Generic Name: Lopinavir and Ritonavir
Class: HIV 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

Introduction

Antiretroviral; fixed combination of 2 HIV protease inhibitors (PIs): lopinavir and ritonavir (lopinavir/ritonavir).1 6 34

Uses for Kaletra

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.1

Usually used in PI-based regimens that include a PI and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).200 201

For initial treatment in antiretroviral-naive adults and adolescents, experts state that lopinavir/ritonavir (once or twice daily) in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is an alternative (not preferred) PI-based regimen.200 Lopinavir/ritonavir (once or twice daily) in conjunction with abacavir and lamivudine (or emtricitabine) is another alternative PI-based regimen for initial treatment, but use only in those who are human leukocyte antigen (HLA)-B*5701 negative.200

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 and 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 and children <3 years of age.201 Also the preferred PI-based regimen for children 3 years to less than 6 years of age and one of several preferred PI-based regimens for those ≥6 years of age.201

Slideshow: Flashback: FDA Drug Approvals 2013

For initial treatment in antiretroviral-naive pregnant women, lopinavir/ritonavir (twice daily) with 2 NRTIs is a preferred PI-based regimen;200 202 do not use once-daily lopinavir/ritonavir during pregnancy.200 202

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; do not use once-daily lopinavir/ritonavir in those with HIV-1 strains with ≥3 viral mutations associated with lopinavir resistance.1 (See Dosage under Dosage and Administration.)

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (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.199

USPHS recommends a 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as preferred regimen for PEP following occupational exposures to HIV.199 Lopinavir/ritonavir and 2 NRTIs is one of several alternative regimens.199 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.199

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.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Postexposure prophylaxis of HIV infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

Kaletra Dosage and Administration

Administration

Oral Administration

Tablets

Administer orally without regard to food.1 Swallow whole; do not chew, break, or crush.1

Solution

Administer orally with food.1 Use calibrated dosing syringe.1

Preferred preparation for children with a body surface area <0.6 m2 or those unable to swallow tablets.1

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.1 (See Pediatric Use under Cautions.)

Highly concentrated (contains 80 mg of lopinavir and 20 mg of ritonavir per mL).1 28 One death has occurred as a result of inadvertent overdosage of lopinavir/ritonavir oral solution.28 To avoid medication errors and overdosage, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1 28

Dosage

Available as fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir); dosage expressed in terms of both drugs.1

Must be given in conjunction with other antiretrovirals.1 200 If used with didanosine, efavirenz, nelfinavir, or nevirapine, dosage adjustments recommended.1 200 (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.1

Do not use once-daily lopinavir/ritonavir in patients receiving efavirenz, nelfinavir, or nevirapine or in those receiving certain anticonvulsants (carbamazepine, phenobarbital, phenytoin).1 (See Specific Drugs under Interactions.)

Pediatric Patients

Treatment of HIV Infection

Dosage based on body weight or body surface area.1 To avoid medication errors and minimize risk for overdosage, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.1 28

Do not use once-daily lopinavir/ritonavir in pediatric patients.1

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.1 Alternatively, recommended dosage based on body weight is lopinavir 16 mg/kg and ritonavir 4 mg/kg twice daily.1 Dosage recommendations not available for concomitant use with efavirenz, nelfinavir, or nevirapine.1

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.1 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.1

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 can be used instead of 4 tablets containing 100 mg of lopinavir and 25 mg of ritonavir.

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

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.1 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.1

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 can be used instead of 4 tablets containing 100 mg of lopinavir and 25 mg of ritonavir.

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

>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) twice daily.1

Alternatively, lopinavir 800 mg/ritonavir 200 mg (4 tablets containing 200 mg of lopinavir/50 mg of ritonavir or 10 mL of oral solution) can be given once daily.1 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).1

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.1

Alternatively, lopinavir 533 mg/ritonavir 133 mg (6.5 mL of oral solution) twice daily.1

Do not use once-daily regimen in patients receiving efavirenz, nelfinavir, or nevirapine.1

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

Lopinavir 400 mg/ritonavir 100 mg 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).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

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

Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Oral

Lopinavir 400 mg/ritonavir 100 mg twice daily.198 Use in conjunction with other antiretrovirals.198

Initiate nPEP as soon as possible following nonoccupational exposure to HIV (preferably ≤72 hours after exposure); continue for 28 days.198

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

Do not exceed adult dosage.1

Special Populations

Hepatic Impairment

Dosage recommendations not available;1 200 use with caution.1 200 Limited pharmacokinetic data in patients with mild to moderate hepatic impairment; not studied to date in those with severe hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Renal clearance is negligible.1 Some experts state avoid once-daily regimen in those undergoing hemodialysis.200

Pregnant Women

Lopinavir 400 mg/ritonavir 100 mg twice daily.202 Some experts recommend an increased dosage of lopinavir 600 mg/ritonavir 150 mg twice daily during second and third trimesters, especially in antiretroviral-experienced pregnant women.202 If usual dosage used during second and third trimesters, these experts recommend monitoring virologic response and lopinavir plasma concentrations.202

Pregnant women receiving efavirenz or nevirapine: 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.202 Alternatively, lopinavir 533 mg/ritonavir 133 mg (6.5 mL of oral solution) twice daily.202

Once-daily regimen not recommended during pregnancy.202 (See Pregnancy under Cautions.)

