Kaletra - Lopinavir And Ritonavir tablet, Film Coated (Lopinavir And Ritonavir)

KALETRA 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 KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA
  [see Microbiology (
  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 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM), and ranged from 4-11 nM (0.003-0.007 µg/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 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. The EC₅₀values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/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 KALETRA in the virus from 37 evaluable KALETRA-treated patients. The selection of resistance to KALETRA in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

  Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA 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 KALETRA 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 KALETRA 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 KALETRA 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 KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

  Virologic response to KALETRA 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

  (

  14.3

  )]

  and study 957 (see below). Once daily administration of KALETRA 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 KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA

  ¹

  Number of protease inhibitor substitutions at baseline 1	Study 888 (Single protease inhibitor-experienced 2 , NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced 3 , NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced 4 , NNRTI-naïve) n=50
  0-2	76/103 (74%)	34/45 (76%)	19/20 (95%)
  3-5	13/26 (50%)	8/11 (73%)	18/26 (69%)
  6 or more	0/1 (0%)	N/A	1/4 (25%)
  1   Substitutions 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. 2   43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 3   41% indinavir, 38% nelfinavir, 4% ritonavir,   16% saquinavir. 4   86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

  Virologic response to KALETRA 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 KALETRA 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 Susceptibility

  ¹

  Lopinavir susceptibility 2 at 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%)
  1   Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2   Fold change in susceptibility from wild type.
  )]
  .

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

Oral solution: must be taken with food. (

KALETRA oral solution is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes composed of silicone or polyvinyl chloride (PVC) can be used. (

• Total recommended daily dosage is 800/200 mg given once or twice daily.
  
  
• KALETRA can be given as once daily or twice daily regimen. See Full Prescribing Information for details.
  
  
• KALETRA 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 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM), and ranged from 4-11 nM (0.003-0.007 µg/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 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. The EC₅₀values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/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 KALETRA in the virus from 37 evaluable KALETRA-treated patients. The selection of resistance to KALETRA in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

  Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA 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 KALETRA 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 KALETRA 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 KALETRA 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 KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

  Virologic response to KALETRA 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

  (

  14.3

  )]

  and study 957 (see below). Once daily administration of KALETRA 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 KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA

  ¹

  Number of protease inhibitor substitutions at baseline 1	Study 888 (Single protease inhibitor-experienced 2 , NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced 3 , NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced 4 , NNRTI-naïve) n=50
  0-2	76/103 (74%)	34/45 (76%)	19/20 (95%)
  3-5	13/26 (50%)	8/11 (73%)	18/26 (69%)
  6 or more	0/1 (0%)	N/A	1/4 (25%)
  1   Substitutions 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. 2   43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 3   41% indinavir, 38% nelfinavir, 4% ritonavir,   16% saquinavir. 4   86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

  Virologic response to KALETRA 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 KALETRA 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 Susceptibility

  ¹

  Lopinavir susceptibility 2 at 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%)
  1   Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2   Fold 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 KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
  HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA 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 KALETRA with respect to safety and efficacy have not been established.
  HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA 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 KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA 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		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA 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 KALETRA oral solution (given with food).
  Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate*	↑ tenofovir	Patients receiving KALETRA 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 KALETRA.
  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 KALETRA or to the class of protease inhibitors [see Contraindications ( 4 )] . Avoid co-administration of encorafenib or ivosidenib with KALETRA due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with KALETRA cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with KALETRA cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with KALETRA. 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 KALETRA 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 KALETRA. 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 KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
  Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
  Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
  Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving KALETRA 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 KALETRA with CLCR30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA 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 KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra 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 KALETRA: 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 KALETRA: 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 KALETRA: 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 KALETRA 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 KALETRA 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 KALETRA 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 KALETRA: 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 KALETRA 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		KALETRA 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 KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, 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 KALETRA 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 KALETRA 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/voxilaprevir 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 KALETRA 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 KALETRA 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 KALETRA.
  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 KALETRA 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 KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
  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 KALETRA 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 KALETRA. Co-administration of KALETRA 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 KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA 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 KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, 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 KALETRA 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 KALETRA tablets to capsules with less pharmacokinetic variability. Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA 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. Kaletra tablet b. Changes in AUC values

  Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD

  Pharmacokinetic Parameter	Twice Daily a	Once Daily b
  Cmax(µg/mL)	9.8 ± 3.7	11.8 ± 3.7
  Cmin(µg/mL)	5.5 ± 2.7	1.7 ± 1.6
  AUCtau(µg•h/mL)	92.6 ± 36.7	154.1 ± 61.4
  19 HIV-1 subjects, Kaletra 400/100 mg twice daily 24 HIV-1 subjects, Kaletra 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

  C max (μg/mL)	C min (μg/mL)	AUC 12 (μg•hr/m )
  Age ≥ 14 Days to < 6 Weeks Cohort (N = 9):
  5.17 ± 1.84a	1.40 ± 0.48a	43.39 ± 14.80a
  Age ≥ 6 Weeks to < 6 Months Cohort (N = 18):
  9.39 ± 4.91a	1.95 ± 1.80a	74.50 ± 37.87a
  Age ≥ 6 Months to ≤ 12 years Cohort (N = 24):
  8.2 ± 2.9b	3.4 ± 2.1b	72.6 ± 31.1b
  10.0 ± 3.3c	3.6 ± 3.5c	85.8 ± 36.9c
  KALETRA oral solution300/75 mg/m2twice daily without concomitant NNRTI therapy KALETRA oral solution 230/57.5 mg/m2twice daily without nevirapine (n=12) KALETRA 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 KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA-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 KALETRA 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). KALETRA 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

  KALETRA is an inhibitor of the P450 isoform CYP3A

  in vitro

  . KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

  KALETRA 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 KALETRA on the AUC, C_maxand C_minare summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA 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 KALETRA (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 day (tablets)	16	0.89 (0.82-0.96)	0.87 (0.83-0.92)	0.80 (0.73-0.88)
  Fosamprenavir2	700 twice daily plus ritonavir 100 twice daily	400/100 capsule twice daily	18	1.30 (0.85, 1.47)	1.37 (0.80, 1.55)	1.52 (0.72, 1.82)
  Ketoconazole	200 single dose	400/100 capsule twice daily	12	0.89 (0.80, 0.99)	0.87 (0.75, 1.00)	0.75 (0.55, 1.00)
  Nelfinavir	1000 twice daily	400/100 capsule twice daily	13	0.79 (0.70, 0.89)	0.73 (0.63, 0.85)	0.62 (0.49, 0.78)
  Nevirapine	200 twice daily steady-state	400/100 capsule twice daily	22, 193	0.81 (0.62, 1.05)	0.73 (0.53, 0.98)	0.49 (0.28, 0.74)
  	7 mg/kg or 4 mg/kg once daily; twice daily 1 wk5	(> 1 yr) 300/ 75 mg/m2 oral solution twice daily	12, 153	0.86 (0.64, 1.16)	0.78 (0.56, 1.09)	0.45 (0.25, 0.81)
  Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir2	25/150/100 + dasabuvir 400	400/100 tablet twice daily	6	0.87 (0.76, 0.99)	0.94 (0.81, 1.10)	1.15 (0.93, 1.42)
  Omeprazole	40 once daily, 5 d	400/100 tablet twice daily, 10 d	12	1.08 (0.99, 1.17)	1.07 (0.99, 1.15)	1.03 (0.90, 1.18)
  	40 once daily, 5 d	800/200 tablet once daily, 10 d	12	0.94 (0.88, 1.00)	0.92 (0.86, 0.99)	0.71 (0.57, 0.89)
  Pravastatin	20 once daily, 4 d	400/100 capsule twice daily, 14 d	12	0.98 (0.89, 1.08)	0.95 (0.85, 1.05)	0.88 (0.77, 1.02)
  Ranitidine	150 single dose	400/100 tablet twice daily, 10 d	12	0.99 (0.95, 1.03)	0.97 (0.93, 1.01)	0.90 (0.85, 0.95)
  	150 single dose	800/200 tablet once daily, 10 d	10	0.97 (0.95, 1.00)	0.95 (0.91, 0.99)	0.82 (0.74, 0.91)
  Rifabutin	150 once daily	400/100 capsule twice daily	14	1.08 (0.97, 1.19)	1.17 (1.04, 1.31)	1.20 (0.96, 1.65)
  Rifampin	600 once daily	400/100 capsule twice daily	22	0.45 (0.40, 0.51)	0.25 (0.21, 0.29)	0.01 (0.01, 0.02)
  	600 once daily	800/200 capsule twice daily	10	1.02 (0.85, 1.23)	0.84 (0.64, 1.10)	0.43 (0.19, 0.96)
  	600 once daily	400/400 capsule twice daily	9	0.93 (0.81, 1.07)	0.98 (0.81, 1.17)	1.03 (0.68, 1.56)
  Rilpivirine	150 once daily	400/100 twice daily (capsules)	15	0.96 (0.88-1.05)	0.99 (0.89-1.10)	0.89 (0.73-1.08)
  Ritonavir	100 twice daily	400/100 capsule twice daily	8, 213	1.28 (0.94, 1.76)	1.46 (1.04, 2.06)	2.16 (1.29, 3.62)
  Tipranavir/ ritonavir	500/200 twice daily	400/100 capsule twice daily	21 693	0.53 (0.40, 0.69)	0.45 (0.32, 0.63)	0.30 (0.17, 0.51) 0.484 (0.40, 0.58)
  1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs. 3 Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available.

  Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen

  Co- administered Drug	Dose of Co- administered Drug (mg)	Dose of KALETRA (mg)	n	Ratio (in combination with KALETRA/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 µg once daily (Ortho Novum®)	400/100 capsule twice daily	12	0.59 (0.52, 0.66)	0.58 (0.54, 0.62)	0.42 (0.36, 0.49)
  Etravirine	200 twice daily	400/100 tablet twice day	16	0.70 (0.64-0.78)	0.65 (0.59-0.71)	0.55 (0.49-0.62)
  Fosamprenavir1	700 twice daily plus ritonavir 100 twice daily	400/100 capsule twice daily	18	0.42 (0.30, 0.58)	0.37 (0.28, 0.49)	0.35 (0.27, 0.46)
  Indinavir	600 twice daily combo nonfasting vs. 800 three times daily alone fasting	400/100 capsule twice daily	13	0.71 (0.63, 0.81)	0.91 (0.75, 1.10)	3.47 (2.60, 4.64)
  Ketoconazole	200 single dose	400/100 capsule twice daily	12	1.13 (0.91, 1.40)	3.04 (2.44, 3.79)	N/A
  Maraviroc1	300 twice daily	400/100 twice daily	11	1.97 (1.66, 2.34)	3.95 (3.43, 4.56)	9.24 (7.98, 10.7)
  Methadone	5 single dose	400/100 capsule twice daily	11	0.55 (0.48, 0.64)	0.47 (0.42, 0.53)	N/A
  Nelfinavir	1000 twice daily combo vs. 1250 twice daily alone	400/100 capsule twice daily	13	0.93 (0.82, 1.05)	1.07 (0.95, 1.19)	1.86 (1.57, 2.22)
  M8 metabolite				2.36 (1.91, 2.91)	3.46 (2.78, 4.31)	7.49 (5.85, 9.58)
  Nevirapine	200 once daily twice daily	400/100 capsule twice daily	5, 63	1.05 (0.72, 1.52)	1.08 (0.72, 1.64)	1.15 (0.71, 1.86)
  Norethindrone	1 once daily (Ortho Novum®)	400/100 capsule twice daily	12	0.84 (0.75, 0.94)	0.83 (0.73, 0.94)	0.68 (0.54, 0.85)
  Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir1	25/150/100 + dasabuvir 400	400/100 tablet twice daily	6	1.14 (1.01, 1.28)	1.17 (1.07, 1.28)	1.24 (1.14, 1.34)
  				2.04 (1.30, 3.20)	2.17 (1.63, 2.89)	2.36 (1.00, 5.55)
  				1.55 (1.16, 2.09)	2.05 (1.49, 2.81)	5.25 (3.33, 8.28)
  				0.99 (0.75, 1.31)	0.93 (0.75, 1.15)	0.68 (0.57, 0.80)
  Pitavastatin1	4 once daily	400/100 tablet twice daily	23	0.96 (0.84-1.10)	0.80 (0.73-0.87)	N/A
  Pravastatin	20 once daily	400/100 capsule twice daily	12	1.26 (0.87, 1.83)	1.33 (0.91, 1.94)	N/A
  Rifabutin	150 once daily combo 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 (1.18-1.40)	1.52 (1.36-1.70)	1.74 (1.46-2.08)
  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 Data extracted from the U.S. prescribing information of co-administered drugs. 2  Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3 Parallel group design N/A = Not available.
  )
  
