Lopinavir And Ritonavir

Contraindications (

Lopinavir and ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV- 1 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
  [

  12.4 Microbiology

  Mechanism of Action

  
  
  

  Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the viral Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

  
  
  

  Antiviral Activity

  
  
  

  In the absence of human serum, the mean 50% effective concentration (EC₅₀) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines ranged from 10 to 27 nM (0.006 to 0.017 mcg/mL, 1 mcg/mL = 1.6 mcM), and ranged from 4 to 11 nM (0.003 to 0.007 mcg/mL) against several HIV-1 subtype B clinical isolates in peripheral blood lymphocytes (n = 6). In the presence of 50% human serum, the mean EC₅₀values of lopinavir against these five HIV-1 laboratory strains ranged from 65 to 289 nM (0.04 to 0.18 mcg/mL), representing a 7 to 11-fold attenuation. The EC₅₀values of lopinavir against three different HIV-2 strains ranged from 12 to 180 nM (0.008 to 113 mcg/mL).

  
  
  

  Resistance

  
  
  

  HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

  
  
  

  In a study of 653 antiretroviral treatment-naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No specific amino acid substitutions could be associated with resistance to lopinavir and ritonavir in the virus from 37 evaluable lopinavir and ritonavir-treated patients. The selection of resistance to lopinavir and ritonavir in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

  
  
  

  Resistance to lopinavir and ritonavir has been noted to emerge in patients treated with other protease inhibitors prior to lopinavir and ritonavir therapy. In studies of 227 antiretroviral treatment-naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with lopinavir and ritonavir for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least 4 substitutions associated with protease inhibitor resistance immediately prior to lopinavir and ritonavir therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance.

  
  
  

  Cross-resistance - Nonclinical Studies

  
  
  

  Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined (Table 18).

  
  
  

  Table 18. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With a Single Protease Inhibitor

  Susceptibility reduced by >4 fold	Susceptibility reduced to LPV
  Indinavir (n=16)	5.7 fold
  Nelfinavir (n=13)	<4 fold
  Ritonavir (n=3)	8.32 fold
  Saquinavir (n=4)	<4 fold

  Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following section.

  
  
  

  Clinical Studies - Antiviral Activity of Lopinavir and Ritonavir in Patients with Previous Protease Inhibitor Therapies

  
  
  

  The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to lopinavir and ritonavir therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

  
  
  

  Virologic response to lopinavir and ritonavir has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 19 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765

  [ see Clinical Studies (14.2)

  and

  ]

  and study 957 (see below). Once daily administration of lopinavir and ritonavir for adult patients with three or more of the above substitutions is not recommended.

  
  
  

  Table 19. Virologic Response (HIV-1 RNA <400 copies/mL) at Week 48 by Baseline Lopinavir and Ritonavir Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to Lopinavir and Ritonavir¹

  Number of protease inhibitor substitutions at baseline1	Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) n=50
  0 to 2	76/103 (74%)	34/45 (76%)	19/20 (95%)
  3 to 5	13/26 (50%)	8/11 (73%)	18/26 (69%)
  6 or more	0/1 (0%)	N/A	1/4 (25%)
  1Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 243% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 341% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 486% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

  Virologic response to lopinavir and ritonavir therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of lopinavir and ritonavir in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC₅₀values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC₅₀value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 20.

  
  
  

  Table 20. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility¹

  Lopinavir susceptibility2at baseline	HIV-1 RNA <400 copies/mL (%)	HIV-1 RNA <50 copies/mL (%)
  < 10 fold	25/27 (93%)	22/27 (81%)
  > 10 and < 40 fold	11/15 (73%)	9/15 (60%)
  ≥ 40 fold	2/8 (25%)	2/8 (25%)
  1Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2Fold change in susceptibility from wild type.

  
  
  

  ]
  .

Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed. (

• 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 Microbiology

    Mechanism of Action

    
    
    

    Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the viral Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

    
    
    

    Antiviral Activity

    
    
    

    In the absence of human serum, the mean 50% effective concentration (EC₅₀) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines ranged from 10 to 27 nM (0.006 to 0.017 mcg/mL, 1 mcg/mL = 1.6 mcM), and ranged from 4 to 11 nM (0.003 to 0.007 mcg/mL) against several HIV-1 subtype B clinical isolates in peripheral blood lymphocytes (n = 6). In the presence of 50% human serum, the mean EC₅₀values of lopinavir against these five HIV-1 laboratory strains ranged from 65 to 289 nM (0.04 to 0.18 mcg/mL), representing a 7 to 11-fold attenuation. The EC₅₀values of lopinavir against three different HIV-2 strains ranged from 12 to 180 nM (0.008 to 113 mcg/mL).

    
    
    

    Resistance

    
    
    

    HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

    
    
    

    In a study of 653 antiretroviral treatment-naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No specific amino acid substitutions could be associated with resistance to lopinavir and ritonavir in the virus from 37 evaluable lopinavir and ritonavir-treated patients. The selection of resistance to lopinavir and ritonavir in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

    
    
    

    Resistance to lopinavir and ritonavir has been noted to emerge in patients treated with other protease inhibitors prior to lopinavir and ritonavir therapy. In studies of 227 antiretroviral treatment-naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with lopinavir and ritonavir for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least 4 substitutions associated with protease inhibitor resistance immediately prior to lopinavir and ritonavir therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance.

    
    
    

    Cross-resistance - Nonclinical Studies

    
    
    

    Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined (Table 18).

    
    
    

    Table 18. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With a Single Protease Inhibitor

    Susceptibility reduced by >4 fold	Susceptibility reduced to LPV
    Indinavir (n=16)	5.7 fold
    Nelfinavir (n=13)	<4 fold
    Ritonavir (n=3)	8.32 fold
    Saquinavir (n=4)	<4 fold

    Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following section.

    
    
    

    Clinical Studies - Antiviral Activity of Lopinavir and Ritonavir in Patients with Previous Protease Inhibitor Therapies

    
    
    

    The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to lopinavir and ritonavir therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

    
    
    

    Virologic response to lopinavir and ritonavir has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 19 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765

    [ see Clinical Studies (14.2)

    and

    ]

    and study 957 (see below). Once daily administration of lopinavir and ritonavir for adult patients with three or more of the above substitutions is not recommended.

    
    
    

    Table 19. Virologic Response (HIV-1 RNA <400 copies/mL) at Week 48 by Baseline Lopinavir and Ritonavir Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to Lopinavir and Ritonavir¹

    Number of protease inhibitor substitutions at baseline1	Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) n=50
    0 to 2	76/103 (74%)	34/45 (76%)	19/20 (95%)
    3 to 5	13/26 (50%)	8/11 (73%)	18/26 (69%)
    6 or more	0/1 (0%)	N/A	1/4 (25%)
    1Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 243% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 341% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 486% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

    Virologic response to lopinavir and ritonavir therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of lopinavir and ritonavir in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC₅₀values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC₅₀value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 20.

    
    
    

    Table 20. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility¹

    Lopinavir susceptibility2at baseline	HIV-1 RNA <400 copies/mL (%)	HIV-1 RNA <50 copies/mL (%)
    < 10 fold	25/27 (93%)	22/27 (81%)
    > 10 and < 40 fold	11/15 (73%)	9/15 (60%)
    ≥ 40 fold	2/8 (25%)	2/8 (25%)
    1Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2Fold change in susceptibility from wild type.

    
    
    
    )
  • In combination with carbamazepine, phenobarbital, or phenytoin. (
    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 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 1,000 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 ritonavir tablets to 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)].
    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 CLCR30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on lopinavir and ritonavir with CLCR< 30 mL/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 (FMF)-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 co- administered 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) ].
    GnRH 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 (ALT) elevations [see Contraindications (4) ].
    Hepatitis C direct acting antivirals: boceprevir* glecaprevir/Pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilaprevi r 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-CoA Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) 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	↑ immunosuppressants	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. Co-administration 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 (PAH): 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 ↑ glucocorticoids	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. #refers to interaction with apalutamide.