Cautions for Kaletra

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.1

  • 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).1 (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.1 (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.1 (See Contraindications and see Specific Drugs under Interactions.)

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

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.1 37

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.1 37 Neonates, especially those born prematurely, are at risk of lopinavir, ethanol, and/or propylene glycol toxicity if they receive lopinavir/ritonavir oral solution.37

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 receiving lopinavir/ritonavir oral solution.1 37 (See Pediatric Use under Cautions.)

Pancreatitis

Pancreatitis (sometimes fatal) with or without marked elevations in triglycerides has occurred.1

Although causal relationship to lopinavir/ritonavir not established, marked triglyceride elevations are a risk factor for pancreatitis.1 (See Lipid Effects under Cautions.)

Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis;1 those with a history of pancreatitis may be at increased risk for recurrence during lopinavir/ritonavir therapy.1

Consider pancreatitis in patients who develop abdominal pain, nausea, and vomiting or elevated serum amylase or lipase concentrations.1 Suspend lopinavir/ritonavir therapy, as well as other antiretroviral therapy, if clinically appropriate.1

Hepatic Effects

Hepatic dysfunction (including some fatalities) reported; causal relationship not established.1 Generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs in the setting of chronic hepatitis or cirrhosis.1

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.1

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.1

Evaluate hepatic function prior to and during therapy.1 Consider increased AST/ALT monitoring in patients with hepatitis or cirrhosis, especially during the first several months of therapy.1

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.1

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.1

Cardiovascular Effects

Prolongation of the PR interval reported;1 second- or third-degree AV block has occurred.1 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.1 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.1 (See Specific Drugs under Interactions.)

Prolongation of the QT interval and torsades de pointes have occurred.1 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).1

Immune Reconstitution Syndrome

During initial treatment, 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.1

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

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.1 Mechanism and long-term consequences of fat redistribution unknown; causal relationship not established.1

Lipid Effects

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred.1 Marked triglyceride elevations are a risk factor for pancreatitis.1 (See Pancreatitis under Cautions.)

Determine serum triglyceride and cholesterol concentrations prior to initiating therapy and monitor concentrations periodically; manage lipid disorders as clinically appropriate.1 (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.1

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

HIV Resistance

Potential for cross-resistance among PIs not fully evaluated in patients receiving lopinavir/ritonavir.1 Possible effect of lopinavir therapy on subsequent therapy with other PIs unknown.1

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.13

Specific Populations

Pregnancy

Category C.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state that lopinavir/ritonavir (twice daily) with 2 NRTIs is a preferred PI-based regimen for initial treatment of HIV-1 in pregnant women.202 Once-daily dosing of lopinavir/ritonavir not recommended during pregnancy.202 Some experts recommend increased lopinavir/ritonavir dosage during second and third trimesters.202 (See Pregnant Women under Dosage and Administration.)

Some experts state lopinavir/ritonavir with 2 NRTIs is the preferred regimen for treatment of HIV-2 infection in pregnant women.202

Available data suggest lopinavir does not increase overall birth defect rate.1

Lactation

Lopinavir and ritonavir distributed into milk in rats.1 Lopinavir concentrations in human milk are very low or undetectable.202

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1

Pediatric Use

Safety, efficacy, and pharmacokinetics not established in neonates <14 days of age.1

Because of possible toxicities, do not use oral solution in neonates with postnatal age <14 days or postmenstrual age <42 weeks.1 201

Oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol.1 37 Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in significant toxicity and is potentially lethal.1 (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.1 37

A safe and effective dose of lopinavir/ritonavir oral solution not established in neonates <14 days of age (whether born prematurely or full term).37 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.1 37 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.1 37

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.1 201

Once-daily regimen not evaluated in pediatric patients;1 do not use once-daily regimen in patients <18 years of age.1 201

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Use with caution since lopinavir plasma concentrations may be increased.1 Not evaluated in severe hepatic impairment.1

Risk of further transaminase elevations in HIV-infected patients with underlying HBV or HCV coinfection or preexisting transaminase elevations.1 Carefully monitor liver function in these patients.1