  • In pregnant women. (
  2.5 Dosage Recommendations in Pregnancy

  Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.

  • Once daily KALETRA 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 KALETRA is required for patients during the postpartum period.
    
    
  • Avoid use of KALETRA 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 KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

  Risk Summary

  Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP)

  (see Data)

  . The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation

  (see Data)

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

  Clinical Considerations

  Dose Adjustments During Pregnancy and the Postpartum Period

  Administer 400/100 mg of KALETRA 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 KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period.

  Once daily KALETRA dosing is not recommended in pregnancy.

  Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%.

  Data

  Human Data

  KALETRA 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 KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.

  Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens. For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.

  Animal Data

  Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a pre- and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.

  No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
  ,
  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 KALETRA tablets to capsules with less pharmacokinetic variability. Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA 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. Kaletra tablet b. Changes in AUC values

  Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD

  Pharmacokinetic Parameter	Twice Daily a	Once Daily b
  Cmax(µg/mL)	9.8 ± 3.7	11.8 ± 3.7
  Cmin(µg/mL)	5.5 ± 2.7	1.7 ± 1.6
  AUCtau(µg•h/mL)	92.6 ± 36.7	154.1 ± 61.4
  19 HIV-1 subjects, Kaletra 400/100 mg twice daily 24 HIV-1 subjects, Kaletra 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

  C max (μg/mL)	C min (μg/mL)	AUC 12 (μg•hr/m )
  Age ≥ 14 Days to < 6 Weeks Cohort (N = 9):
  5.17 ± 1.84a	1.40 ± 0.48a	43.39 ± 14.80a
  Age ≥ 6 Weeks to < 6 Months Cohort (N = 18):
  9.39 ± 4.91a	1.95 ± 1.80a	74.50 ± 37.87a
  Age ≥ 6 Months to ≤ 12 years Cohort (N = 24):
  8.2 ± 2.9b	3.4 ± 2.1b	72.6 ± 31.1b
  10.0 ± 3.3c	3.6 ± 3.5c	85.8 ± 36.9c
  KALETRA oral solution300/75 mg/m2twice daily without concomitant NNRTI therapy KALETRA oral solution 230/57.5 mg/m2twice daily without nevirapine (n=12) KALETRA 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 KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA-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 KALETRA 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). KALETRA 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

