Lopinavir and Ritonavir (Monograph)

Brand name: Kaletra
Drug class: HIV Protease Inhibitors

Medically reviewed by Drugs.com on May 10, 2024. Written by ASHP.

[Web]

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

Used in conjunction with other antiretrovirals for treatment of HIV-1 infection in adults and pediatric patients ≥14 days of age.

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

Not recommended as part of an initial regimen due to a higher pill burden and higher ritonavir dose compared to other PI-based regimens for adults and adolescents.

Recommended as the preferred PI-based regimen for infants with a postmenstrual age ≥42 weeks and postnatal age ≥14 days to <4 weeks; and as an alternative PI-based regimen for children ≥4 weeks of age.

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Recommended as an alternative regimen in conjunction with other antiretrovirals (NNRTIs/NRTIs) for postexposure prophylaxis of HIV infection following occupational exposure ^{† [off-label]}(PEP) in health-care personnel and other individuals.

The US Public Health Service (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.

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)

Recommended as an alternative regimen in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure ^{† [off-label]}(nPEP) after sexual, injection drug use, or other nonoccupational exposures in individual.

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).

Lopinavir/ritonavir is included as an alternative agent in conjunction with other antiretroviral agents in certain pediatric patients.

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

General

Pretreatment Screening

• Perform genotypic or phenotypic testing and collect treatment history to guide the use of lopinavir/ritonavir.

• Monitor liver function prior to initiation of lopinavir/ritonavir, especially in patients with underlying hepatic disease, including hepatitis B virus (HBV) and hepatitis C virus (HCV), or with marked transaminase elevations.

• Monitor cholesterol and triglycerides prior to initiation of lopinavir/ritonavir.

Patient Monitoring

• Monitor liver function closely during treatment with lopinavir/ritonavir, especially in patients with underlying hepatic disease, including HBV and HCV, or with marked transaminase elevations.

• Monitor cholesterol and triglycerides at periodic intervals during treatment with lopinavir/ritonavir.

• Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus during treatment with lopinavir/ritonavir.

Administration

Oral Administration

Available as film-coated tablets containing 100 mg of lopinavir and 25 mg of ritonavir (100 mg of lopinavir/25 mg of ritonavir) or 200 mg of lopinavir and 50 mg of ritonavir (200 mg of lopinavir/50 mg of ritonavir).

Available as an oral solution containing 80 mg of lopinavir per mL and 20 mg of ritonavir per mL (80 mg of lopinavir/20 mg of ritonavir per mL).

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

A once-daily lopinavir/ritonavir regimen is not recommended in patients <18 years of age.

A once-daily lopinavir/ritonavir regimen is not recommended in pregnant women.

A once-daily lopinavir/ritonavir regimen is not recommended in patients receiving efavirenz, nelfinavir, or nevirapine or in those receiving certain anticonvulsants (carbamazepine, phenobarbital, phenytoin).

Film-coated Tablets

Administer orally without regard to food. Swallow whole; do not chew, break, or crush. May be used in children who can reliably swallow an intact tablet.

Oral Solution

Administer orally with food. Administer using a calibrated cup (supplied) or an oral dosing syringe.

Can be used in adults and pediatric patients unable to swallow tablets.

Contains approximately 42% (v/v) alcohol and 15% (w/v) propylene glycol; do not use in neonates with postnatal age <14 days or postmenstrual age <42 weeks. Avoid use in pregnant women.

Do not use with polyurethane feeding tubes due to potential incompatibility. Use feeding tubes that are compatible with ethanol and propylene glycol (e.g., silicone and polyvinyl chloride feeding tubes).