Common Adverse Effects

Diarrhea, nausea, vomiting, abdominal pain, fatigue (including asthenia), headache (including migraine), hypercholesterolemia, hypertriglyceridemia, musculoskeletal pain, upper or lower respiratory tract infection.1 Higher incidence of diarrhea reported with once-daily regimen compared with twice-daily regimen.1

Interactions for Kaletra

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

Fixed-combination of lopinavir and ritonavir induces glucuronidation.1

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.1

Drugs Metabolized by Glucuronidation

May decrease plasma concentrations of drugs metabolized by glucuronidation.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

Possible decreased abacavir concentrations1

Clinical importance unknown1

Alfuzosin

Increased alfuzosin concentrations; may result in hypotension1

Concomitant use contraindicated1

Antiarrhythmic agents (amiodarone, dronedarone, systemic lidocaine, quinidine)

Possible increased antiarrhythmic agent concentrations1

Use concomitantly with caution; monitor serum concentrations of antiarrhythmic if possible1

Amiodarone or dronedarone: Some experts state do not use concomitantly with lopinavir/ritonavir200

Anticoagulants, oral

Rivaroxaban: Possible increased rivaroxaban concentrations; possible increased risk of bleeding1 200

Warfarin: Possible altered warfarin concentrations1

Rivaroxaban: Avoid concomitant use1 200

Warfarin: Monitor INR,1 especially when initiating or discontinuing lopinavir/ritonavir;200 adjust warfarin dosage accordingly200

Anticonvulsants (carbamazepine, lamotrigine, phenobarbital, phenytoin, valproic acid)

Carbamazepine: Possible increased carbamazepine concentrations; possible decreased lopinavir concentrations and possible decreased effectiveness of the antiretroviral1 200

Lamotrigine: Decreased lamotrigine AUC; no clinically important change in lopinavir concentrations1 200

Phenobarbital: Possible decreased lopinavir concentrations and decreased effectiveness of the antiretroviral1 200

Phenytoin: Decreased phenytoin AUC; decreased lopinavir concentrations and AUC and possible decreased effectiveness of the antiretroviral1 200

Valproate or valproic acid: Possible decreased or no change in valproic acid concentrations;1 19 23 200 increased lopinavir concentrations and AUC200

Carbamazepine, phenobarbital, phenytoin: Use concomitantly with caution; do not use once-daily lopinavir/ritonavir;1 consider use of an alternative anticonvulsant or monitor anticonvulsant and lopinavir concentrations and virologic response200

Lamotrigine: Increased lamotrigine dosage may be needed and lamotrigine concentration monitoring indicated, especially during dosage adjustment;1 200 alternatively, consider a different anticonvulsant200

Valproate or valproic acid: Increased dosage of the anticonvulsant may be needed and anticonvulsant concentration monitoring indicated, especially during dosage adjustment;1 200 monitor for virologic response and lopinavir-associated toxicity200

Antifungals, azoles

Fluconazole: Clinically important interactions not expected1

Itraconazole: Increased antifungal concentrations1

Ketoconazole: Increased antifungal concentrations1

Voriconazole: Possible decreased antifungal concentrations and AUC200

Itraconazole: High itraconazole dosage (>200 mg daily) not recommended;1 200 consider monitoring itraconazole concentrations200

Ketoconazole: High ketoconazole dosage (>200 mg daily) not recommended1

Voriconazole: Avoid concomitant use unless benefits outweigh risks;1 200 if used concomitantly, some experts recommend monitoring voriconazole concentrations and adjusting voriconazole dosage accordingly200

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 unknown200

Fixed combination of atovaquone and proguanil (atovaquone/proguanil): Decreased atovaquone and proguanil concentrations200

Artemether/lumefantrine: Monitor for antimalarial efficacy and lumefantrine toxicity200

Atovaquone/proguanil: Consider alternative antimalarial, if possible200

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Increased bedaquiline AUC;44 200 clinical importance unknown200

Rifabutin: Increased rifabutin and rifabutin metabolite concentrations and AUCs1 200

Rifampin: Substantially decreased lopinavir concentrations with possible loss of virologic response and increased risk of lopinavir resistance1

Rifapentine: Possible decreased lopinavir concentrations200

Bedaquiline: Use concomitantly with caution and only if potential benefits outweigh risks;200 monitor for QTc interval prolongation and liver dysfunction200

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);1 monitor closely for adverse effects;1 some experts recommend rifabutin 150 mg once daily or 300 mg 3 times weekly in addition to monitoring plasma rifabutin concentrations200

Rifampin: Concomitant use contraindicated1

Rifapentine: Concomitant use not recommended200

Antipsychotics (pimozide, quetiapine)

Pimozide: Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Quetiapine: Increased quetiapine concentrations expected200