  KALETRA is an inhibitor of the P450 isoform CYP3A

  in vitro

  . KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

  KALETRA 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 KALETRA on the AUC, C_maxand C_minare summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA 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 KALETRA (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 day (tablets)	16	0.89 (0.82-0.96)	0.87 (0.83-0.92)	0.80 (0.73-0.88)
  Fosamprenavir2	700 twice daily plus ritonavir 100 twice daily	400/100 capsule twice daily	18	1.30 (0.85, 1.47)	1.37 (0.80, 1.55)	1.52 (0.72, 1.82)
  Ketoconazole	200 single dose	400/100 capsule twice daily	12	0.89 (0.80, 0.99)	0.87 (0.75, 1.00)	0.75 (0.55, 1.00)
  Nelfinavir	1000 twice daily	400/100 capsule twice daily	13	0.79 (0.70, 0.89)	0.73 (0.63, 0.85)	0.62 (0.49, 0.78)
  Nevirapine	200 twice daily steady-state	400/100 capsule twice daily	22, 193	0.81 (0.62, 1.05)	0.73 (0.53, 0.98)	0.49 (0.28, 0.74)
  	7 mg/kg or 4 mg/kg once daily; twice daily 1 wk5	(> 1 yr) 300/ 75 mg/m2 oral solution twice daily	12, 153	0.86 (0.64, 1.16)	0.78 (0.56, 1.09)	0.45 (0.25, 0.81)
  Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir2	25/150/100 + dasabuvir 400	400/100 tablet twice daily	6	0.87 (0.76, 0.99)	0.94 (0.81, 1.10)	1.15 (0.93, 1.42)
  Omeprazole	40 once daily, 5 d	400/100 tablet twice daily, 10 d	12	1.08 (0.99, 1.17)	1.07 (0.99, 1.15)	1.03 (0.90, 1.18)
  	40 once daily, 5 d	800/200 tablet once daily, 10 d	12	0.94 (0.88, 1.00)	0.92 (0.86, 0.99)	0.71 (0.57, 0.89)
  Pravastatin	20 once daily, 4 d	400/100 capsule twice daily, 14 d	12	0.98 (0.89, 1.08)	0.95 (0.85, 1.05)	0.88 (0.77, 1.02)
  Ranitidine	150 single dose	400/100 tablet twice daily, 10 d	12	0.99 (0.95, 1.03)	0.97 (0.93, 1.01)	0.90 (0.85, 0.95)
  	150 single dose	800/200 tablet once daily, 10 d	10	0.97 (0.95, 1.00)	0.95 (0.91, 0.99)	0.82 (0.74, 0.91)
  Rifabutin	150 once daily	400/100 capsule twice daily	14	1.08 (0.97, 1.19)	1.17 (1.04, 1.31)	1.20 (0.96, 1.65)
  Rifampin	600 once daily	400/100 capsule twice daily	22	0.45 (0.40, 0.51)	0.25 (0.21, 0.29)	0.01 (0.01, 0.02)
  	600 once daily	800/200 capsule twice daily	10	1.02 (0.85, 1.23)	0.84 (0.64, 1.10)	0.43 (0.19, 0.96)
  	600 once daily	400/400 capsule twice daily	9	0.93 (0.81, 1.07)	0.98 (0.81, 1.17)	1.03 (0.68, 1.56)
  Rilpivirine	150 once daily	400/100 twice daily (capsules)	15	0.96 (0.88-1.05)	0.99 (0.89-1.10)	0.89 (0.73-1.08)
  Ritonavir	100 twice daily	400/100 capsule twice daily	8, 213	1.28 (0.94, 1.76)	1.46 (1.04, 2.06)	2.16 (1.29, 3.62)
  Tipranavir/ ritonavir	500/200 twice daily	400/100 capsule twice daily	21 693	0.53 (0.40, 0.69)	0.45 (0.32, 0.63)	0.30 (0.17, 0.51) 0.484 (0.40, 0.58)
  1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs. 3 Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available.

  Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen

  Co- administered Drug	Dose of Co- administered Drug (mg)	Dose of KALETRA (mg)	n	Ratio (in combination with KALETRA/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 µg once daily (Ortho Novum®)	400/100 capsule twice daily	12	0.59 (0.52, 0.66)	0.58 (0.54, 0.62)	0.42 (0.36, 0.49)
  Etravirine	200 twice daily	400/100 tablet twice day	16	0.70 (0.64-0.78)	0.65 (0.59-0.71)	0.55 (0.49-0.62)
  Fosamprenavir1	700 twice daily plus ritonavir 100 twice daily	400/100 capsule twice daily	18	0.42 (0.30, 0.58)	0.37 (0.28, 0.49)	0.35 (0.27, 0.46)
  Indinavir	600 twice daily combo nonfasting vs. 800 three times daily alone fasting	400/100 capsule twice daily	13	0.71 (0.63, 0.81)	0.91 (0.75, 1.10)	3.47 (2.60, 4.64)
  Ketoconazole	200 single dose	400/100 capsule twice daily	12	1.13 (0.91, 1.40)	3.04 (2.44, 3.79)	N/A
  Maraviroc1	300 twice daily	400/100 twice daily	11	1.97 (1.66, 2.34)	3.95 (3.43, 4.56)	9.24 (7.98, 10.7)
  Methadone	5 single dose	400/100 capsule twice daily	11	0.55 (0.48, 0.64)	0.47 (0.42, 0.53)	N/A
  Nelfinavir	1000 twice daily combo vs. 1250 twice daily alone	400/100 capsule twice daily	13	0.93 (0.82, 1.05)	1.07 (0.95, 1.19)	1.86 (1.57, 2.22)
  M8 metabolite				2.36 (1.91, 2.91)	3.46 (2.78, 4.31)	7.49 (5.85, 9.58)
  Nevirapine	200 once daily twice daily	400/100 capsule twice daily	5, 63	1.05 (0.72, 1.52)	1.08 (0.72, 1.64)	1.15 (0.71, 1.86)
  Norethindrone	1 once daily (Ortho Novum®)	400/100 capsule twice daily	12	0.84 (0.75, 0.94)	0.83 (0.73, 0.94)	0.68 (0.54, 0.85)
  Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir1	25/150/100 + dasabuvir 400	400/100 tablet twice daily	6	1.14 (1.01, 1.28)	1.17 (1.07, 1.28)	1.24 (1.14, 1.34)
  				2.04 (1.30, 3.20)	2.17 (1.63, 2.89)	2.36 (1.00, 5.55)
  				1.55 (1.16, 2.09)	2.05 (1.49, 2.81)	5.25 (3.33, 8.28)
  				0.99 (0.75, 1.31)	0.93 (0.75, 1.15)	0.68 (0.57, 0.80)
  Pitavastatin1	4 once daily	400/100 tablet twice daily	23	0.96 (0.84-1.10)	0.80 (0.73-0.87)	N/A
  Pravastatin	20 once daily	400/100 capsule twice daily	12	1.26 (0.87, 1.83)	1.33 (0.91, 1.94)	N/A
  Rifabutin	150 once daily combo 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 (1.18-1.40)	1.52 (1.36-1.70)	1.74 (1.46-2.08)
  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 Data extracted from the U.S. prescribing information of co-administered drugs. 2  Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3 Parallel group design N/A = Not available.
  )

• KALETRA 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 KALETRA may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. (
  2.3 Dosage Recommendations in Adults

  KALETRA can be given in once daily or twice daily dosing regimen at dosages noted in Tables 1 and 2. KALETRA 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 - KALETRA Once Daily Regimen

  KALETRA 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 - KALETRA Twice Daily Regimen

  KALETRA 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 KALETRA must be increased when administered in combination with efavirenz, nevirapine or nelfinavir. Table 3 outlines the dosage recommendations for twice daily dosing when KALETRA is taken in combination with these agents.

  Table 3. Recommended Dosage in Adults - KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir

  KALETRA 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

  KALETRA 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. KALETRA 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

  KALETRA 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

  )]

  .

  KALETRA 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 KALETRA 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 KALETRA 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 KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:

  Volume of KALETRA 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.

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

  Table 4. KALETRA 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/m 2 )	Frequency
  14 days to 6 months	16/4		300/75	Given twice daily
  Older than 6 months to less than 18 years	Less than15 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 KALETRA tablets.

  Table 5. KALETRA 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 (m 2 ) *	Recommended number of 100/25 mg Tablets Twice Daily
  ≥15 to 25	≥0.6 to < 0.9	2
  >25 to 35	≥0.9 to < 1.4	3
  >35	≥1.4	4
  * KALETRA 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 KALETRA Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

  Table 6. KALETRA 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/m 2 )	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 KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.