    
    
    
    )
  • In combination with efavirenz, nevirapine, or nelfinavir. (
    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 ↑ 130%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 Dailya	Once Dailyb
    Cmax(mcg/mL)	9.8 ± 3.7	11.8 ± 3.7
    Cmin(mcg/mL)	5.5 ± 2.7	1.7 ± 1.6
    AUCtau(mcg•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/m²twice daily regimen without nevirapine and the 300/75 mg/m²twice 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(mcg/mL)	Cmin(mcg/mL)	AUC12(mcg•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
    a. Lopinavir and ritonavir oral solution 300/75 mg/m2twice daily without concomitant NNRTI therapy b. Lopinavir and ritonavir oral solution 230/57.5 mg/m2twice daily without nevirapine (n=12) c. Lopinavir and ritonavir oral solution 300/75 mg/m2twice daily with nevirapine (n=12)

    Pregnancy

    
    
    

    The C_12hvalues 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 C_maxcompared 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, C_maxand C_minare 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
    				C max	AUC	C min
    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 daily (tablets)	16	0.89 (0.82 to 0.96)	0.87 (0.83 to 0.92)	0.80 (0.73 to 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	1,000 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/m2oral 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 to 1.05)	0.99 (0.89 to 1.10)	0.89 (0.73 to 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)
    1.000000000000000e+00Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2.000000000000000e+00Data extracted from the U.S. prescribing information of co-administered drugs. 3.000000000000000e+00Parallel group design 4.000000000000000e+00Drug levels obtained at 8 to 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 Lopinavir and Ritonavir/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
    				C max	AUC	C min
    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 mcg 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 to 0.78)	0.65 (0.59 to 0.71)	0.55 (0.49 to 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	1,000 twice daily combo vs. 1,250 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 to 1.10)	0.80 (0.73 to 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 vs. 300 once daily alone	400/100 capsule twice daily	12	2.12 (1.89, 2.38)	3.03 (2.79, 3.30)	4.90 (3.18, 5.76)
    25- O -desacetyl rifabutin				23.6 (13.7, 25.3)	47.5 (29.3, 51.8)	94.9 (74.0, 122)
    Rifabutin + 25- O -desacetyl rifabutin				3.46 (3.07, 3.91)	5.73 (5.08, 6.46)	9.53 (7.56, 12.01)
    Rilpivirine	150 once daily	400/100 capsules twice daily	15	1.29 (1.18 to 1.40)	1.52 (1.36 to 1.70)	1.74 (1.46 to 2.08)
    Rosuvastatin2	20 once daily	400/100 tablet twice daily	15	4.66 (3.4, 6.4)	2.08 (1.66, 2.6)	1.04 (0.9, 1.2)
    Tenofovir alafenamide1	10 once daily	800/200 tablet once daily	10	2.19 (1.72, 2.79)	1.47 (1.17, 1.85)	N/A
    Tenofovir disoproxil fumarate1	300 once daily	400/100 capsule twice daily	24	No Change	1.32 (1.26, 1.38)	1.51 (1.32, 1.66)
    1.000000000000000e+00Data extracted from the U.S. prescribing information of co-administered drugs. 2.000000000000000e+00Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3Parallel group design N/A = Not available.

    
    
    
    )
  • In pregnant women. (
    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.
    • Avoid use of lopinavir and ritonavir oral solution in pregnant women
      [see Use in Specific Populations (8.1)].
    ,
    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 to 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% to 3%) following first-trimester exposure to lopinavir-containing regimens and 3% (95% CI: 2.4% to 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% to 2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4% to 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 to 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 to 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).
    ,
    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 ↑ 130%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 Dailya	Once Dailyb
    Cmax(mcg/mL)	9.8 ± 3.7	11.8 ± 3.7
    Cmin(mcg/mL)	5.5 ± 2.7	1.7 ± 1.6
    AUCtau(mcg•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/m²twice daily regimen without nevirapine and the 300/75 mg/m²twice 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(mcg/mL)	Cmin(mcg/mL)	AUC12(mcg•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
    a. Lopinavir and ritonavir oral solution 300/75 mg/m2twice daily without concomitant NNRTI therapy b. Lopinavir and ritonavir oral solution 230/57.5 mg/m2twice daily without nevirapine (n=12) c. Lopinavir and ritonavir oral solution 300/75 mg/m2twice daily with nevirapine (n=12)