Pimozide: Concomitant use contraindicated1

Quetiapine: Initiate quetiapine at lowest dosage and titrate as needed; if initiating lopinavir/ritonavir in patient receiving quetiapine, reduce quetiapine to one-sixth of original dosage; monitor for quetiapine efficacy and adverse effects200

Atazanavir

Prolonged PR interval reported with both atazanavir and lopinavir1

In vitro evidence of additive to synergistic antiretroviral effects;1 no in vitro evidence of antagonism203

Use concomitantly with caution and clinical monitoring1

Atovaquone

Atovaquone: Decreased atovaquone concentrations; clinical importance unknown1

Atovaquone: Increased atovaquone dosage may be needed1

Avanafil

Increased avanafil concentrations and increased risk of avanafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1 200

Do not use concomitantly;1 200 safe and effective dosages for concomitant use not established1

Benzodiazepines

Midazolam or 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 midazolam1 200

Alprazolam or diazepam: Possible increased benzodiazepine concentrations200

Oral midazolam or triazolam: Concomitant use contraindicated1

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;200 manufacturer of lopinavir states use concomitantly only in a monitored setting where respiratory depression and/or prolonged sedation can be managed1

Alprazolam or diazepam: Consider alternative benzodiazepines with less potential for interaction (e.g., lorazepam, oxazepam, temazepam)200

Boceprevir

Decreased concentrations and AUC of boceprevir, lopinavir, and ritonavir;1 17 18 185 200 possible reduced efficacy of HCV and HIV treatment regimens17 18

Concomitant use not recommended1 12 18 185 200

If boceprevir was initiated for treatment of chronic HCV in a patient coinfected with HIV receiving a suppressive antiretroviral regimen containing lopinavir/ritonavir, inform patient of possible drug interaction and closely monitor for HCV treatment response and potential HCV and HIV virologic rebound12 17 18 200

Bosentan

Increased bosentan concentrations1 200

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 tolerability1 200

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 tolerability1 200

Buprenorphine

No clinically important effects on pharmacokinetics of either drug200

Dosage adjustments not needed200

Bupropion

Decreased bupropion and hydroxybupropion (active metabolite) concentrations1 200

Monitor for clinical response to bupropion; titrate bupropion dosage as needed1 200

Calcium-channel blocking agents

Dihydropyridines (e.g., felodipine, nifedipine, nicardipine): Possible increased concentrations of the calcium-channel blocking agent1

Diltiazem: Possible increased diltiazem concentrations200

Dihydropyridines (e.g., felodipine, nifedipine, nicardipine): Use concomitantly with caution; clinical monitoring recommended1

Diltiazem: Use concomitantly with caution; adjust diltiazem dosage based on clinical response and toxicity200

Cisapride

Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1

Colchicine

Increased colchicine concentrations1

Patients with renal or hepatic impairment: Concomitant use not recommended1

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 later1

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 daily1

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)1

Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone)

Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected200

Budesonide or fluticasone (orally inhaled, intranasal): Increased corticosteroid concentrations;1 200 may result in adrenal insufficiency, including Cushing's syndrome200

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency, including Cushing's syndrome200

Budesonide, dexamethasone, prednisone (systemic): Increased corticosteroid concentrations;1 200 may result in adrenal insufficiency, including Cushing's syndrome1 200

Budesonide or fluticasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects;1 200 consider alternative (e.g., beclomethasone)200

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)200

Budesonide, dexamethasone, prednisone (systemic): Use concomitantly with caution only when potential benefits outweigh risks of systemic corticosteroid adverse effects;1 200 Consider alternative to dexamethasone for long-term corticosteroid use200

Co-trimoxazole

Clinically important interactions unlikely1

Dapsone

Clinically important interactions unlikely1

Darunavir

Decreased darunavir concentrations; no change in lopinavir concentrations204

No in vitro evidence of antagonistic antiretroviral effects204

Concomitant use not recommended; appropriate dosages with respect to safety and efficacy not established204

Dasatinib

Increased dasatinib concentrations and possible increased dasatinib adverse effects 1

May need to decrease dasatinib dose or adjust dosing interval1

Delavirdine

Possible increased lopinavir concentrations1

Appropriate dosages for concomitant use with respect to safety and efficacy not established1

Didanosine

Lopinavir/ritonavir oral solution: Conflicting administration instructions regarding food1

Lopinavir/ritonavir oral solution: Administer didanosine (without food) 1 hour before or 2 hours after lopinavir (given with food)1

Lopinavir/ritonavir tablets: May be administered at the same time as didanosine1

Disulfiram

Lopinavir/ritonavir oral solution: Possible disulfiram-like reaction because of alcohol content1

