Ritonavir Drug Information
Generic name: LOPINAVIR AND RITONAVIR
Cytochrome P450 3A Inhibitor [EPC] Protease Inhibitor [EPC]
Uses of Ritonavir
Lopinavir and ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV1 infection in adults and pediatric patients 14 days and older. Limitations of Use: Genotypic or phenotypic testing and/or treatment history should guide the use of lopinavir and ritonavir. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to lopinavir and ritonavir.
Dosage & Administration of Ritonavir
General Administration Recommendations Lopinavir and ritonavir tablets may be taken with or without food. Swallow lopinavir and ritonavir tablets whole. Do not chew, break, or crush lopinavir and ritonavir tablets.
Dosage Recommendations in Adults
Give lopinavir and ritonavir in once daily or twice daily dosing regimen at dosages noted in Tables 1 and 2. Lopinavir and ritonavir once daily dosing regimen is not recommended in: •Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. •In combination with carbamazepine, phenobarbital, or phenytoin. •In combination with efavirenz, nevirapine, or nelfinavir. •In pediatric patients younger than 18 years of age. In pregnant women.
Table 1. Recommended Dosage in Adults -Lopinavir And Ritonavir Twice Daily Regimen Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets 400 mg/100 mg (2 tablets) twice daily Increase the dose of lopinavir and ritonavir when administered in combination with efavirenz, nevirapine or nelfinavir. Table 3 outlines the dosage recommendations for twice daily dosing when lopinavir and ritonavir is taken in combination with these agents.
Table 3. Recommended Dosage in Adults -Lopinavir And Ritonavir Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets and 100 mg/25 mg Tablets 500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily
Dosage Recommendations in Pediatric Patients Lopinavir and ritonavir tablets are not recommended for once daily dosing in pediatric patients younger than 18 years of age. Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet. Pediatric Dosage Calculations Calculate the appropriate dose of lopinavir and ritonavir for each individual pediatric patient based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.
Body surface area (BSA) can be calculated as follows: The lopinavir and ritonavir dose can be calculated based on weight or BSA: Based on Weight: Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg) Based on BSA: Patient BSA (m 2 ) × Prescribed lopinavir dose (mg/m 2 ) = Administered lopinavir dose (mg) Tablet Dosage Recommendation in Pediatric Patients Older than 6 Months to Less than 18 Years: Table 5 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for lopinavir and ritonavir tablets. Table 5. Lopinavir And Ritonavir Tablet Daily Dosage Recommendations in Pediatric Patients > 6 Months to < 18 Years of Age Without Concomitant Efavirenz, Nevirapine, or Nelfinavir 4 Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir Dosing recommendations using tablets Table 7 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for lopinavir and ritonavir tablets when given in combination with efavirenz, nevirapine, or nelfinavir.
Table 7. Lopinavir And Ritonavir Tablet Daily Dosage Recommendations for Pediatric Patients > 6 Months to < 18 Years of Age With Concomitant Efavirenz†, Nevirapine, or Nelfinavir† 5 Please refer to the individual product labels for appropriate dosing in children. 288
Dosage Recommendations in Pregnancy Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions. No dosage adjustment of lopinavir and ritonavir is required for patients during the postpartum period.
| Lopinavir And Ritonavir Dosage Form | Recommended Dosage |
|---|---|
| 200 mg/50 mg Tablets | 800 mg/200 mg (4 tablets) once daily |
| Lopinavir And Ritonavir Dosage Form | Recommended Dosage |
|---|---|
| 200 mg/50 mg Tablets | 400 mg/100 mg (2 tablets) twice daily |
| Lopinavir And Ritonavir Dosage Form | Recommended Dosage |
|---|---|
| 200 mg/50 mg Tablets and 100 mg/25 mg Tablets | 500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily |
| Body Weight (kg) | Body Surface Area (m 2 ) | Recommended number of 100/25 mg Tablets Twice Daily |
|---|---|---|
| ≥15 to 25 | ≥0.6 to < 0.9 | 2 |
| >25 to 35 | ≥0.9 to < 1.4 | 3 |
| >35 | ≥1.4 | 4 |
| Body Weight (kg) | Body Surface Area (m 2 ) | Recommended number of 100/25 mg Tablets Twice Daily |
|---|---|---|
| ≥15 to 20 | ≥0.6 to < 0.8 | 2 |
| >20 to 30 | ≥0.8 to < 1.2 | 3 |
| >30 to 45 | ≥1.2 to < 1.7 | 4 |
| >45 | ≥1.7 | 5 [ see Dosage and Administration ( 2.4 )] |
Side Effects of Ritonavir
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, lopinavir and ritonavir was used in combination with efavirenz or nevirapine. In clinical studies the incidence of diarrhea in patients treated with either lopinavir and ritonavir capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily.
Any grade of diarrhea was reported by at least half of patients taking once daily lopinavir and ritonavir capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily lopinavir and ritonavir and 1.8-3.7% of those taking twice daily lopinavir and ritonavir reported ongoing diarrhea. Commonly reported adverse reactions to lopinavir and ritonavir included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia.
Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 8): Table 8. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving Lopinavir And Ritonavir in Combined Phase II/IV Studies N=2, Laboratory Abnormalities in Adults The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 9 (treatment-naïve patients) and Table 10 (treatment-experienced patients).
Table 9. Grade 3-4 Laboratory Abnormalities Reported in ≥. The adverse reaction profile seen during Study 940 was similar to that for adult patients.
A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).
The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2).
Patients also had saquinavir mesylate added to their regimen at Week 4. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.
Laboratory Abnormalities in Pediatric Patients The percentages of pediatric patients treated with combination therapy including lopinavir and ritonavir with Grade 3-4 laboratory abnormalities are presented in Table 11. Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ Postmarketing Experience The following adverse reactions have been reported during postmarketing use of lopinavir and ritonavir.
Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to lopinavir and ritonavir exposure. Body as a Whole Redistribution/accumulation of body fat has been reported. Cardiovascular Bradyarrhythmias.
First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes. Renal and Urinary Disorders Nephrolithiasis Skin and Appendages Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
| System Organ Class (SOC) and Adverse Reaction | n | % |
|---|---|---|
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | ||
| anemia* | 54 | 2.1 |
| leukopenia and neutropenia* | 44 | 1.7 |
| lymphadenopathy* | 35 | 1.3 |
| CARDIAC DISORDERS | ||
| atherosclerosis such as myocardial infarction* | 10 | 0.4 |
| atrioventricular block* | 3 | 0.1 |
| tricuspid valve incompetence* | 3 | 0.1 |
| EAR AND LABYRINTH DISORDERS | ||
| vertigo* | 7 | 0.3 |
| tinnitus | 6 | 0.2 |
| ENDOCRINE DISORDERS | ||
| hypogonadism* | 16 | 0.8 1 |
| EYE DISORDERS | ||
| visual impairment* | 8 | 0.3 |
| GASTROINTESTINAL DISORDERS | ||
| diarrhea* | 510 | 19.5 |
| nausea | 269 | 10.3 |
| vomiting* | 177 | 6.8 |
| abdominal pain (upper and lower) | 160 | 6.1 |
| gastroenteritis and colitis* | 66 | 2.5 |
| dyspepsia | 53 | 2.0 |
| pancreatitis* | 45 | 1.7 |
| Gastroesophageal Reflux Disease (GERD) | 40 | 1.5 |
| hemorrhoids | 39 | 1.5 |
| flatulence | 36 | 1.4 |
| abdominal distension | 34 | 1.3 |
| constipation* | 26. | 1.0 |
| stomatitis and oral ulcers* | 24 | 0.9 |
| duodenitis and gastritis* | 20 | 0.8 |
| gastrointestinal hemorrhage including rectal hemorrhage* | 13 | 0.5 |
| dry mouth | 9 | 0.3 |
| gastrointestinal ulcer* | 6 | 0.2 |
| fecal incontinence | 5 | 0.2 |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||
| fatigue including asthenia* | 198 | 7.6 |
| HEPATOBILIARY DISORDERS | ||
| hepatitis including AST, ALT, and GGT increases* | 91 | 3.5 |
| hepatomegaly | 5 | 0.2 |
| cholangitis | 3 | 0.1 |
| hepatic steatosis | 3 | 0.1 |
| IMMUNE SYSTEM DISORDERS | ||
| hypersensitivity including urticaria and angioedema* | 70 | 2.7 |
| immune reconstitution syndrome | 3 | 0.1 |
| INFECTIONS AND INFESTATIONS | ||
| upper respiratory tract infection* | 363 | 13.9 |
| lower respiratory tract infection* | 202 | 7.7 |
| skin infections including cellulitis, folliculitis, and furuncle* | 86 | 3.3 |
| METABOLISM AND NUTRITION DISORDERS | ||
| hypercholesterolemia* | 192 | 7.4 |
| hypertriglyceridemia* | 161 | 6.2 |
| weight decreased* | 61 | 2.3 |
| decreased appetite | 52 | 2.0 |
| blood glucose disorders including diabetes mellitus* | 30 | 1.1 |
| weight increased* | 20 | 0.8 |
| lactic acidosis* | 11 | 0.4 |
| increased appetite | 5 | 0.2 |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | ||
| musculoskeletal pain including arthralgia and back pain* | 166 | 6.4 |
| myalgia* | 46 | 1.8 |
| muscle disorders such as weakness and spasms* | 34 | 1.3 |
| rhabdomyolysis* | 18 | 0.7 |
| osteonecrosis | 3 | 0.1 |
| NERVOUS SYSTEM DISORDERS | ||
| headache including migraine* | 165 | 6.3 |
| insomnia* | 99 | 3.8 |
| neuropathy and peripheral neuropathy* | 51 | 2.0 |
| dizziness* | 45 | 1.7 |
| ageusia* | 19 | 0.7 |
| convulsion* | 9 | 0.3 |
| tremor* | 9 | 0.3 |
| cerebral vascular event* | 6 | 0.2 |
| PSYCHIATRIC DISORDERS | ||
| anxiety* | 101 | 3.9 |
| abnormal dreams* | 19 | 0.7 |
| libido decreased | 19 | 0.7 |
| RENAL AND URINARY DISORDERS | ||
| renal failure* | 31 | 1.2 |
| hematuria* | 20 | 0.8 |
