 75% if Cl_cr <30 mL/minute
Maraviroc	Substantially increased maraviroc concentrations and AUC No in vitro evidence of antagonistic antiretroviral effects	Recommended maraviroc dosage is 150 mg twice daily
Methadone	Decreased methadone concentrations and AUC; opiate withdrawal may occur	Monitor closely for signs of opiate withdrawal; consider need to increase methadone dosage
Metronidazole	Lopinavir/ritonavir oral solution: Possible disulfiram-like reaction because of alcohol content
Nelfinavir	Decreased lopinavir concentrations and increased nelfinavir concentrations In vitro evidence of additive to antagonistic antiretroviral effects	Once-daily lopinavir/ritonavir regimen not recommended with nelfinavir If used with nelfinavir in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily; alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 520 mg/ritonavir 130 mg twice daily For dosage recommendations in pediatric patients receiving nelfinavir, see Pediatric Dosage under Dosage and Administration
Nevirapine	Decreased lopinavir concentrations and AUC	Once-daily lopinavir/ritonavir regimen not recommended with nevirapine If used with nevirapine in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily; alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 520 mg/ritonavir 130 mg twice daily ; use usual nevirapine dosage For dosage recommendations in pediatric patients receiving nevirapine, see Pediatric Dosage under Dosage and Administration
Nilotinib	Increased nilotinib concentrations and possible increased nilotinib adverse effects	May need to decrease nilotinib dose or adjust dosing interval
Ombitasvir, paritaprevir, and ritonavir	Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir: Increased paritaprevir concentrations	Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Concomitant use not recommended
Oxycodone	Increased oxycodone AUC	Monitor for opioid-related adverse effects; reduced oxycodone dosage may be needed
Proton-pump inhibitors (e.g., omeprazole)	Omeprazole: No clinically important change in lopinavir concentrations or AUC	Dosage adjustments not necessary when used with a proton-pump inhibitor
Raltegravir	Decreased raltegravir concentrations; no change in lopinavir/ritonavir concentrations In vitro evidence of additive to synergistic antiretroviral effects	Dosage adjustments not needed
Rilpivirine	Increased rilpivirine concentrations and AUC; no clinically important effect on lopinavir concentrations or AUC No in vitro evidence of antagonistic antiretroviral effects	Dosage adjustments not needed
Ritonavir	Increased lopinavir concentrations and AUC; used to therapeutic advantage as fixed combination lopinavir/ritonavir	In patients receiving lopinavir/ritonavir, appropriate dosages of additional ritonavir not established with respect to safety and efficacy
Salmeterol	Increased salmeterol concentrations; may increase risk of QT prolongation, palpitations, or sinus tachycardia	Concomitant use not recommended
Saquinavir	Increased saquinavir concentrations Potential additive effects on QT and/or PR interval prolongation In vitro evidence of additive to synergistic antiretroviral effects	Use concomitantly with caution If used concomitantly, recommended dosage is saquinavir 1 g twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily Lopinavir/ritonavir once-daily regimen not studied in conjunction with saquinavir
St. John’s wort (Hypericum perforatum)	Decreased lopinavir concentrations; possible loss of virologic response and increased risk of lopinavir resistance	Concomitant use contraindicated
Sildenafil	Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with lopinavir/ritonavir is contraindicated; lopinavir/ritonavir manufacturer states that a safe and effective dose for concomitant use not established Sildenafil for treatment of erectile dysfunction: Use caution and do not exceed 25 mg once every 48 hours; closely monitor for sildenafil-related adverse effects
Simeprevir	Possible increased simeprevir concentrations	Concomitant use not recommended
Sofosbuvir and velpatasvir	Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important effect on pharmacokinetics of lopinavir/ritonavir
Stavudine	No clinically important pharmacokinetic interactions
Suvorexant	Increased suvorexant concentrations expected	Experts state concomitant use not recommended
Tadalafil	Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Tadalafil for treatment of PAH in patients who have been receiving lopinavir/ritonavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, increase dosage to 40 mg once daily Lopinavir/ritonavir in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating lopinavir/ritonavir; after ≥1 week of the antiretroviral agent, may resume tadalafil at a dosage of 20 mg once daily, and, if tolerated, may increase dosage to 40 mg once daily Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily
Tenofovir alafenamide	Increased tenofovir concentrations and AUC; no effect on lopinavir concentrations Fixed combination of emtricitabine and tenofovir alafenamide (emtricitabine/tenofovir alafenamide): Clinically important interactions not expected	Experts state dosage adjustments not needed
Tenofovir DF	Increased tenofovir concentration and AUC; no clinically important change in lopinavir concentrations and AUC	Clinical importance unknown Monitor for tenofovir toxicity; discontinue tenofovir if such effects occur
Tipranavir	Decreased lopinavir concentrations and AUC In vitro evidence of additive to antagonistic or additive to synergistic antiretroviral effects	Concomitant use not recommended
Trazodone	Possible increased trazodone concentrations; adverse effects (nausea, dizziness, hypotension, syncope) reported when trazodone and ritonavir used concomitantly	Use concomitantly with caution; consider reduced trazodone dosage; monitor for adverse CNS and cardiovascular effects
Tricyclic antidepressants (amitriptyline, desipramine, doxepin, imipramine, nortriptyline)	Amitriptyline, imipramine, nortriptyline: Possible increased concentrations of the tricyclic antidepressant Desipramine: Pharmacokinetic interactions unlikely	Use lowest possible antidepressant dosage; titrate antidepressant dosage based on plasma antidepressant concentrations and/or clinical assessment
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Vardenafil for treatment of erectile dysfunction: Do not exceed vardenafil dosage of 2.5 mg once every 72 hours; closely monitor for vardenafil-related adverse effects
Vinblastine	Possible increased vinblastine concentrations and adverse effects	Manufacturer of lopinavir/ritonavir recommends considering temporarily withholding ritonavir-containing antiretroviral regimens in patients who develop substantial hematologic or GI toxicity: alternatively, if antiretroviral regimen must be withheld for prolonged periods, consider using a regimen that does not include CYP3A or P-glycoprotein (P-gp) transport system inhibitors
Vincristine	Possible increased vincristine concentrations and adverse effects	Manufacturer of lopinavir/ritonavir recommends considering temporarily withholding ritonavir-containing antiretroviral regimens in patients who develop substantial hematologic or GI toxicity; alternatively, if antiretroviral regimen must be withheld for prolonged periods, consider using a regimen that does not include CYP3A or P-gp inhibitors
Zidovudine	Possible decreased zidovudine concentrations	Clinical importance unknown
Zolpidem	Possible increased zolpidem concentrations	Experts state initiate using low dosage of zolpidem; dosage reduction may be needed