Dolutegravir

No clinically important effect on dolutegravir pharmacokinetics;200 does not appear to affect lopinavir pharmacokinetics236

Dosage adjustments not needed for either drug; once- or twice-daily dosage of lopinavir/ritonavir may be used200

Efavirenz

Decreased lopinavir concentrations and AUC1

In vitro evidence of additive antiretroviral effects213

Once-daily lopinavir/ritonavir regimen not recommended with efavirenz1

If used with efavirenz in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily;1 alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 533 mg/ritonavir 133 mg (6.5 mL) twice daily1

For dosage recommendations in pediatric patients receiving efavirenz, see Pediatric Dosage under Dosage and Administration

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir, cobicistat, and/or lopinavir200

EVG/COBI/TDF/FTC: Do not use concomitantly200

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Potential for serious or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)1

Concomitant use contraindicated1

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 possible202

Estrogens/Progestins

Oral hormonal contraceptives containing ethinyl estradiol or norethindrone: Decreased ethinyl estradiol and norethindrone concentrations1 200

Use alternative or additional nonhormonal contraceptive measures1 200

Etravirine

Decreased etravirine concentrations and AUC; decreased lopinavir concentrations and AUC200 214

No in vitro evidence of antagonistic antiretroviral effects214

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), manufacturer and some experts state that dosage adjustments not needed for either drug200 214

Fentanyl

Increased fentanyl concentrations1

Carefully monitor for therapeutic and adverse effects (e.g., respiratory depression)1

Fosamprenavir

Fosamprenavir: Decreased concentrations and AUC of amprenavir (active metabolite of fosamprenavir); no change in lopinavir concentrations or AUC205

Ritonavir-boosted fosamprenavir: Decreased amprenavir concentrations and AUC; altered lopinavir concentrations and AUC (increased or decreased)1 205

Increased incidence of adverse effects reported1 205

In vitro evidence of additive to synergistic antiretroviral effects1 205

Fosamprenavir or ritonavir-boosted fosamprenavir: Concomitant use not recommended; appropriate dosages for concomitant use with respect to safety and efficacy not established1 205

Histamine H2-receptor antagonists (e.g., ranitidine)

Ranitidine: No clinically important effect on lopinavir/ritonavir concentrations or AUC1

Dosage adjustments not necessary when used with a histamine H2-receptor antagonist200

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 rhabdomyolysis1 186 200

Pitavastatin: Decreased concentrations and AUC of pitavastatin and lopinavir;1 43 200 not considered clinically important1

Pravastatin: Increased pravastatin concentrations and AUC;1 200 not considered clinically important1

Atorvastatin: Use concomitantly with caution and use lowest necessary atorvastatin dosage1 186 200

Lovastatin: Concomitant use contraindicated1 186 200

Pitavastatin: Dosage adjustments not necessary200

Pravastatin: Dosage adjustments not necessary200

Rosuvastatin: Do not exceed rosuvastatin dosage of 10 mg once daily;1 186 200 carefully titrate rosuvastatin dosage and use lowest necessary dosage1 200

Simvastatin: Concomitant use contraindicated1 186 200

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1

Monitor immunosuppressive agent concentrations1

Indinavir

Increased indinavir concentrations1

In vitro evidence of additive to synergistic antiretroviral effects1

Use indinavir 600 mg twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily;1 lopinavir once-daily regimen not studied in patients receiving indinavir1

Lamivudine

No clinically important pharmacokinetic interactions1

Macrolides (azithromycin, clarithromycin, erythromycin)

Clarithromycin: Increased clarithromycin concentrations1

Azithromycin or erythromycin: Clinically important interactions not expected1

Clarithromycin: If used concomitantly, monitor for clarithromycin adverse effects or consider alternative macrolide (e.g., azithromycin);200 in patients with renal impairment, reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute or by 75% if Clcr <30 mL/minute1

Maraviroc

Substantially increased maraviroc concentrations and AUC1 200 224

No in vitro evidence of antagonistic antiretroviral effects 224

Recommended maraviroc dosage is 150 mg twice daily1 200 224

Methadone

Decreased methadone concentrations and AUC;1 opiate withdrawal may occur200

Monitor closely for signs of opiate withdrawal;200 consider need to increase methadone dosage1 200

Metronidazole

Lopinavir/ritonavir oral solution: Possible disulfiram-like reaction because of alcohol content1

Nelfinavir

Decreased lopinavir concentrations and increased nelfinavir concentrations1

In vitro evidence of additive to antagonistic antiretroviral effects1

Once-daily lopinavir/ritonavir regimen not recommended with nelfinavir1

If used with nelfinavir in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily;1 alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 533 mg/ritonavir 133 mg (6.5 mL) twice daily1