| nephritis* | 3 | 0.1 |
| REPRODUCTIVE SYSTEM AND BREAST DISORDERS | ||
| erectile dysfunction* | 34 | 1.7 1 |
| menstrual disorders - amenorrhea, menorrhagia* | 10 | 1.7 2 |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||
| rash including maculopapular rash* | 99 | 3.8 |
| lipodystrophy acquired including facial wasting* | 58 | 2.2 |
| dermatitis/rash including eczema and seborrheic dermatitis* | 50 | 1.9 |
| night sweats* | 42 | 1.6 |
| pruritus* | 29 | 1.1 |
| alopecia | 10 | 0.4 |
| capillaritis and vasculitis* | 3 | 0.1 |
| VASCULAR DISORDERS | ||
| hypertension* | 47 | 1.8 |
| deep vein thrombosis* | 17 | 0.7 |
| *Represents a medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574) | ||
| Study 863 (48 Weeks) | Study 720 (360 Weeks) | Study 730 (48 Weeks) | ||||
|---|---|---|---|---|---|---|
| Variable | Limit 1 | Lopinavir And Ritonavir 400/100 mg Twice Daily + d4T +3TC (N = 326) | Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) | Lopinavir And Ritonavir Twice Daily + d4T + 3TC (N = 100) | Lopinavir And Ritonavir Once Daily + TDF +FTC (N=333) | Lopinavir And Ritonavir Twice Daily + TDF +FTC (N=331) |
| Chemistry | High | |||||
| Glucose | > 250 mg/dL | 2% | 2% | 4% | 0% | <1% |
| Uric Acid | >12 mg/dL | 2% | 2% | 5% | <1% | 1% |
| SGOT/ AST 2 | > 180 U/L | 2% | 4% | 10% | 1% | 2% |
| SGPT/ ALT 2 | >215 U/L | 4% | 4% | 11% | 1% | 1% |
| GGT | >300 U/L | N/A | N/A | 10% | N/A | N/A |
| Total Cholesterol | >300 mg/dL | 9% | 5% | 27% | 4% | 3% |
| Triglycerides | >750 mg/dL | 9% | 1% | 29% | 3% | 6% |
| Amylase | >2 x ULN | 3% | 2% | 4% | N/A | N/A |
| Lipase | >2 x ULN | N/A | N/A | N/A | 3% | 5% |
| Chemistry | Low | |||||
| Calculated Creatinine Clearance | <50 mL/min | N/A | N/A | N/A | 2% | 2% |
| Hematology | Low | |||||
| Neutrophils | <0.75 x 10 9 /L | 1% | 3% | 5% | 2% | 1% |
| 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Criterion for Study 730 was >5x ULN (AST/ALT). | ||||||
| Study 888 (48 Weeks) | Study 957 2 and Study 765 3 (84-144 Weeks) | Study 802 (48 Weeks) | ||||
|---|---|---|---|---|---|---|
| Variable | Limit 1 | Lopinavir And Ritonavir 400/100 mg Twice Daily + NVP + NRTIs (N = 148) | Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140) | Lopinavir And Ritonavir Twice Daily + NNRTI + NRTIs (N = 127) | Lopinavir And Ritonavir 800/200 mg Once Daily +NRTIs (N=300) | Lopinavir And Ritonavir 400/100 mg Twice Daily +NRTIs (N=299) |
| Chemistry | High | |||||
| Glucose | >250 mg/dL | 1% | 2% | 5% | 2% | 2% |
| Total Bilirubin | >3.48 mg/dL | 1% | 3% | 1% | 1% | 1% |
| SGOT/AST 4 | >180 U/L | 5% | 11% | 8% | 3% | 2% |
| SGPT/ALT 4 | >215 U/L | 6% | 13% | 10% | 2% | 2% |
| GGT | >300 U/L | N/A | N/A | 29% | N/A | N/A |
| Total Cholesterol | >300 mg/dL | 20% | 21% | 39% | 6% | 7% |
| Triglycerides | >750 mg/dL | 25% | 21% | 36% | 5% | 6% |
| Amylase | >2 x ULN | 4% | 8% | 8% | 4% | 4% |
| Lipase | >2 x ULN | N/A | N/A | N/A | 4% | 1% |
| Creatine Phosphokinase | >4 x ULN | N/A | N/A | N/A | 4% | 5% |
| Chemistry | Low | |||||
| Calculated Creatinine Clearance | <50 mL/min | N/A | N/A | N/A | 3% | 3% |
| Inorganic Phosphorus | <1.5 mg/dL | 1% | 0% | 2% | 1% | <1% |
| Hematology | Low | |||||
| Neutrophils | <0.75 x 10 9 /L | 1% | 2% | 4% | 3% | 4% |
| Hemoglobin | <80 g/L | 1% | 1% | 1% | 1% | 2% |
| 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and efavirenz. 3 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 36) or 400/200 mg twice daily (n = 34) for 144 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was >5x ULN (AST/ALT). | ||||||
| Variable | Limit 1 | Lopinavir and Ritonavir Twice Daily + RTIs (N = 100) |
| Chemistry | High | |
| Sodium | > 149 mEq/L | 3% |
| Total Bilirubin | ≥ 3.0 x ULN | 3% |
| SGOT/AST | > 180 U/L | 8% |
| SGPT/ALT | > 215 U/L | 7% |
| Total Cholesterol | > 300 mg/dL | 3% |
| Amylase | > 2.5 x ULN | 7%2 |
| Chemistry | Low | |
| Sodium | < 130 mEq/L | 3% |
| Hematology | Low | |
| Platelet Count | < 50 x 109/L | 4% |
| Neutrophils | < 0.40 x 109/L | 2% |
| 1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase. | ||
Warnings & Cautions for Ritonavir
Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of lopinavir and ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving lopinavir and ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of lopinavir and ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of lopinavir and ritonavir. Loss of therapeutic effect of lopinavir and ritonavir and possible development of resistance. See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.