Dosage

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

Adults

Oral

Patients not receiving efavirenz, nelfinavir, or nevirapine:

Tablets: lopinavir 400 mg/ritonavir 100 mg twice daily (2 tablets containing 200 mg of lopinavir/50 mg of ritonavir twice daily)

Oral solution:5 mL twice daily (400 mg of lopinavir/100 mg of ritonavir twice daily)

Tablets: Once-daily regimens can be used alternatively to provide lopinavir 800 mg/ritonavir 200 mg once daily (4 tablets containing 200 mg of lopinavir/50 mg of ritonavir once daily)

Oral solution: 10 mL once daily (800 mg of lopinavir/200 mg of ritonavir once daily)

A once-daily regimen is not recommended 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)

Oral

Patients receiving efavirenz, nelfinavir, or nevirapine:

Tablets: 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

Oral solution:alternatively, 6.5 mL of oral solution twice daily (lopinavir 520 mg/ritonavir 130 mg twice daily)

A once-daily regimen is not recommended in patients receiving efavirenz, nelfinavir, or nevirapine

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 nucleoside reverse transcriptase inhibitors (NRTIs).

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

Pediatric Patients

Dosage based on body weight or body surface area (BSA). Pediatric dosage should not exceed adult dosage. A once daily lopinavir-ritonavir regimen is not recommended in pediatric patients.

Oral

Patients not receiving efavirenz, nelfinavir, or nevirapine

Pediatric patients 14 days to <18 years of age (oral solution): See Table 1. Total dosage should not exceed the recommended adult daily dose of lopinavir 400 mg/ritonavir 100 mg (5 mL) twice daily.

Pediatric patients >6 months to <18 years of age (tablets): See Table 2.

Use lopinavir/ritonavir oral solution for pediatric patients with a body surface area <0.6 m² or those who are not able to reliably swallow a tablet

Oral

Pediatric Patients Receiving Efavirenz, Nelfinavir, or Nevirapine

Do notuse lopinavir/ritonavir in conjunction with efavirenz, nelfinavir, or nevirapine in children <6 months of age.

Pediatric patients >6 months to <18 years of age (oral solution): See Table 3.

Pediatric patients >6 months to <18 years of age (tablets): See Table 4.

Use lopinavir/ritonavir oral solution for pediatric patients with a body surface area <0.6 m² or those who are not able to reliably swallow a tablet.

Oral

Pediatric patients 14 days to 12 months of age (oral solution): Lopinavir 16 mg/kg and ritonavir 4 mg/kg (based on body weight) or lopinavir 300 mg/m²and ritonavir 75 mg/m² twice daily (based on body surface area).

Pediatric patients >12 months to 18 years of age (lopinavir/ritonavir 100/25 mg tablets): 2 tablets twice daily (weight 15–25 kg), 3 tablets twice daily (weight >25–35 kg), or 4 tablets twice daily (weight >35 kg). Alternatively, 2 tablets of lopinavir/ritonavir 200/50 mg can be used in patients weighing >35 kg.

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

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. Use with caution since lopinavir concentrations may be increased. Limited pharmacokinetic data in patients with mild to moderate hepatic impairment; not studied to date in those with severe hepatic impairment.

Renal Impairment

No specific dosage recommendations at this time. Renal clearance is negligible.

Geriatric Patients

No specific dosage recommendations at this time. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Pregnancy

Pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations: Lopinavir 400 mg/ritonavir 100 mg twice daily. Data insufficient to make dosage recommendations for pregnant women infected with HIV-1 strains with lopinavir-associated resistance mutations.

Dosage adjustments not needed in postpartum women.

Once-daily regimen not recommended during pregnancy. 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 other ingredient in the formulation.

• Concomitant use of lopinavir/ritonavir with drugs that are highly dependent on cytochrome P-450 (CYP) isoenzyme 3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events: alfuzosin, cisapride, colchicine, dronedarone, fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir), ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), lomitapide, lovastatin, lurasidone, oral midazolam, pimozide, ranolazine, simvastatin, sildenafil used for treatment of pulmonary arterial hypertension, triazolam.

• Concomitant use of lopinavir/ritonavir with drugs that are potent inducers of CYP3A: apalutamide, rifampin, St. John’s wort (Hypericum perforatum); such use is expected to result in significantly reduced lopinavir plasma concentrations and may be associated with loss of virologic response and development of resistance and cross-resistance.