For dosage recommendations in pediatric patients receiving nelfinavir, see Pediatric Dosage under Dosage and Administration

Nevirapine

Decreased lopinavir concentrations and AUC1 200

Once-daily lopinavir/ritonavir regimen not recommended with nevirapine1

If used with nevirapine in adults, recommended dosage of lopinavir/ritonavir tablets is lopinavir 500 mg/ritonavir 125 mg twice daily;1 200 alternatively, recommended dosage of lopinavir/ritonavir oral solution is lopinavir 533 mg/ritonavir 133 mg (6.5 mL) twice daily1 200 ; use usual nevirapine dosage200

For dosage recommendations in pediatric patients receiving nevirapine, see Pediatric Dosage under Dosage and Administration

Nilotinib

Increased nilotinib concentrations and possible increased nilotinib adverse effects1

May need to decrease nilotinib dose or adjust dosing interval1

Oxycodone

Increased oxycodone AUC200

Monitor for opioid-related adverse effects; reduced oxycodone dosage may be needed200

Proton-pump inhibitors (e.g., omeprazole)

Omeprazole: No clinically important change in lopinavir concentrations or AUC1

Dosage adjustments not necessary when used with a proton-pump inhibitor200

Raltegravir

Decreased raltegravir concentrations; no change in lopinavir/ritonavir concentrations200

In vitro evidence of additive to synergistic antiretroviral effects225

Dosage adjustments not needed200

Rilpivirine

Increased rilpivirine concentrations and AUC; no clinically important effect on lopinavir concentrations or AUC226

No in vitro evidence of antagonistic antiretroviral effects226

Dosage adjustments not needed226

Ritonavir

Increased lopinavir concentrations and AUC; used to therapeutic advantage as fixed combination lopinavir/ritonavir1 200

In patients receiving lopinavir/ritonavir, appropriate dosages of additional ritonavir not established with respect to safety and efficacy1

Salmeterol

Increased salmeterol concentrations; may increase risk of QT prolongation, palpitations, or sinus tachycardia1

Concomitant use not recommended1

Saquinavir

Increased saquinavir concentrations1

Potential additive effects on QT and/or PR interval prolongation210

In vitro evidence of additive to synergistic antiretroviral effects1

Use concomitantly with caution210

If used concomitantly, recommended dosage is saquinavir 1 g twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily1

Lopinavir/ritonavir once-daily regimen not studied in conjunction with saquinavir1

St. John’s wort (Hypericum perforatum)

Decreased lopinavir concentrations; possible loss of virologic response and increased risk of lopinavir resistance1

Concomitant use contraindicated1

Sildenafil

Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

Sildenafil (Revatio) for treatment of pulmonary arterial hypertension (PAH): Concomitant use with lopinavir/ritonavir is contraindicated;1 lopinavir/ritonavir manufacturer states that a safe and effective dose for concomitant use not established1

Sildenafil for treatment of erectile dysfunction: Use caution and do not exceed 25 mg once every 48 hours;1 200 closely monitor for sildenafil-related adverse effects1

Simeprevir

Possible altered (increased or decreased) simeprevir concentrations187

Concomitant use not recommended187 200

Stavudine

No clinically important pharmacokinetic interactions1

Tadalafil

Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

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 daily1 200

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 daily1

Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects1

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200

Telaprevir

Decreased telaprevir concentrations and AUC; no clinically important effect on lopinavir concentrations or AUC1 184 200

Concomitant use not recommended1 184 200

Tenofovir

Increased tenofovir concentration and AUC; no clinically important change in lopinavir concentrations and AUC1 200 221

Clinical importance unknown200

Monitor for tenofovir toxicity;1 221 discontinue tenofovir if such effects occur221

Tipranavir

Decreased lopinavir concentrations and AUC1 211

In vitro evidence of additive to antagonistic or additive to synergistic antiretroviral effects1 211

Concomitant use not recommended1 211

Trazodone

Possible increased trazodone concentrations; adverse effects (nausea, dizziness, hypotension, syncope) reported when trazodone and ritonavir used concomitantly1

Use concomitantly with caution;1 consider reduced trazodone dosage;1 use lowest possible trazodone dosage and monitor for adverse CNS and cardiovascular effects200

Tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline)

Amitriptyline, imipramine, nortriptyline: Possible increased concentrations of the tricyclic antidepressant200

Desipramine: Pharmacokinetic interactions unlikely1

Use lowest possible antidepressant dosage; titrate antidepressant dosage based on plasma antidepressant concentrations and/or clinical assessment200