Consider the potential for drug interactions prior to and during lopinavir and ritonavir therapy; review concomitant medications during lopinavir and ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications.
Toxicity in Preterm Neonates Lopinavir and ritonavir oral solution contains the excipients ethanol, approximately 42% (v/v) and propylene glycol, approximately 15% (w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.
Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir and ritonavir oral solution. Lopinavir and ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of Lopinavir and ritonavir oral solution in this patient population has not been established.
However, if the benefit of using Lopinavir and ritonavir oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to Lopinavir and ritonavir oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of ethanol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients.
Pancreatitis Pancreatitis has been observed in patients receiving lopinavir and ritonavir therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to lopinavir and ritonavir have not been established, marked triglyceride elevations are a risk factor for development of pancreatitis.
Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during lopinavir and ritonavir therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and lopinavir and ritonavir and/or other antiretroviral therapy should be suspended as clinically appropriate.
Hepatotoxicity Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of lopinavir and ritonavir. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis.
A causal relationship with lopinavir and ritonavir therapy has not been established. Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of lopinavir and ritonavir in conjunction with other antiretroviral agents. Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir and ritonavir and patients should be monitored closely during treatment.
Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of lopinavir and ritonavir treatment.
QT Interval Prolongation
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of lopinavir and ritonavir could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval.
PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. Lopinavir and ritonavir should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of lopinavir and ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of lopinavir and ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred.
In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with lopinavir and ritonavir.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lopinavir and ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis) which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Lipid Elevations Treatment with lopinavir and ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating lopinavir and ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with lopinavir and ritonavir and HMG-CoA reductase inhibitors.
Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Patients with Hemophilia
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced.
Resistance/Cross-resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in lopinavir and ritonavir -treated patients, it is unknown what effect therapy with lopinavir and ritonavir will have on the activity of subsequently administered protease inhibitors.
Drug Interactions with Ritonavir
Potential for Lopinavir And Ritonavir to Affect Other Drugs Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with lopinavir and ritonavir. Thus, co-administration of lopinavir and ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.
Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 12. Additionally, lopinavir and ritonavir induces glucuronidation. Published data suggest that lopinavir is an inhibitor of OATP1B1.
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.
Potential for Other Drugs to Affect Lopinavir Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce lopinavir and ritonavir’s therapeutic effect. Although not observed in the lopinavir and ritonavir /ketoconazole drug interaction study, co-administration of lopinavir and ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Established and Other Potentially Significant Drug Interactions Table 12 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction for magnitude of interaction. Table 12.
Established and Other Potentially Significant Drug Interactions Lopinavir and ritonavir once daily in combination with nelfinavir is not recommended. Lopinavir and ritonavir once daily in combination with efavirenz or nevirapine is not recommended. Contraindicated due to potential hypotension.
Analgesics Opioid: methadone* fentanyl ↓ methadone ↑ fentanyl Dosage of methadone may need to be increased when co-administered with lopinavir and ritonavir. Non-opioid analgesic (selective blocker of Nav1.8 sodium channels): suzetrigine ↑ suzetrigine and active metabolite M6-SUZ Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions. Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions.
Antiarrhythmics: dronedarone ↑ dronedarone Contraindicated due to potential for cardiac arrhythmias. Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with lopinavir and ritonavir. Anticancer Agents: abemaciclib, apalutamide, encorafenib, ibrutinib, ivosidenib, dasatinib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓lopinavir/ritonavir# Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors.
Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment. Antimycobacterial: rifampin ↓ lopinavir Contraindicated due to potential loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors or other co-administered antiretroviral agents. Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI Motility Agent: cisapride ↑ cisapride Contraindicated due to potential for cardiac arrhythmias. Contraindicated due to increased risk of alanine transaminase (AL-T) elevations.
Lipid-modifying agents HMG-Co A Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTT-P) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity. Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio®) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PA-H): Sildenafil (Revatio®) is contraindicated. Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression. see Clinical Pharmacology for magnitude of interaction.
Drugs with No Observed or Predicted Interactions with Lopinavir And Ritonavir Drug interaction or clinical studies reveal no clinically significant interaction between lopinavir and ritonavir and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine. Based on known metabolic profiles, clinically significant drug interactions are not expected between lopinavir and ritonavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.
| Concomitant Drug Class: Drug Name | Effect on Concentration of Lopinavir or Concomitant Drug | Clinical Comments |
|---|---|---|
| HIV-1 Antiviral Agents | ||
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir | ↓ amprenavir ↓ lopinavir | An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* | ↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with indinavir. |
| HIV-1 Protease Inhibitor: nelfinavir* | ↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir | Lopinavir and ritonavir once daily in combination with nelfinavir is not recommended. [see Dosage and Administration ( 2 )]. |
| HIV-1 Protease Inhibitor: ritonavir* | ↑ lopinavir | Appropriate doses of additional ritonavir in combination with lopinavir and ritonavir with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir | ↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir* | ↓ lopinavir | Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended. |
| HIV CCR5 – Antagonist: maraviroc* | ↑ maraviroc | When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc. |
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* | ↓ lopinavir | Increase the dose of lopinavir and ritonavirto 500/125 mg when lopinavir and ritonavir tablet is co-administered with efavirenz or nevirapine. Lopinavir and ritonavir once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration ( 2 )]. |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine | ↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine | Lopinavir and ritonavir tablets can be administered simultaneously with didanosine without food. For lopinavir and ritonavir oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after lopinavir and ritonavir oral solution (given with food). | |
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate* | ↑ tenofovir | Patients receiving lopinavir and ritonavir and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine | ↓ abacavir ↓ zidovudine | The clinical significance of this potential interaction is unknown. |
| Other Agents | ||
| Alpha 1-Adrenoreceptor Antagonist: alfuzosin | ↑ alfuzosin | Contraindicated due to potential hypotension [see Contraindications ( 4 )]. |
| Analgesics Opioid: methadone* fentanyl | ↓ methadone ↑ fentanyl | Dosage of methadone may need to be increased when co-administered with lopinavir and ritonavir. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with lopinavir and ritonavir. |
| Non-opioid analgesic (selective blocker of Nav1.8 sodium channels): suzetrigine | ↑ suzetrigine and active metabolite M6-SUZ | Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions [see Contraindications ( 4 )]. |
| Antianginal: ranolazine | ↑ ranolazine | Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications ( 4 )]. |
| Antiarrhythmics: dronedarone | ↑ dronedarone | Contraindicated due to potential for cardiac arrhythmias [see Contraindications ( 4 )]. |
| Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine | ↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with lopinavir and ritonavir. |
| Anticancer Agents: abemaciclib, apalutamide, encorafenib, ibrutinib, ivosidenib, dasatinib, neratinib, nilotinib, venetoclax, vinblastine, vincristine | ↑ anticancer agents ↓lopinavir/ritonavir# | Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors [see Contraindications ( 4 )]. Avoid co-administration of encorafenib or ivosidenib with lopinavir and ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with lopinavir and ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with lopinavir and ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with lopinavir and ritonavir. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir and ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as lopinavir and ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants: warfarin, rivaroxaban | ↑↓ warfarin ↑ rivaroxaban | Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during lopinavir and ritonavir and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and lopinavir and ritonavir. Co-administration of lopinavir and ritonavir and rivaroxaban may lead to increased risk of bleeding. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin | ↓ lopinavir ↓ phenytoin | Lopinavir and ritonavir may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. Lopinavir and ritonavir once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and lopinavir and ritonavir may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with lopinavir and ritonavir |
| Anticonvulsants: lamotrigine, valproate | ↓ lamotrigine ↓ or ↔ valproate | A dose increase of lamotrigine or valproate may be needed when co-administered with lopinavir and ritonavir and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. |
| Antidepressant: bupropion | ↓ bupropion ↓ active metabolite, hydroxybupropion | Patients receiving lopinavir and ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone | ↑ trazodone | Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin | ↑ clarithromycin | For patients with renal impairment, adjust clarithromycin dose as follows: For patients on lopinavir and ritonavir with CL CR 30 to 60 m L/min the dose of clarithromycin should be reduced by 50%. For patients on lopinavir and ritonavir with CL CR < 30 m L/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate* | ↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium | High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and lopinavir and ritonavir should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and lopinavir and ritonavir should be coadministered with caution. Alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine | ↑ colchicine | Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications ( 4 )]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FM-F)-co-administration of colchicine in patients on lopinavir and ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifampin | ↓ lopinavir | Contraindicated due to potential loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors or other co-administered antiretroviral agents [see Contraindications ( 4 )]. |