    Pregnancy

    
    
    

    The C_12hvalues 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 C_maxcompared 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, C_maxand C_minare 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
    				C max	AUC	C min
    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 daily (tablets)	16	0.89 (0.82 to 0.96)	0.87 (0.83 to 0.92)	0.80 (0.73 to 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	1,000 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/m2oral 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 to 1.05)	0.99 (0.89 to 1.10)	0.89 (0.73 to 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)
    1.000000000000000e+00Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2.000000000000000e+00Data extracted from the U.S. prescribing information of co-administered drugs. 3.000000000000000e+00Parallel group design 4.000000000000000e+00Drug levels obtained at 8 to 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 Lopinavir and Ritonavir/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
    				C max	AUC	C min
    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 mcg 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 to 0.78)	0.65 (0.59 to 0.71)	0.55 (0.49 to 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	1,000 twice daily combo vs. 1,250 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 to 1.10)	0.80 (0.73 to 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 vs. 300 once daily alone	400/100 capsule twice daily	12	2.12 (1.89, 2.38)	3.03 (2.79, 3.30)	4.90 (3.18, 5.76)
    25- O -desacetyl rifabutin				23.6 (13.7, 25.3)	47.5 (29.3, 51.8)	94.9 (74.0, 122)
    Rifabutin + 25- O -desacetyl rifabutin				3.46 (3.07, 3.91)	5.73 (5.08, 6.46)	9.53 (7.56, 12.01)
    Rilpivirine	150 once daily	400/100 capsules twice daily	15	1.29 (1.18 to 1.40)	1.52 (1.36 to 1.70)	1.74 (1.46 to 2.08)
    Rosuvastatin2	20 once daily	400/100 tablet twice daily	15	4.66 (3.4, 6.4)	2.08 (1.66, 2.6)	1.04 (0.9, 1.2)
    Tenofovir alafenamide1	10 once daily	800/200 tablet once daily	10	2.19 (1.72, 2.79)	1.47 (1.17, 1.85)	N/A
    Tenofovir disoproxil fumarate1	300 once daily	400/100 capsule twice daily	24	No Change	1.32 (1.26, 1.38)	1.51 (1.32, 1.66)
    1.000000000000000e+00Data extracted from the U.S. prescribing information of co-administered drugs. 2.000000000000000e+00Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3Parallel group design N/A = Not available.

    
    
    
    )

2.4 Dosage Recommendations in Pediatric Patients

Lopinavir and ritonavir tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

Lopinavir and ritonavir oral solution is not recommended in neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained

[see

Warnings and Precautions (5.2)]

.

Lopinavir and ritonavir oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients

[see Warnings and Precautions (5.2)

and

Overdosage (10)].

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 (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)

If lopinavir and ritonavir oral solution is used, the volume (mL) of lopinavir and ritonavir solution can be determined as follows:

Volume of lopinavir and ritonavir solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:

Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution.

Lopinavir and ritonavir administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of lopinavir and ritonavir oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.

Table 4. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
14 days to 6 months	16/4		300/75	Given twice daily
Older than 6 months to less than 18 years	Less than 15 kg	12/3	230/57.5	Given twice daily
	15 kg to 40 kg	10/2.5

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
* Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet.

Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

Dosing recommendations using oral solution

Table 6 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 Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

Table 6. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations for Pediatric Patients >6 Months to < 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir

Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
> 6 months to < 18 years	<15 kg	13/3.25	300/75	Given twice daily
	≥15 kg to 45 kg	11/2.75

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)]
* Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet. † Please refer to the individual product labels for appropriate dosing in children.

• 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.