Vardenafil

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

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 effects1

Vinblastine

Possible increased vinblastine concentrations and adverse effects1

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 inhibitors1

Vincristine

Possible increased vincristine concentrations and adverse effects1

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 inhibitors1

Zidovudine

Possible decreased zidovudine concentrations1

Clinical importance unknown1

Kaletra Pharmacokinetics

Absorption

Bioavailability

Lopinavir administered as a fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir).1 Ritonavir decreases metabolism of lopinavir, resulting in increased lopinavir plasma concentrations.1

Absolute bioavailability of lopinavir co-formulated with ritonavir has not been established.1

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.1

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.1

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.1 Tablet formulation associated with less pharmacokinetic variability than capsule formulation.1

Bioavailability of lopinavir and ritonavir following oral administration of crushed tablets is reduced compared with administration of an intact tablet.32

Food

Tablets: Administration with moderate- or high-fat meal does not have clinically important effect on lopinavir AUC or peak plasma concentration.1

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.1 Administration with a high-fat meal (872 kcal, 56% from fat) increases lopinavir AUC and peak concentration 130 and 56%, respectively.1

Special Populations

Pregnant women: AUC of lopinavir/ritonavir decreased in the second and third trimesters.202

Distribution

Extent

Lopinavir and, to a lesser extent, ritonavir cross the human placenta.202

Lopinavir and ritonavir distributed into milk in rats;1 lopinavir concentrations in human milk are very low or undetectable.202

Plasma Protein Binding

Approximately 98–99%.1 Lopinavir binds to both α1-acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.1

Elimination

Metabolism

Lopinavir extensively metabolized by CYP enzyme system, almost exclusively by CYP3A.1 Ritonavir, a potent inhibitor of CYP3A, is included in the fixed-combination preparation to inhibit metabolism of and increase plasma concentrations of lopinavir.1

Elimination Route

Both lopinavir and ritonavir principally eliminated by the liver.1

Approximately 10 and 83% of a lopinavir dose excreted in urine and feces, respectively, within 8 days.1 After multiple doses, <3% of a lopinavir dose excreted unchanged in urine.1

Half-life

Adults: Mean lopinavir half-life is 4.1–5.8 hours following multiple doses of lopinavir/ritonavir (twice-daily dosing).34

Special Populations

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 versus 99.31%).1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Pharmacokinetics not studied in renal impairment; alterations not expected since renal clearance of lopinavir is negligible.1

Stability

Storage

Oral

Solution

2–8°C until dispensed; avoid exposure to excessive heat.1

For patient use, solution stored at 2–8°C is stable until expiration date.1 If stored at room temperature (≤25°C), use within 2 months.1

Tablets

20–25°C (may be exposed to 15–30°C).1 Dispense in original container.1 Exposure to high humidity outside the original container for >2 weeks not recommended.1

Actions and Spectrum

  • A fixed combination of 2 HIV PIs (lopinavir and ritonavir).1 6 34

  • Lopinavir is extensively metabolized by CYP3A;1 5 6 ritonavir is a potent inhibitor of CYP3A.1 5 6 34 Use of the fixed combination of lopinavir and ritonavir results in decreased metabolism and increased plasma concentrations of lopinavir.1 5 6 34

  • Antiretroviral activity is due to lopinavir.1 34 Concentration of ritonavir in fixed-combination preparation is sufficient to inhibit CYP3A, but is much lower than that used therapeutically.1

  • Active against HIV-1;1 has some in vitro activity against HIV-2.1 40 200

  • Lopinavir inhibits replication of HIV-1 by interfering with HIV protease.1

  • 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.1

  • Varying degrees of cross-resistance occur among PIs;1 only limited information available to date regarding cross-resistance between lopinavir and other PIs.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1

  • 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.200 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.1 200

  • Importance of reading patient information provided by the manufacturer.1

  • Provide patient or their caregiver with complete dosing instructions.1 Advise patient or their caregiver to pay special attention to dosing instructions to minimize risk of accidental overdosage or underdosage.1 Importance of informing clinician if child’s weight changes.1

  • Importance of taking lopinavir/ritonavir as directed and importance of not missing a dose.1 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.1

  • When lopinavir/ritonavir tablets are used, doses may be taken with or without food.1 If also taking didanosine, both drugs may be taken at the same time without food.1

  • When lopinavir/ritonavir oral solution is used, importance of taking with food.1 If also taking didanosine, take didanosine 1 hour before or 2 hours after lopinavir/ritonavir oral solution.1

  • Advise patients that mild to severe skin reactions have occurred.1 Importance of contacting clinician if rash occurs.1

  • Advise patients that liver disease (including fatalities) reported.1 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).1

  • Advise patients that severe pancreatitis (including fatalities) reported.1 Importance of notifying clinician if manifestations of pancreatitis occur (e.g., nausea, vomiting, stomach pain).1