| Antimycobacterial: bedaquiline | ↑ bedaquiline | Bedaquiline should only be used with lopinavir and ritonavir if the benefit of co-administration outweighs the risk. |
| Antimycobacterial: rifabutin* | ↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antiparasitic: atovaquone | ↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Antipsychotics: lurasidone pimozide | ↑ lurasidone ↑ pimozide | Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications ( 4 )]. Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications ( 4 )]. |
| Antipsychotics: quetiapine | ↑ quetiapine | Initiation of lopinavir and ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking lopinavir and ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Contraceptive: ethinyl estradiol* | ↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when lopinavir and ritonavir is coadministered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine | ↑ dihydropyridine calcium channel blockers | Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered. |
| Disulfiram/metronidazole | Lopinavir and ritonavir oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan | ↑ bosentan | Co-administration of bosentan in patients on lopinavir and ritonavir: In patients who have been receiving lopinavir and ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of lopinavir and ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of lopinavir and ritonavir. After at least 10 days following the initiation of lopinavir and ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine | ↑ ergot derivatives | Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications ( 4 )]. |
| GI Motility Agent: cisapride | ↑ cisapride | Contraindicated due to potential for cardiac arrhythmias [see Contraindications ( 4 )]. |
| Gn RH Receptor Antagonists: elagolix | ↑ elagolix ↓ lopinavir/ritonavir | Concomitant use of elagolix 200 mg twice daily and lopinavir and ritonavir for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and lopinavir and ritonavir to 6 months. |
| Hepatitis C direct acting antiviral: elbasvir/grazoprevir | ↑ elbasvir/grazoprevir | Contraindicated due to increased risk of alanine transaminase (AL-T) elevations [see Contraindications ( 4 )]. |
| Hepatitis C direct acting antivirals: boceprevir* glecaprevir/pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilapre vir ombitasvir/paritaprevir/ ritonavir and dasabuvir* | ↓ lopinavir ↓ boceprevir ↓ ritonavir ↑glecaprevir ↑ pibrentasvir ↑ simeprevir ↑ sofosbuvir ↑ velpatasvir ↑ voxilaprevir ↑ ombitasvir ↑ paritaprevir ↑ ritonavir ↔ dasabuvir | It is not recommended to co-administer lopinavir and ritonavir and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir. |
| Herbal Products: St. John's Wort (hypericum perforatum) | ↓ lopinavir | Contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors [see Contraindications ( 4 )]. |
| Lipid-modifying agents HMG-Co A Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTT-P) Inhibitor: lomitapide | ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide | Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 )]. Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications ( 4 )]. |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus | ↑ immuno suppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with lopinavir and ritonavir. |
| Kinase Inhibitors: fostamatinib (also see anticancer agents above) | ↑ fostamatinib metabolite R406 | Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. |
| Long-acting beta-adrenoceptor Agonist: salmeterol | ↑ salmeterol | Concurrent administration of salmeterol and lopinavir and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics: methadone, fentanyl | ↓ methadone ↑ fentanyl | Dosage of methadone may need to be increased when co-administered with lopinavir and ritonavir. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with lopinavir and ritonavir. |
| PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil | ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil | Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio®) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications ( 4 )]. Do not use lopinavir and ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving lopinavir and ritonavir. Coadministration of lopinavir and ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PA-H): Sildenafil (Revatio®) is contraindicated [see Contraindications ( 4 )]. The following dose adjustments are recommended for use of tadalafil (Adcirca®) with lopinavir and ritonavir: Co-administration of ADCIRCA in patients on lopinavir and ritonavir: In patients receiving lopinavir and ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of lopinavir and ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of lopinavir and ritonavir. Stop ADCIRCA at least 24 hours prior to starting lopinavir and ritonavir. After at least one week following the initiation of lopinavir and ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| Sedative/Hypnotics: triazolam, orally administered midazolam | ↑ triazolam ↑ midazolam | Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications ( 4 )]. |
| Sedative/Hypnotics: parenterally administered midazolam | ↑ midazolam | If lopinavir and ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone | ¯ lopinavir ↑ glucocorticoide | Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. |
| see Clinical Pharmacology ( 12.3 ) for magnitude of interaction. | ||
Pregnancy Safety for Ritonavir
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lopinavir and ritonavir during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data).
The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group.
The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses. Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.
There are insufficient data to recommend lopinavir and ritonavir dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period. Once daily lopinavir and ritonavir dosing is not recommended in pregnancy.
Avoid use of lopinavir and ritonavir oral solution during pregnancy due to the ethanol content. Lopinavir and ritonavir oral solution contains the excipients ethanol, approximately 42% v/v and propylene glycol, approximately 15%. Data Human Data Lopinavir and ritonavir was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial.
No new trends in the safety profile were identified in pregnant women dosed with lopinavir and ritonavir compared to the safety described in non-pregnant adults, based on the review of these limited data. Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.
