Aluvia

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALUVIA® (ALUVIA®)

Composition:

Tablets 200 mg/50 mg:

Active substances: each tablet contains lopinavir 200 mg and ritonavir 50 mg;

Excipients: copovidone, sorbitan laurate, colloidal anhydrous silicon dioxide, sodium stearyl fumarate, hypromellose, titanium dioxide (E 171), hydroxypropyl cellulose, talc, macrogol, iron oxide red (E172), polysorbate.

Tablets 100 mg/25 mg:

Active substances: each tablet contains lopinavir 100 mg and ritonavir 25 mg;

Excipients: copovidone, sorbitan laurate, colloidal anhydrous silicon dioxide, sodium stearyl fumarate, polyvinyl alcohol, titanium dioxide (E 171), talc, macrogol, iron oxide red (E172).

Pharmaceutical form.

Film-coated tablets.

Basic physical and chemical properties.

Aluvia® 200 mg/50 mg: film-coated tablets, red in color, oval-shaped, with an imprint "AL" on one side of the tablet.

Aluvia® 100 mg/25 mg: film-coated tablets, light pink in color, oval-shaped, with an imprint "AC" on one side of the tablet.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Antiviral agents for the treatment of HIV infections, combinations. ATC code J05A R10.

Pharmacological Properties.

Pharmacodynamics.

Lopinavir is a protease inhibitor of HIV-1 and HIV-2 that prevents cleavage of the gag pol polyprotein, resulting in the production of immature, non-infectious virus particles.

Ritonavir is an orally administered peptidomimetic inhibitor of HIV-1 and HIV-2 aspartyl protease. Inhibition of HIV protease prevents processing of the gag pol polyprotein precursor, leading to the formation of morphologically immature HIV particles incapable of initiating new infection cycles. Ritonavir has selective affinity for HIV protease and low inhibitory activity against human aspartyl proteases.

In vitro antiviral activity.

The in vitro antiviral activity of lopinavir against laboratory strains of HIV and clinical isolates of HIV was evaluated in acutely infected lymphoblastoid cells and peripheral blood lymphocytes. In the absence of human serum, the mean 50% effective concentration (EC50) of lopinavir against five different laboratory strains of HIV-1 was 19 nM. In the presence of 50% human serum, the mean EC50 of lopinavir against HIV-1IIIB in MT4 cells ranged from 17 to 102 nM. In the absence of human serum, the mean EC50 of lopinavir against several clinical isolates of HIV-1 was 6.5 nM.

Resistance.

In vitro experiments have isolated HIV-1 isolates with reduced susceptibility to lopinavir. HIV-1 was passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentrations reflecting the plasma concentration range observed during lopinavir/ritonavir therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggests that the presence of ritonavir at these concentrations has no measurable effect on the selection of lopinavir-resistant viruses. Overall, in vitro characterization of phenotypic cross-resistance between lopinavir and other protease inhibitors indicates that reduced susceptibility to lopinavir strongly correlates with reduced susceptibility to ritonavir and indinavir, but such a strong correlation is not observed with reduced susceptibility to amprenavir, saquinavir, and nelfinavir.

Cross-resistance.

The activity of other protease inhibitors against isolates exhibiting increased resistance to lopinavir after lopinavir/ritonavir therapy was evaluated in patients previously treated with protease inhibitors. Cross-resistance to other protease inhibitors was analyzed in 18 isolates obtained after a significant increase in viral load in patients previously treated with protease inhibitors, who showed increased resistance to lopinavir in three phase II and one phase III lopinavir/ritonavir trials. The mean EC50 of lopinavir for these 18 isolates, collected at baseline and after a significant increase in viral load, was 6.9–63 times higher than the EC50 against wild-type HIV, respectively. Overall, isolates obtained after a significant increase in viral load showed either the same cross-resistance (if cross-resistance existed at baseline) or developed new substantial cross-resistance to indinavir, saquinavir, and atazanavir. A moderate reduction in amprenavir activity was observed, with a mean increase in EC50 of isolates collected at baseline and after a significant increase in viral load by 3.7–8 times, respectively. Isolates retained sensitivity to tipranavir, with a mean increase in EC50 of isolates collected at baseline and after a significant increase in viral load by 1.9–1.8 times compared to EC50 against wild-type HIV, respectively.

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses emerging under pressure of other protease inhibitors.

The in vitro antiviral activity of lopinavir was evaluated against 112 clinical isolates obtained from patients who, despite prior treatment with one or more protease inhibitors, had HIV RNA levels exceeding 1000 copies/mL. In this group, reduced in vitro susceptibility to lopinavir was associated with the following mutations in HIV protease: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M.

Electrocardiogram changes.