Warnings/Precautions

Drug Interactions

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

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

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 approximately 42% (v/v) alcohol and approximately 15% (w/v) propylene glycol. Preterm neonates may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.

Life-threatening cardiac toxicity (including complete 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. Consider total amounts of ethanol and propylene glycol from all drugs administered to infants 14 days to 6 months of age in order to avoid toxicity.

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.

Patients with advanced HIV-1 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-1 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 protease inhibitors (PIs); diabetic ketoacidosis has occurred. Causal relationship not established.

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed. Consider monitoring for hyperglycemia, new-onset diabetes mellitus, or exacerbation of diabetes mellitus during treatment.

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.

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., patients with hypokalemia or congenital long QT syndrome; concomitant 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, M. tuberculosis, cytomegalovirus, Pneumocystis jirovecii); 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. Assess serum triglyceride and cholesterol concentrations prior to initiating therapy and periodically during treatment; manage lipid disorders as clinically appropriate.

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.

Specific Populations

Pregnancy

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

Available data from the APR suggest lopinavir and ritonavir do not increase risk of overall major birth defects compared with background rate for major birth defects.

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

Per US Department of Health and Human Services Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission, initiation of lopinavir/ritonavir in combination with 2 NRTIs not recommended, except in special circumstances, for treatment of HIV-1 infection in antiretroviral-naïve or antiretroviral-experienced 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.

Decreased plasma concentrations of lopinavir observed during second and third trimesters compared with postpartum; not clinically important when usual dosage used in pregnant women infected with HIV-1 strains without lopinavir-associated resistance mutations.

Lactation

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

Females and Males of Reproductive Potential

Reduced efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or additional barrier method during therapy.

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 approximately 42% (v/v) alcohol and approximately 15% (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.

Life-threatening cases of cardiac toxicity, 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 this population. 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 S_cr 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, and 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, consider the total amounts of alcohol and propylene glycol from all drugs the child is receiving to avoid toxicity associated with these excipients.

A once-daily regimen is not recommended 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.

Renal Impairment

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

Common Adverse Effects

Most common adverse effects include diarrhea, nausea, vomiting, hypertriglyceridemia, hypercholesterolemia.

Drug Interactions

Lopinavir is metabolized by CYP3A. Lopinavir/ritonavir inhibits CYP3A4. Does not inhibit CYP2D6, 2C9, 2C19, 2E1, 2B6, or 1A2.

Lopinavir/ritonavir induces glucuronidation and inhibits organic anion transport protein (OATP) 1B1.

The following drug interactions are based on studies using lopinavir and/or ritonavir. When using the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), consider drug interactions associated with both agents. The following list is a guide and is not comprehensive of all drugs that may interact with lopinavir/ritonavir. Consider appropriate references for comprehensive information.

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 the other drug.

Concomitant use contraindicated with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Concomitant use with other CYP3A substrates may require dosage adjustment or additional monitoring.

Drugs Metabolized by Glucuronidation

May decrease plasma concentrations of drugs metabolized by glucuronidation.

Drugs Transported by Organic Anion Transport Protein

May increase plasma concentrations of OATP1B1 substrates.

Specific Drugs

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.

Following administration of lopinavir/ritonavir tablet, peak plasma lopinavir concentrations attained in 4.4 ± 0.8 hours.

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 fed conditions. Tablet formulation associated with less pharmacokinetic variability than capsule formulation. Lopinavir concentrations similar following administration of lopinavir/ritonavir capsules and oral solution under fed conditions (500 kcal, 25% from fat).

Food

Tablets: Administration with a meal increased lopinavir AUC by 19% compared to fasted state.

Oral solution: Administration with a meal increased lopinavir AUC by 130% compared to fasted state.