Animal Data Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a pre-and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.
No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
Pediatric Use of Ritonavir
Pediatric Use The safety, efficacy, and pharmacokinetic profiles of lopinavir and ritonavir in pediatric patients below the age of 14 days have not been established. Lopinavir and ritonavir should not be administered once daily in pediatric patients. An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of lopinavir and ritonavir oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m2 twice daily plus two NRTIs in HIVinfected infants ≥14 days and < 6 months of age.
Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-1 RNA <400 copies/mL at Week 24. Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of lopinavir and ritonavir oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years.
Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m2 oral solution 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). Patients also had saquinavir mesylate added to their regimen.
This strategy was intended to assess whether higher than approved doses of lopinavir and ritonavir could overcome protease inhibitor cross-resistance. High doses of lopinavir and ritonavir exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks.
A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of lopinavir and ritonavir tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged < 18 years, ≥ 15 kg in weight, receiving cART that included lopinavir and ritonavir, HIV-1 ribonucleic acid (RNA) < 50 copies/mL for at least 24 weeks and able to swallow tablets. At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing.
The safety profile was similar between the two treatment arms although there was a greater incidence of diarrhea in the once daily treated subjects.
Contraindications for Ritonavir
Lopinavir and ritonaviris contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir. Lopinavir and ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or lifethreatening reactions. o Alpha 1-Adrenoreceptor Antagonist: alfuzosin o Antianginal: ranolazine o Antiarrhythmic: dronedarone o Anti-gout: colchicine o Antipsychotics: lurasidone, pimozide o Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine o GI Motility Agent: cisapride o Hepatitis C direct acting antiviral: elbasvir/grazoprevir o HMG-CoA Reductase Inhibitors: lovastatin, simvastatin o Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide o Non-opioid Analgesic(selective blocker of Nav1.8 sodium channels): suzetrigine o PDE5 Inhibitor: sildenafil (Revatio®) when used for the treatment of pulmonary arterial hypertension o Sedative/Hypnotics: triazolam, orally administered midazolam Lopinavir and ritonavir is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. o Anticancer Agents: apalutamide o Antimycobacterial: rifampin o Herbal Products: St. John's Wort (hypericum perforatum) Hypersensitivity to lopinavir and ritonavir tablets (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir.
Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or lifethreatening events.
Overdosage Information for Ritonavir
Overdoses with lopinavir and ritonavir oral solution have been reported. One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of lopinavir and ritonavir oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure.
Healthcare professionals should be aware that lopinavir and ritonavir oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of lopinavir and ritonavir, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose. This is especially important for infants and young children. Lopinavir and ritonavir oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol.
Ingestion of the product over the recommended dose by an infant or a young child could result in significant toxicity and could potentially be lethal. Human experience of acute overdosage with lopinavir and ritonavir tablets is limited. Treatment of overdose with lopinavir and ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
There is no specific antidote for overdose with lopinavir and ritonavir. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.
Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
Clinical Studies of Ritonavir
Adult
- Patients without Prior Antiretroviral Therapy Study 863: Lopinavir and Ritonavir Capsules twice daily + stavudine + lamivudine compared to nelfinavir three times daily + stavudine + lamivudine Study 863 was a randomized, double-blind, multicenter trial comparing treatment with lopinavir and ritonavir capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir (750 mg three times daily) plus stavudine and lamivudine in 653 antiretroviral treatment naïve patients. Treatment response and outcomes of randomized treatment are presented in Table 21. Table 21. Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 22. Table 22. Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863) Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm3 for the lopinavir and ritonavir arm and 195 cells/mm3 for the nelfinavir arm.
- Study 730: Lopinavir and Ritonavir Tablets once daily + tenofovir DF + emtricitabine compared to lopinavir and ritonavir Tablets twice daily + tenofovir DF + emtricitabine Study 730 was a randomized, open-label, multicenter trial comparing treatment with lopinavir and ritonavir 800/200 mg once daily plus tenofovir DF and emtricitabine versus lopinavir and ritonavir 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.
- Further stratification within each group was 1: 1 (tablet vs. capsule). Patients administered the capsule were switched to the tablet formulation at Week 8 and maintained on their randomized dosing schedule. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Table 23. Mean CD4+ cell count increases at Week 48 were 186 cells/mm3 for the lopinavir and ritonavir once daily arm and 198 cells/mm3 for the lopinavir and ritonavir twice daily arm.
- Adult Patients with Prior Antiretroviral Therapy Study 888: Lopinavir and Ritonavir Capsules twice daily + nevirapine + NRTIs compared to investigatorselected protease inhibitor(s) + nevirapine + NRTIs Study 888 was a randomized, open-label, multicenter trial comparing treatment with lopinavir and ritonavir capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients. Table 24. Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm3 for the lopinavir and ritonavir arm and 112 cells/mm3 for the investigator-selected protease inhibitor(s) arm.