• Dose adjustments of lopinavir and ritonavir may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. (
  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
  80 mg/20 mg per mL Oral Solution	800 mg/200 mg (10 mL) 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
  80 mg/20 mg per mL Oral Solution	400 mg/100 mg (5 mL) 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
  80 mg/20 mg per mL Oral Solution	520 mg/130 mg (6.5 mL) twice daily

  
  
  
  ,
  2.4 Dosage Recommendations in Pediatric Patients

  Lopinavir and ritonavir tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

  
  
  

  Lopinavir and ritonavir oral solution is not recommended in neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained

  [see

  Warnings and Precautions (5.2)]

  .

  
  
  

  Lopinavir and ritonavir oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients

  [see Warnings and Precautions (5.2)

  and

  Overdosage (10)].

  
  
  

  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 (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)

  
  
  

  If lopinavir and ritonavir oral solution is used, the volume (mL) of lopinavir and ritonavir solution can be determined as follows:

  
  
  

  Volume of lopinavir and ritonavir solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

  
  
  

  Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:

  Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution.

  
  
  

  Lopinavir and ritonavir administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of lopinavir and ritonavir oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.

  Table 4. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

  Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
  14 days to 6 months	16/4		300/75	Given twice daily
  Older than 6 months to less than 18 years	Less than 15 kg	12/3	230/57.5	Given twice daily
  	15 kg to 40 kg	10/2.5

  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
  * Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet.

  
  
  

  Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

  Dosing recommendations using oral solution

  Table 6 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 Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

  Table 6. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations for Pediatric Patients >6 Months to < 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir

  Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
  > 6 months to < 18 years	<15 kg	13/3.25	300/75	Given twice daily
  	≥15 kg to 45 kg	11/2.75

  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)]
  * Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet. † Please refer to the individual product labels for appropriate dosing in children.

  
  
  

  

  ,
  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 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 1,000 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 ritonavir tablets to 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)].
  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 CLCR30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on lopinavir and ritonavir with CLCR< 30 mL/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 (FMF)-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 co- administered 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) ].
  GnRH 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 (ALT) elevations [see Contraindications (4) ].
  Hepatitis C direct acting antivirals: boceprevir* glecaprevir/Pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilaprevi r 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-CoA Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) 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	↑ immunosuppressants	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. Co-administration 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 (PAH): 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 ↑ glucocorticoids	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. #refers to interaction with apalutamide.

  
  
  
  )
• Lopinavir and ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained (
  2.4 Dosage Recommendations in Pediatric Patients

  Lopinavir and ritonavir tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

  
  
  

  Lopinavir and ritonavir oral solution is not recommended in neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained

  [see

  Warnings and Precautions (5.2)]

  .

  
  
  

  Lopinavir and ritonavir oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients

  [see Warnings and Precautions (5.2)

  and

  Overdosage (10)].

  
  
  

  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 (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)

  
  
  

  If lopinavir and ritonavir oral solution is used, the volume (mL) of lopinavir and ritonavir solution can be determined as follows:

  
  
  

  Volume of lopinavir and ritonavir solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

  
  
  

  Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:

  Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution.

  
  
  

  Lopinavir and ritonavir administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of lopinavir and ritonavir oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.

  Table 4. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

  Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
  14 days to 6 months	16/4		300/75	Given twice daily
  Older than 6 months to less than 18 years	Less than 15 kg	12/3	230/57.5	Given twice daily
  	15 kg to 40 kg	10/2.5

  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
  * Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet.

  
  
  

  Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

  Dosing recommendations using oral solution

  Table 6 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 Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

  Table 6. Lopinavir and Ritonavir Oral Solution Daily Dosage Recommendations for Pediatric Patients >6 Months to < 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir

  Patient Age	Based on Weight (mg/kg)		Based on BSA (mg/m2)	Frequency
  > 6 months to < 18 years	<15 kg	13/3.25	300/75	Given twice daily
  	≥15 kg to 45 kg	11/2.75

  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)]
  * Lopinavir and ritonavir oral solution is available for children with a BSA less than 0.6 m2or those who are unable to reliably swallow a tablet. † Please refer to the individual product labels for appropriate dosing in children.

  
  
  

  

  ,
  5.1 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

  [ see Drug Interactions (7)]

  . 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

  [ see Contraindications (4)

  and

  Drug Interactions (7)]

  .
  )