Lopinavir and Ritonavir Pharmacokinetics

Absorption

Bioavailability

Lopinavir administered as a fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir). Ritonavir decreases metabolism of lopinavir, resulting in increased lopinavir plasma concentrations.

Absolute bioavailability of lopinavir co-formulated with ritonavir has not been established.

Following multiple dosing for 3 weeks (400 mg of lopinavir/100 mg of ritonavir twice daily with food), peak plasma lopinavir concentrations attained approximately 4 hours after a dose.

When a once-daily regimen is given for 4 weeks (800 mg of lopinavir/200 mg of ritonavir once daily with food), peak plasma lopinavir concentrations are attained approximately 6 hours after a dose.

Plasma concentrations of lopinavir and ritonavir following administration as tablets similar to those following administration as capsules (no longer commercially available in the US) under nonfasting conditions. Tablet formulation associated with less pharmacokinetic variability than capsule formulation.

Bioavailability of lopinavir and ritonavir following oral administration of crushed tablets is reduced compared with administration of an intact tablet.

Food

Tablets: Administration with moderate- or high-fat meal does not have clinically important effect on lopinavir AUC or peak plasma concentration.

Oral solution: Compared with administration in the fasting state, administration with a moderate-fat meal (500–682 kcal, 23–25% calories from fat) increases lopinavir AUC and peak plasma concentrations 80 and 54%, respectively. Administration with a high-fat meal (872 kcal, 56% from fat) increases lopinavir AUC and peak concentration 130 and 56%, respectively.

Special Populations

Pediatric patients (<18 years of age weighing ≥15 kg): Increased lopinavir peak plasma concentrations and decreased lopinavir AUC observed with once-daily lopinavir/ritonavir regimens compared with twice-daily lopinavir/ritonavir regimens. Once-daily lopinavir/ritonavir regimens not bioequivalent to twice-daily regimens in pediatric patients.

HIV-infected pregnant women: Lopinavir plasma concentrations decreased in second and third trimesters compared with concentrations observed at 8 weeks postpartum. Although total clearance of lopinavir increased during pregnancy, unbound lopinavir concentrations in pregnant women are similar to nonpregnant and postpartum women.

Distribution

Extent

Lopinavir and, to a lesser extent, ritonavir cross the human placenta.

Lopinavir and ritonavir distributed into milk in rats; lopinavir concentrations in human milk are very low or undetectable.

Plasma Protein Binding

Approximately 98–99%. Lopinavir binds to both α₁-acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.

Elimination

Metabolism

Lopinavir extensively metabolized by CYP enzyme system, almost exclusively by CYP3A. Ritonavir, a potent inhibitor of CYP3A, is included in the fixed-combination preparation to inhibit metabolism of and increase plasma concentrations of lopinavir.