- Study 802: Lopinavir and ritonavir tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Co-administered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in AntiretroviralExperienced, HIV-1 Infected Subjects M06-802 was a randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of lopinavir and ritonavir tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Of the enrolled subjects, 55% on both treatment arms had not been previously treated with a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti-HIV treatment regimen. Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Table 25. Outcomes of Randomized Treatment Through Week 48 (Study 802) Through 48 weeks of treatment, the mean change from baseline for CD4 + cell count was 135 cells/mm3 for the once daily group and 122 cells/mm3 for the twice daily group.
- Other Studies Supporting Approval in Adult Patients Study 720: Lopinavir and ritonavir twice daily + stavudine + lamivudine Study 765: Lopinavir and ritonavir twice daily + nevirapine + NRTIs Study 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with lopinavir and ritonavir at up to three dose levels (200/100 mg twice daily, 400/100 mg twice daily, and 400/200 mg twice daily). In Study 720, all patients switched to 400/100 mg twice daily between Weeks 48-72. Mean (range) baseline CD4+ cell counts for patients in study 720 and study cells/mm3, respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study log10 copies/mL, respectively. Among patients completing 360 weeks of treatment with CD4+ cell count measurements, the mean (median) increase in CD4+ cell count was 501 cells/mm3. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/mL. Seven of 10 infants had HIV-1 RNA <400 copies/mL at Week 24. At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log10 copies/mL. Ten of 21 infants had HIV RNA <400 copies/mL at Week 24. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m2 dose. Mean baseline CD4+ cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/mL. The mean increase from baseline in CD4+ cell count was 404 cells/mm3 for antiretroviral naïve and 284 cells/mm3 for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naïve patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event. • Dose selection in pediatric patients was based on the following: Among patients 14 days to 6 months of age receiving 300/75 mg/m2 twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age. Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose. • For all age groups, the body surface area dosing was converted to body weight dosing using the patient’s prescribed lopinavir dose.
| Outcome | Lopinavir and Ritonavir +d4T+3TC (N = 326) | Nelfinavir+d4T+3TC (N = 327) |
|---|---|---|
| Responder1 | 75% | 62% |
| Virologic failure2 Rebound Never suppressed through Week 48 | 9% 7% 2% | 25% 15% 9% |
| Death | 2% | 1% |
| Discontinued due to adverse events | 4% | 4% |
| Discontinued for other reasons3 | 10% | 8% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the lopinavir and ritonavir arm and 24% in the nelfinavir arm. | ||
| Baseline Viral Load (HIV-1 RNA copies/mL) | Lopinavir and Ritonavir +d4T+3TC | Nelfinavir +d4T+3TC | ||||
|---|---|---|---|---|---|---|
| <400 copies/mL 1 | <50 copies/mL 2 | n | <400 copies/mL 1 | <50 copies/mL 2 | n | |
| < 30,000 | 74% | 71% | 82 | 79% | 72% | 87 |
| ≥ 30,000 to < 100,000 | 81% | 73% | 79 | 67% | 54% | 79 |
| ≥ 100,000 to < 250,000 | 75% | 64 | 83 | 60% | 47% | 72 |
| ≥ 250,000 | 72% | 60% | 82 | 44% | 33% | 89 |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Patients achieved HIV-1 RNA < 50 copies/mL at Week 48. | ||||||
| Outcome | Lopinavir and Ritonavir Once Daily + TDF + FTC (n = 333) | Lopinavir and Ritonavir Twice Daily + TDF + FTC (n = 331) |
|---|---|---|
| Responder1 | 78% | 77% |
| Virologic failure2 Rebound Never suppressed through Week 48 | 10% 5% 5% | 8% 5% 3% |
| Death | 1% | <1% |
| Discontinued due to adverse events | 4% | 3% |
| Discontinued for other reasons3 | 8% | 11% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. | ||
| Outcome | Lopinavir and Ritonavir + nevirapine + NRTIs (n = 148) | Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n = 140) |
|---|---|---|
| Responder1 | 57% | 33% |
| Virologic failure2 Rebound Never suppressed through Week 48 | 24% 11% 13% | 41% 19% 23% |
| Death | 1% | 2% |
| Discontinued due to adverse events | 5% | 11% |
| Discontinued for other reasons3 | 14% | 13% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. | ||
| Outcome | Lopinavir and Ritonavir Once Daily + NRTIs (n = 300) | Lopinavir and Ritonavir Twice Daily + NRTIs (n = 299) |
|---|---|---|
| Virologic Success (HIV-1 RNA <50 copies/mL) | 57% | 54% |
| Virologic failure1 | 22% | 24% |
| No virologic data in Week 48 window | ||
| Discontinued study due to adverse event or death2 | 5% | 7% |
| Discontinued study for other reasons3 | 13% | 12% |
| Missing data during window but on study | 3% | 3% |
| 1 Includes patients who discontinued prior to Week 48 for lack or loss of efficacy and patients with HIV-1 RNA ≥ 50 copies/mL at Week 48. 2 Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48. 3 Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons. | ||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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