Special Populations

HIV-infected pregnant women: Lopinavir plasma concentrations decreased in second and third trimesters compared with concentrations postpartum. Decrease not considered clinically important when the usual dosage of lopinavir/ritonavir is used in pregnant women infected with HIV type (HIV-1) strains without lopinavir-associated resistance mutations.

Distribution

Extent

Lopinavir and ritonavir cross the human placenta.

Plasma Protein Binding

Lopinavir >98% bound to human plasma proteins.

Elimination

Metabolism

Lopinavir metabolized 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

Approximately 10 and 83% of a lopinavir dose excreted in urine and feces, respectively.

Half-life

Plasma elimination half-life of lopinavir following administration of lopinavir/ritonavir tablet: 6.9 ± 2.2 hours.

Special Populations

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

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.

Patients should be advised that solution stored at 2–8°C is stable until expiration date. If stored at room temperature (≤25°C), use within 2 months.

Tablets

20–25°C (excursions permitted between 15–30°C). Dispense in original container or United States Pharmacopeia (USP) equivalent tight container.

Patients should be advised that exposure to high humidity outside the original container or USP equivalent tight container for >2 weeks not recommended.

Actions

• A fixed combination of 2 HIV protease inhibitors (PIs): lopinavir and ritonavir (lopinavir/ritonavir).

• Lopinavir 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 type 1 (HIV-1);1, has some in vitro activity against HIV type 2 (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

• Inform patients of the critical nature of compliance with human immunodeficiency virus (HIV) therapy and importance of remaining under the care of a clinician. Advise patients to take the antiretroviral regimen as prescribed, and to not alter or discontinue the regimen without consulting a clinician.

• Advise patients and caregivers that the oral solution should be administered using the calibrated dosing cup (supplied by the manufacturer) or an oral dosing syringe.

• Advise caregiver of a pediatric patient to inform their healthcare provider if the child’s weight changes in order to make sure that the child’s lopinavir/ritonavir dose is adjusted as needed.

• Advise patients to take lopinavir/ritonavir on a regular schedule and to not miss a dose since this may result in development of resistance. If a dose is missed, inform patients to take the dose as soon as it is remembered and take the next dose at the regularly scheduled time; if a dose is skipped, inform patients to not double the next dose.

• Inform patients that lopinavir/ritonavir tablets may be taken with or without food and to take lopinavir/ritonavir oral solution with food.

• Inform patients that there may be an increased risk of diarrhea with the once-daily regimen of lopinavir/ritonavir as compared with the twice-daily regimen.

• Advise patients that mild to severe skin reactions have occurred. Inform patients to contact a clinician if rash occurs.

• Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as lopinavir/ritonavir.

• Inform patients of the importance of notifying a clinician if manifestations of liver disease occur (e.g., jaundice of skin or eyes, itchy skin, loss of appetite, or pain, aching, or sensitivity in right upper quadrant of abdomen).

• Inform patients to notify a clinician if manifestations of pancreatitis occur (e.g., nausea, vomiting, stomach pain).

• Advise patients to inform a clinician if signs or symptoms of diabetes (e.g., frequent urination, excessive thirst, extreme hunger, unusual weight loss, increased blood glucose) occur.

• Advise patients that changes in an electrocardiogram may occur and to inform a clinician if they experience signs or symptoms of cardiac effects (e.g., dizziness, lightheadedness, heart rhythm changes, loss of consciousness).

• Advise patients that lopinavir/ritonavir therapy can cause substantial increases in total cholesterol and triglyceride concentrations.

• Advise patients that redistribution or accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.

• Inform caregivers that lopinavir/ritonavir oral solution contains alcohol and propylene glycol, which can cause serious adverse effects in neonates. Inform caregivers to immediately inform a clinician if an infant appears too sleepy or if their breathing has changed.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John’s wort), as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant. Advise women that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to lopinavir/ritonavir during pregnancy. Inform patients using hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with lopinavir/ritonavir.

• Advise women to inform their clinician if they plan to breast-feed. Advise HIV-infected women not to breast-feed.

• Advise patients of other precautionary information.

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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