Elimination Route

Both lopinavir and ritonavir principally eliminated by the liver.

Approximately 10 and 83% of a lopinavir dose excreted in urine and feces, respectively, within 8 days. After multiple doses, <3% of a lopinavir dose excreted unchanged in urine.

Half-life

Adults: Mean lopinavir half-life is 4.1–5.8 hours following multiple doses of lopinavir/ritonavir (twice-daily dosing).

Special Populations

Peak plasma concentrations and AUC of lopinavir increased 20 and 30%, respectively, in patients with mild to moderate hepatic impairment. Plasma protein binding decreased in these patients compared with other individuals (99.09 versus 99.31%). Pharmacokinetics not studied in patients with severe hepatic impairment.

Pharmacokinetics not studied in renal impairment; alterations not expected since renal clearance of lopinavir is negligible.

Stability

Storage

Oral

Solution

2–8°C until dispensed; avoid exposure to excessive heat.

For patient use, solution stored at 2–8°C is stable until expiration date. If stored at room temperature (≤25°C), use within 2 months.

Film-coated Tablets

20–25°C (may be exposed to 15–30°C). Dispense in original container. Exposure to high humidity outside the original container for >2 weeks not recommended.

Actions and Spectrum

A fixed combination of 2 HIV PIs (lopinavir and ritonavir).
Lopinavir is extensively metabolized by CYP3A; ritonavir is a potent inhibitor of CYP3A. Use of the fixed combination of lopinavir and ritonavir results in decreased metabolism and increased plasma concentrations of lopinavir.
Antiretroviral activity is due to lopinavir. Concentration of ritonavir in fixed-combination preparation is sufficient to inhibit CYP3A, but is much lower than that used therapeutically.
Active against HIV-1; has some in vitro activity against HIV-2.
Lopinavir inhibits replication of HIV-1 by interfering with HIV protease.
HIV-1 with reduced susceptibility to lopinavir have been selected in vitro and have emerged during therapy with the fixed combination of lopinavir and ritonavir; presence of ritonavir does not appear to affect selection of lopinavir-resistant strains.
Varying degrees of cross-resistance occur among PIs; only limited information available to date regarding cross-resistance between lopinavir and other PIs.

Advice to Patients

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.
Importance of using in conjunction with other antiretrovirals—not for monotherapy.
Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur. Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.
Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.
Importance of reading patient information provided by the manufacturer.
Provide patient or their caregiver with complete dosing instructions. Advise patient or their caregiver to pay special attention to dosing instructions to minimize risk of accidental overdosage or underdosage. Importance of informing clinician if child’s weight changes.
Importance of taking lopinavir/ritonavir as directed and importance of not missing a dose. If a dose is missed, the dose should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time; if a dose is skipped, do not double the next dose.
When lopinavir/ritonavir tablets are used, doses may be taken with or without food. If also taking didanosine, both drugs may be taken at the same time without food.
When lopinavir/ritonavir oral solution is used, importance of taking with food. If also taking didanosine, take didanosine 1 hour before or 2 hours after lopinavir/ritonavir oral solution.
Advise patients that mild to severe skin reactions have occurred. Importance of contacting clinician if rash occurs.
Advise patients that liver disease (including fatalities) reported. Importance of notifying clinician if manifestations of liver disease occur (e.g., jaundice of skin or eyes, dark tea-colored urine, pale stools, itchy skin, loss of appetite, or pain, aching, or sensitivity in right upper quadrant of abdomen).
Advise patients that severe pancreatitis (including fatalities) reported. Importance of notifying clinician if manifestations of pancreatitis occur (e.g., nausea, vomiting, stomach pain).
Importance of informing clinicians if signs or symptoms of diabetes (e.g., frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased blood sugar), or cardiac effects (e.g., dizziness, lightheadedness, heart rhythm changes, loss of consciousness) occur.
Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.
Advise patients receiving a selective phosphodiesterase type 5 (PDE5) inhibitor (e.g., avanafil, sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician. Should not be used concomitantly with sildenafil used for treatment of PAH or avanafil.
If lopinavir/ritonavir oral solution is used in young infants, advise caregiver that the oral solution contains alcohol and propylene glycol which can cause serious adverse effects in neonates younger than 14 days of age (whether premature or full-term). Importance of immediately informing clinician if infant appears too sleepy or if their breathing has changed.
Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lopinavir and Ritonavir
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	Lopinavir 400 mg/5 mL and Ritonavir 100 mg/5 mL	Kaletra	AbbVie
	Tablets, film-coated	Lopinavir 100 mg and Ritonavir 25 mg	Kaletra	AbbVie
		Lopinavir 200 mg and Ritonavir 50 mg	Kaletra	AbbVie