  Table 7. KALETRA 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 (m 2 ) *	Recommended number of 100/25 mg Tablets Twice Daily
  ≥15 to 20	≥0.6 to < 0.8	2
  >20 to 30	≥0.8 to < 1.2	3
  >30 to 45	≥1.2 to <1.7	4
  >45	≥1.7	5 [see Dosage and Administration ( 2.4 )]
  * KALETRA 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 KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
  HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA 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 KALETRA with respect to safety and efficacy have not been established.
  HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA 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 KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA 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		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA 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 KALETRA oral solution (given with food).
  Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate*	↑ tenofovir	Patients receiving KALETRA 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 KALETRA.
  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 KALETRA or to the class of protease inhibitors [see Contraindications ( 4 )] . Avoid co-administration of encorafenib or ivosidenib with KALETRA due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with KALETRA cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with KALETRA cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with KALETRA. 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 KALETRA 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 KALETRA. 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 KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
  Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
  Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
  Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving KALETRA 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 KALETRA with CLCR30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA 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 KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra 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 KALETRA: 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 KALETRA: 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 KALETRA: 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 KALETRA 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 KALETRA 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 KALETRA 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 KALETRA: 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 KALETRA 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		KALETRA 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 KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, 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 KALETRA 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 KALETRA 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/voxilaprevir 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 KALETRA 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 KALETRA 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 KALETRA.
  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 KALETRA 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 KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
  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 KALETRA 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 KALETRA. Co-administration of KALETRA 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 KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA 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 KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, 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 KALETRA 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.
  )
  
  
• KALETRA 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

  KALETRA 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. KALETRA 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

  KALETRA 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

  )]

  .

  KALETRA 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 KALETRA 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 KALETRA 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 KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:

  Volume of KALETRA 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.

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

  Table 4. KALETRA 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/m 2 )	Frequency
  14 days to 6 months	16/4		300/75	Given twice daily
  Older than 6 months to less than 18 years	Less than15 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 KALETRA tablets.

  Table 5. KALETRA 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 (m 2 ) *	Recommended number of 100/25 mg Tablets Twice Daily
  ≥15 to 25	≥0.6 to < 0.9	2
  >25 to 35	≥0.9 to < 1.4	3
  >35	≥1.4	4
  * KALETRA 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 KALETRA Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

  Table 6. KALETRA 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/m 2 )	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 KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.

  Table 7. KALETRA 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 (m 2 ) *	Recommended number of 100/25 mg Tablets Twice Daily
  ≥15 to 20	≥0.6 to < 0.8	2
  >20 to 30	≥0.8 to < 1.2	3
  >30 to 45	≥1.2 to <1.7	4
  >45	≥1.7	5 [see Dosage and Administration ( 2.4 )]
  * KALETRA 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.
  ,
  5.2 Toxicity in Preterm Neonates

  KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v) and propylene glycol, approximately 15% (w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving KALETRA oral solution.

  KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of KALETRA oral solution in this patient population has not been established. However, if the benefit of using KALETRA oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of ethanol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients

  [see Dosage and Administration (

  2.4

  )

  and

  Overdosage (

  10

  )]

  .
  )

• 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.
  
  
• There are insufficient data to recommend a KALETRA dose for pregnant patients with any documented KALETRA-associated resistance substitutions.
  
  
• No dose adjustment of KALETRA is required for patients during the postpartum period.

• Tablets:
  
  ○ 200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the “a” logo and the code KA containing 200 mg lopinavir and 50 mg ritonavir.
  
  ○ 100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with the “a” logo and the code KC containing 100 mg lopinavir and 25 mg ritonavir.
  
  ○ 200 mg lopinavir, 50 mg ritonavir: Red, film-coated, ovaloid, debossed with the code AL containing 200 mg lopinavir and 50 mg ritonavir.
  
  ○ 100 mg lopinavir, 25 mg ritonavir: Pink, film-coated, ovaloid, debossed with the code AC containing 100 mg lopinavir and 25 mg ritonavir.
  
  
• Oral Solution:
  
  ○ Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL).

Lactation: Breastfeeding not recommended. (