  • 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.1

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1

  • 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.1

  • 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.1 200 Should not be used concomitantly with sildenafil used for treatment of PAH or avanafil.1

  • 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).1 37 Importance of immediately informing clinician if infant appears too sleepy or if their breathing has changed.1 37

  • Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

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

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Kaletra 100-25MG Tablets (ABBOTT): 30/$103.99 or 90/$279.98

Kaletra 200-50MG Tablets (ABBOTT): 30/$199.99 or 90/$575.99

Kaletra 400-100MG/5ML Solution (ABBOTT): 160/$419.98 or 480/$1,212.84

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. AbbVie Inc. Kaletra (lopinavir/ritonavir) film-coated oral tablets and oral solution prescribing information. North Chicago, IL; 2013 Nov.

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.

7. Walmsley S, Bernstein B, King M et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med. 2002; 346:2039-46. [PubMed 12087139]

12. Reddy SS. Dear healthcare professional letter. Results of pharmacokinetic study in healthy volunteers given Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. West Point, PA: Merck; 2012 Feb 6.

13. Magnus L. Dear healthcare professional letter: Dispensing error alert. Smyrna, GA: UCB Pharma, Inc; 2003 Sep.

14. Institute for Safe Medication Practices. What’s in a name? Ways to prevent dispensing errors linked to name confusion. ISMP Medication Safety Alert!. Huntingdon Valley, PA; 2002 Jun 12.

17. Food and Drug Administration. FDA drug safety communication: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. 2012 Feb 8. From FDA website. Accessed 2012 Apr 23.

18. Food and Drug Administration. FDA drug safety communication: Updated information on drug interactions between Victrelis (boceprevir) and certain boosted HIV protease inhibitor drugs. 2012 Apr 26. From FDA website. Accessed 2012 Jul 9.

19. DiCenzo R, Peterson D, Cruttenden K et al. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004; 48:4328-31. [IDIS 524915] [PubMed 15504860]

23. Sheehan NL, Brouillette MJ, Delisle MS et al. Possible interaction with lopinavir/ritonavir and valproic acid exacerbates bipolar disorder. Ann Pharmacother. 2006; 40:147-50. [PubMed 16368918]

24. van der Lee MJ, Dawood L, ter Hofstede HJ et al. Lopinavir/ritonavir reduced lamotrigine plasma concentrations in healthy subjects. Clin Pharmacol Ther. 2006; 80:159-68. [PubMed 16890577]

27. Corbett AH, Patterson KB, Tien H-C et al. Dose separation does not overcome the pharmacokinetic interaction between fosamprenavir and lopinavir/ritonavir. Antimicrob Agents Chemother. 2006; 50:2756-61. [PubMed 16870769]

28. Hoff R. Dear healthcare professional-communication on Kaletra (lopinavir/ritonavir) oral solution and accidental overdose in children. 2007 Aug 6.

32. Hoff R. Dear Healthcare Provider: Introducing a new strength of Kaletra (lopinavir/ritonavir); 100/25 mg tablets. 2007 Nov. From Kaletra web cite.

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]

36. Kaletra (lopinavir/ritonavir) tablets and oral solution risk evaluation and mitigation strategy (REMS). From FDA website.

37. US Food and Drug Administration. FDA Drug Safety Communication: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution. Rockville, MD; Mar 8, 2011. From FDA website.

38. Marcus KA. Supplemental approval release REMS requirement. Silver Spring, MD: US Food and Drug Administration; 2011 May 6. From FDA website.

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]

43. Kowa Pharmaceuticals America. Livalo (pitavastatin) tablets prescribing information. Montgomery, AL; 2012 Feb.

44. Janssen Therapeutics. Sirturo (bedaquiline) tablets prescribing information. Titusville, NJ; 2013 Jun.

184. Vertex Pharmaceuticals Incorporated. Incivek (telaprevir) film-coated tablets prescribing information. Cambridge, MA; 2011 Jun.

185. Merck & Co. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23.

187. Janssen Products LP. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.

198. Center for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the U.S. Department of Health and Human Services. MMWR Morb Mortal Wkly Rep. 2005; 54(No. RR-2):1-19. [PubMed 15647722]

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 (May 1, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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 (February 12, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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 (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

203. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules and oral powder prescribing information. Princeton, NJ; 2014 Jun.

204. Janssen Therapeutics. Prezista (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2014 Apr.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2013 Apr.

210. Genentech USA. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2014 Apr.

213. Bristol-Myers Squibb. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2012 Jun.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

221. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets and powder for oral use prescribing information. Foster City, CA; 2013 Oct.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Janssen Therapeutics. Edurant (rilpivirine) tablets prescribing information. Titusville, NJ; 2014 May.

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2014 May.

Hide
(web1)