INN monograph
Ritonavir
Cytochrome P450 3A Inhibitor [EPC], Protease Inhibitor [EPC] · POM
Source-linked · Updated 03 Aug 2026 · Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Antiviral / antiretroviral)
Kenya market
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Risk first
Contraindications
- (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 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]. 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 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 [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. 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.
- ( 4 ) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or lifethreatening events.
- ( 4 ) Co-administration with 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.
Precautions
- ritonavir: The concomitant use of lopinavir and ritonavir and certain other drugs may result in known or potentially significant drug interactions.
- Consult the full prescribing information prior to and during treatment for potential drug interactions.
- ( 5.1 , 7.3 ) Toxicity in preterm neonates: 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 ritonaviroral solution in this patient population has not been established.
- ( 2.4 , 5.2) Pancreatitis: Fatalities have occurred
- suspend therapy as clinically appropriate.
- ( 5.3 ) Hepatotoxicity: Fatalities have occurred.
- Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations.
- ( 5.4 , 8.6 ) QT interval prolongation and isolated cases of torsade de pointes have been reported although causality 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.
- ( 5.1 , 5.5 , 12.3 ) PR interval prolongation may occur in some patients.
- Cases of second and third degree heart block have been reported.
Point of care
Dosing
Adult
Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed. ( 2.1 ) Adults ( 2.3 ): Total recommended daily dosage is 800/200 mg given once or twice daily. Lopinavir and ritonavir can be given as once daily or twice daily regimen. See Full Prescribing Information for details. 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. ( 12.4 ) In combination with carbamazepine, phenobarbital, or phenytoin. ( 7.3 ) In combination with efavirenz, nevirapine, or nelfinavir. ( 12.3 ) In pregnant women. ( 2.5 , 8.1 , 12.3 ) Pediatric Patients (14 days and older) ( 2.4 ): Lopinavir and ritonavir once daily dosing regimen is not recommended in pediatric patients. Twice daily dose is based on body weight or body surface area. Concomitant Therapy in Adults and Pediatric Patients: Dose adjustments of lopinavir and ritonavir may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. ( 2.3 , 2.4 , 7.3 ) Pregnancy ( 2.5 ): 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. There are insufficient data to recommend a lopinavir and ritonavir dose for pregnant patients with any documented lopinavir and ritonavir -associated resistance substitutions. No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period. 2.1 General Administration Recommendations Lopinavir and ritonavir tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed. 2.3 Dosage Recommendations in Adults Lopinavir and ritonavir can be given 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 [ see Microbiology ( 12.4 ) ]. • In combination with carbamazepine, phenobarbital, or phenytoin [ see Drug Interactions ( 7.3 )]. • In combination with efavirenz, nevirapine, or nelfinavir [ see Drug Interactions ( 7.3) and Clinical Pharmacology ( 12.3 )]. • In pediatric patients younger than 18 years of age [see Dosage and Administration ( 2.4 )]. In pregnant women [ see Dosage and Administration ( 2.5 ), Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )]. Table 1. Recommended Dosage in Adults -Lopinavir And Ritonavir Once Daily Regimen Lopinavir And Ritonavir Dosage Form Recommended Dosage 200 mg/50 mg Tablets 800 mg/200 mg (4 tablets) once daily Table 2. 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 The dose of lopinavir and ritonavir must be increased 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 2.4 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 Body Weight (kg) Body Surface Area (m2) * 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 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† Body Weight (kg) Body Surface Area (m2) 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 )] † Please refer to the individual product labels for appropriate dosing in children. 288 2.5 Dosage Recommendations in Pregnancy Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily lopinavir and ritonavir dosing is not recommended in pregnancy [see Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )]. 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.
Paediatric
8.4 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 [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.3 ), Clinical Studies (14.4)]. 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) [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.3 ), Clinical Studies (14.4)]. A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose lopinavir and ritonavir with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m2 twice daily+ ≥ 1 NRTI + 1 NNRTI) in 26 children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy. 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 [see Adverse Reactions ( 6.2 ), Clinical Pharmacology ( 12.3 )]. 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.
Renal
Dose-adjust renally cleared NRTIs; TDF nephrotoxicity monitoring.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Hepatic
Several agents hepatotoxic; monitor with HBV/HCV co-infection.
Safety
Drug interactions
- Use national HIV guidelines for first-line combinations.
- Do not cease ART without plan.
- For HSV/VZV: early therapy improves outcomes
- dose by IBW/renal function for IV aciclovir.
Safety
Adverse effects
- labeling.
- QT Interval Prolongation, PR Interval Prolongation [see Warnings and Precautions ( 5.5 , 5.6 )] Drug Interactions [see Warnings and Precautions ( 5.1 )] Pancreatitis [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Commonly reported adverse reactions to lopinavir and ritonavir included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia.
- ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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.
- Adverse Reactions in Adults The safety of lopinavir and ritonavir has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily.
- 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=2,612) 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) 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).
Use
Indications
- 1 INDICATIONS AND USAGE 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 [see Microbiology ( 12.4 )].
- Lopinavir and ritonavir is an HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older).
Pharmacology
Mode of action
HIV-1 antiviral drugs lopinavir [see Microbiology ( 12.
Full mechanism text
HIV-1 antiviral drugs lopinavir [see Microbiology ( 12.4 )] and ritonavir. As co-formulated in lopinavir and ritonavir tablets, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
ADME
Pharmacokinetics & PD
| Onset | Varies (hours–days) |
|---|---|
| Duration | Regimen-dependent; ART lifelong |
| Route | ORAL / IV / TOPICAL |
| Absorption | Tmax (hr)a 4.4 ± 0.8 Effect of meal (relative to fasting) Tablet Oral Solution ↑ 19%b |
| Distribution | % Bound to human plasma proteins > 98 Vd/Fa (L) 16.9 |
| Metabolism | of lopinavir, thereby providing increased plasma levels of lopinavir. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lopinavir and ritonavir on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 hea... |
| Elimination | Major route of elimination hepatic t1/2 (h)a 6.9 ± 2.2 % of dose excreted in urine 10.4 ± 2.3 % of dose excreted in feces 82.6 ± 2.5 a.Lopinavir and ritonavir tablet b. Changes in AUC values Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD Pharmacokinetic... |
| Half-life | (h)a 6.9 ± 2.2 % of dose excreted in urine 10.4 ± 2.3 % of dose excreted in feces 82.6 ± 2.5 a.Lopinavir and ritonavir tablet b. Changes in AUC values Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD Pharmacokinetic Parameter Twice Daily a Once Daily b Cm... |
Full PK/PD text
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lopinavir and ritonavir tablets are a fixed-dose combination of HIV-1 antiviral drugs lopinavir [see Microbiology ( 12.4 )] and ritonavir. As co-formulated in lopinavir and ritonavir tablets, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lopinavir and ritonavir on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean timematched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir and ritonavir, respectively. Lopinavir and ritonavir 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily lopinavir and ritonavir doses at steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir and ritonavir, respectively [see Warnings and Precautions ( 5.5 , 5.6 )]. 12.3 Pharmacokinetics The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of lopinavir and ritonavir tablets to capsules with less pharmacokinetic variability.Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of lopinavir and ritonavir capsules and oral solution. Table 13. Pharmacokinetic Properties of Lopinavir Absorption Tmax (hr)a 4.4 ± 0.8 Effect of meal (relative to fasting) Tablet Oral Solution ↑ 19%b Distribution % Bound to human plasma proteins > 98 Vd/Fa (L) 16.9 Metabolism Metabolism CYP3A Elimination Major route of elimination hepatic t1/2 (h)a 6.9 ± 2.2 % of dose excreted in urine 10.4 ± 2.3 % of dose excreted in feces 82.6 ± 2.5 a.Lopinavir and ritonavir tablet b. Changes in AUC values Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD Pharmacokinetic Parameter Twice Daily a Once Daily b Cmax (µg/mL) 9.8 ± 3.7 11.8 ± 3.7 Cmin (µg/mL) 5.5 ± 2.7 1.7 ± 1.6 AUCtau (µg•h/mL) 92.6 ± 36.7 154.1 ± 61.4 a. 19 HIV-1 subjects, Lopinavir and ritonavir 400/100 mg twice daily b. 24 HIV-1 subjects, Lopinavir and ritonavir 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg Specific Populations Gender, Race and Age No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients. 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. Table 15. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean ± SD Cmax (μg/mL) Cmin (μg/mL) AUC12 (μg•hr/m ) Age ≥ 14 Days to < 6 Weeks Cohort (N = 9): 5.17 ± 1.84a 1.40 ± 0.48a 43.39 ± 14.80a Age ≥ 6 Weeks to < 6 Months Cohort (N = 18): 9.39 ± 4.91a 1.95 ± 1.80a 74.50 ± 37.87a Age ≥ 6 Months to ≤ 12 years Cohort (N = 24): 8.2 ± 2.9b 3.4 ± 2.1b 72.6 ± 31.1b 10.0 ± 3.3c 3.6 ± 3.5c 85.8 ± 36.9c Lopinavir and ritonavir oral solution300/75 mg/m2 twice daily without concomitant NNRTI therapy Lopinavir and ritonavir oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12) Lopinavir and ritonavir oral solution 300/75 mg/m2 twice daily with nevirapine (n=12) Pregnancy The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received lopinavir and ritonavir 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented lopinavir and ritonavir -associated resistance substitutions receiving 400 mg/100 mg twice daily [see Use in Specific Populations ( 8.1 )]. Renal Impairment Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment. Hepatic Impairment Multiple dosing of lopinavir and ritonavir 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Lopinavir and ritonavir has not been studied in patients with severe hepatic impairment [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.6) ]. Drug Interactions Lopinavir and ritonavir is an inhibitor of the P450 isoform CYP3A in vitro. Lopinavir and ritonavir does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations. Lopinavir and ritonavir has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation. The effects of co-administration of lopinavir and ritonavir on the AUC, Cmax and Cmin are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of lopinavir and ritonavir on other drugs). For information regarding clinical recommendations, see Table 12 in Drug Interactions ( 7 ). Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen Co- administered Drug Dose of Co- administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Efavirenz1 600 at bedtime 400/100 capsule twice daily 11, 73 0.97 (0.78, 1.22) 0.81 (0.64, 1.03) 0.61 (0.38, 0.97) 600 at bedtime 500/125 tablet twice daily 19 1.12 (1.02, 1.23) 1.06 (0.96, 1.17) 0.90 (0.78, 1.04) 600 at bedtime 600/150 tablet twice daily 23 1.36 (1.28, 1.44) 1.36 (1.28, 1.44) 1.32 (1.21, 1.44) Etravirine 200 twice daily 400/100 mg twice day (tablets) 16 0.89 (0.82-0.96) 0.87 (0.83-0.92) 0.80 (0.73-0.88) Fosamprenavir2 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 1.30 (0.85, 1.47) 1.37 (0.80, 1.55) 1.52 (0.72, 1.82) Ketoconazole 200 single dose 400/100 capsule twice daily 12 0.89 (0.80, 0.99) 0.87 (0.75, 1.00) 0.75 (0.55, 1.00) Nelfinavir 1000 twice daily 400/100 capsule twice daily 13 0.79 (0.70, 0.89) 0.73 (0.63, 0.85) 0.62 (0.49, 0.78) Nevirapine 200 twice daily steady-state 400/100 capsule twice daily 22, 193 0.81 (0.62, 1.05) 0.73 (0.53, 0.98) 0.49 (0.28, 0.74) 7 mg/kg or 4 mg/kg once daily; twice daily 1 wk5 (> 1 yr) 300/ 75 mg/m2 oral solution twice daily 12, 153 0.86 (0.64, 1.16) 0.78 (0.56, 1.09) 0.45 (0.25, 0.81) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir2 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 0.87 (0.76, 0.99) 0.94 (0.81, 1.10) 1.15 (0.93, 1.42) Omeprazole 40 once daily, 5 d 400/100 tablet twice daily, 10 d 12 1.08 (0.99, 1.17) 1.07 (0.99, 1.15) 1.03 (0.90, 1.18) 40 once daily, 5 d 800/200 tablet once daily, 10 d 12 0.94 (0.88, 1.00) 0.92 (0.86, 0.99) 0.71 (0.57, 0.89) Pravastatin 20 once daily, 4 d 400/100 capsule twice daily, 14 d 12 0.98 (0.89, 1.08) 0.95 (0.85, 1.05) 0.88 (0.77, 1.02) Ranitidine 150 single dose 400/100 tablet twice daily, 10 d 12 0.99 (0.95, 1.03) 0.97 (0.93, 1.01) 0.90 (0.85, 0.95) 150 single dose 800/200 tablet once daily, 10 d 10 0.97 (0.95, 1.00) 0.95 (0.91, 0.99) 0.82 (0.74, 0.91) Rifabutin 150 once daily 400/100 capsule twice daily 14 1.08 (0.97, 1.19) 1.17 (1.04, 1.31) 1.20 (0.96, 1.65) Rifampin 600 once daily 400/100 capsule twice daily 22 0.45 (0.40, 0.51) 0.25 (0.21, 0.29) 0.01 (0.01, 0.02) 600 once daily 800/200 capsule twice daily 10 1.02 (0.85, 1.23) 0.84 (0.64, 1.10) 0.43 (0.19, 0.96) 600 once daily 400/400 capsule twice daily 9 0.93 (0.81, 1.07) 0.98 (0.81, 1.17) 1.03 (0.68, 1.56) Rilpivirine 150 once daily 400/100 twice daily (capsules) 15 0.96 (0.88-1.05) 0.99 (0.89-1.10) 0.89 (0.73-1.08) Ritonavir 100 twice daily 400/100 capsule twice daily 8, 213 1.28 (0.94, 1.76) 1.46 (1.04, 2.06) 2.16 (1.29, 3.62) Tipranavir/ ritonavir 500/200 twice daily 400/100 capsule twice daily 21 693 0.53 (0.40, 0.69) 0.45 (0.32, 0.63) 0.30 (0.17, 0.51) 0.484 (0.40, 0.58) 1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs. 3 Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available. Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Lopinavir And Ritonavir for Recommended Alterations in Dose or Regimen Co- administered Drug Dose of Co- administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Lpinavir and Ritonavir /alone) of Co- administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Bedaquiline1 400 single dose 400/100 twice daily N/A N/A 1.22 (1.11, 1.34) N/A Efavirenz 600 at bedtime 400/100 capsule twice daily 11, 123 0.91 (0.72, 1.15) 0.84 (0.62, 1.15) 0.84 (0.58, 1.20) Elbasvir/ grazoprevir1 50 once daily 400/100 twice daily 10 2.87 (2.29, 3.58) 3.71 (3.05, 4.53) 4.58 (3.72, 5.64) 200 once daily 13 7.31 (5.65, 9.45) 12.86 (10.25, 16.13) 21.70 (12.99, 36.25) Ethinyl Estradiol 35 µg once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.59 (0.52, 0.66) 0.58 (0.54, 0.62) 0.42 (0.36, 0.49) Etravirine 200 twice daily 400/100 tablet twice day 16 0.70 (0.64-0.78) 0.65 (0.59-0.71) 0.55 (0.49-0.62) Fosamprenavir1 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 0.42 (0.30, 0.58) 0.37 (0.28, 0.49) 0.35 (0.27, 0.46) Indinavir 600 twice daily combo nonfasting vs. 800 three times daily alone fasting 400/100 capsule twice daily 13 0.71 (0.63, 0.81) 0.91 (0.75, 1.10) 3.47 (2.60, 4.64) Ketoconazole 200 single dose 400/100 capsule twice daily 12 1.13 (0.91, 1.40) 3.04 (2.44, 3.79) N/A Maraviroc1 300 twice daily 400/100 twice daily 11 1.97 (1.66, 2.34) 3.95 (3.43, 4.56) 9.24 (7.98, 10.7) Methadone 5 single dose 400/100 capsule twice daily 11 0.55 (0.48, 0.64) 0.47 (0.42, 0.53) N/A Nelfinavir 1000 twice daily combo vs. 1250 twice daily alone 400/100 capsule twice daily 13 0.93 (0.82, 1.05) 1.07 (0.95, 1.19) 1.86 (1.57, 2.22) M8 metabolite 2.36 (1.91, 2.91) 3.46 (2.78, 4.31) 7.49 (5.85, 9.58) Nevirapine 200 once daily twice daily 400/100 capsule twice daily 5, 63 1.05 (0.72, 1.52) 1.08 (0.72, 1.64) 1.15 (0.71, 1.86) Norethindrone 1 once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.84 (0.75, 0.94) 0.83 (0.73, 0.94) 0.68 (0.54, 0.85) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir1 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 1.14 (1.01, 1.28) 1.17 (1.07, 1.28) 1.24 (1.14, 1.34) 2.04 (1.30, 3.20) 2.17 (1.63, 2.89) 2.36 (1.00, 5.55) 1.55 (1.16, 2.09) 2.05 (1.49, 2.81) 5.25 (3.33, 8.28) 0.99 (0.75, 1.31) 0.93 (0.75, 1.15) 0.68 (0.57, 0.80) Pitavastatin1 4 once daily 400/100 tablet twice daily 23 0.96 (0.84-1.10) 0.80 (0.73-0.87) N/A Pravastatin 20 once daily 400/100 capsule twice daily 12 1.26 (0.87, 1.83) 1.33 (0.91, 1.94) N/A Rifabutin 150 once daily combo v
Kenya
Brands & prices
| Brand | Company | Pack | KES |
|---|---|---|---|
| Norvir Oral Powder | Abbvie (Pty) Ltd | Powder For Oral Suspension 100 mg ritonavir per sachet | — |
Special populations
Pregnancy & lactation
Pregnancy
8.1 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 [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. 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 [see Clinical Pharmacology (12.3)]. 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. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens. 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).
Lactation
8.3 Females and Males of Reproductive Potential Contraception Use of lopinavir and ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions ( 7.3 )].
Diet
Food & alcohol
- Drug & food interactions (label) 7 DRUG INTERACTIONS Co-administration of lopinavir and ritonavir can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. The potential for drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.1 , 7 , 12.3 ) 7.1 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. 7.2 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. 7.3 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 [see Contraindications (4), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)] for magnitude of interaction. Table 12. Established and Other Potentially Significant Drug Interactions 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 Proteas
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Sources & disclaimer
Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Antiviral / antiretroviral)
Clinical review date not recorded.
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