Lopinavir and ritonavir

Co-administration of KALETRA can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. The potential for drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.1 , 7 , 12.3 )

7.1 Potential for KALETRA to Affect Other Drugs Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.

Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 12. Additionally, KALETRA induces glucuronidation. Published data suggest that lopinavir is an inhibitor of OATP1B1. These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

7.2 Potential for Other Drugs to Affect Lopinavir Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

7.3 Established and Other Potentially Significant Drug Interactions Table 12 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )] for magnitude of interaction. Table 12.

Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments HIV-1 Antiviral Agents HIV-1 Protease Inhibitor: fosamprenavir/ritonavir ↓ amprenavir ↓ lopinavir An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV-1 Protease Inhibitor: indinavir* ↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with 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 )] .

Analgesics Opioid: methadone* fentanyl Non-opioid analgesic (selective blocker of Na v 1.8 sodium channels): suzetrigine ↓ methadone ↑ fentanyl ↑ suzetrigine and active metabolite M6-SUZ 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. Co-administration contraindicated due to potential for serious and/or life-threatening suzetrigine adverse reactions [ see Contraindications ( 4 ) ] .

Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications ( 4 )] . Antiarrhythmics: dronedarone ↑ dronedarone Contraindicated due to potential for cardiac arrhythmias [see Contraindications ( 4 )] . Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with 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:…

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…