The QTcF interval was assessed in a randomized, placebo-controlled, active-controlled crossover study (moxifloxacin 400 mg once daily) involving 39 healthy adult volunteers, with 10 measurements taken over 12 hours on day 3. The maximum mean (95% upper confidence interval) difference from placebo in QTcF values was 3.6 (6.3) and 13.1 (15.8) for the 400/100 mg twice-daily dose and the supratherapeutic dose of 800/200 mg twice daily of lopinavir/ritonavir, respectively. High-dose lopinavir/ritonavir (800/200 mg twice daily) induced QRS interval prolongation from 6 msec to 9.5 msec, contributing to QT prolongation. Both regimens resulted in exposures on day 3 approximately 1.5 and 3 times higher than those observed with the standard maintenance dose of lopinavir/ritonavir (once or twice daily). No increases in QTcF > 60 msec from baseline or QTcF intervals exceeding the potentially clinically significant threshold of 500 msec were observed.

A moderate prolongation of the PR interval was also observed in patients receiving lopinavir/ritonavir in the same study on day 3. Mean deviations from baseline for the PR interval ranged from 11.6 msec to 24.4 msec over the 12-hour interval. The maximum PR interval was 286 msec, and no second- or third-degree heart block was observed.

Pharmacokinetics.

The pharmacokinetic properties of lopinavir when administered with ritonavir were studied in healthy adult volunteers and HIV-infected individuals, with no significant differences observed between the two groups. Lopinavir is almost completely metabolized by CYP3A. Ritonavir inhibits the metabolic degradation of lopinavir, thereby increasing lopinavir plasma concentrations. Comparing results from different studies, administration of lopinavir/ritonavir at a dose of 400/100 mg twice daily to HIV-infected patients resulted in mean lopinavir plasma concentrations at steady state being 15–20 times higher than ritonavir concentrations. The plasma concentration of ritonavir is less than 7% of that observed after administration of ritonavir at 600 mg twice daily. In vitro experiments have shown that the antiviral effective concentration (EC50) of lopinavir is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of Aluvia® is attributable to the presence of lopinavir.

Absorption.

Repeated administration of lopinavir/ritonavir at a dose of 400/100 mg twice daily for 2 weeks without dietary restrictions resulted in a Cmax of lopinavir in plasma of 12.3 ± 5.4 µg/mL (mean ± standard deviation) approximately 4 hours after administration. The mean plasma concentration at steady state prior to morning dosing was 8.1 ± 5.7 µg/mL. The mean AUC for lopinavir over 12 hours after administration was 113.2 ± 60.5 µg·hr/mL. The absolute bioavailability of lopinavir when administered with ritonavir in humans has not been established.

Effect of food on absorption following oral administration.

Single-dose administration of 400/100 mg lopinavir/ritonavir in tablet form after a high-fat meal (872 kcal, 56% from fat) was compared to administration in the fasting state. No significant changes in Cmax and AUCinf values were observed. Therefore, lopinavir/ritonavir in tablet form can be administered independently of food intake. Additionally, lower pharmacokinetic variability related to food intake was observed compared to the Aluvia® soft gel capsule formulation.

Distribution.

At steady state, approximately 98–99% of lopinavir is bound to plasma proteins. Lopinavir can bind to both alpha-1-acid glycoprotein and albumin, but its affinity for alpha-1-acid glycoprotein is higher. When lopinavir/ritonavir is administered at a dose of 400/100 mg twice daily, protein binding of lopinavir at steady state remains constant across a wide concentration range and does not differ between healthy volunteers and HIV-infected patients.

Biotransformation.

In vitro experiments using human liver microsomes showed that lopinavir is primarily metabolized via oxidation. Lopinavir undergoes extensive hepatic metabolism by the cytochrome P450 system, particularly the CYP3A isoenzyme. Ritonavir is a potent inhibitor of CYP3A activity and thereby inhibits lopinavir metabolism, increasing its plasma concentration. Studies with 14C-labeled lopinavir showed that after a single 400/100 mg dose of lopinavir/ritonavir administered to humans, 89% of total radioactivity in plasma was attributable to the parent compound. At least 13 oxidative metabolites of lopinavir have been identified in humans. The 4-oxo and 4-hydroxymetabolite isomeric pairs are the main metabolites with antiviral activity, although they represent only minor fractions of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzyme activity, thereby accelerating its own metabolism and likely accelerating lopinavir metabolism as well. With repeated dosing, lopinavir concentrations prior to the next dose decrease, with steady-state concentrations achieved approximately 10 days to 2 weeks after initiation.

Elimination.

After administration of 14C-lopinavir/ritonavir at a dose of 400/100 mg, 10.4 ± 2.3% and 82.6 ± 2.5% of the administered radioactive dose of 14C-lopinavir was excreted in urine and feces, respectively. Unchanged lopinavir accounted for 2.2% and 19.8% of the dose in urine and feces, respectively. After multiple doses, less than 3% of the administered lopinavir dose was excreted unchanged in urine. The elimination half-life (decline from maximum to minimum concentration at steady state) of lopinavir over the 12-hour dosing interval averages 5–6 hours, and the apparent total clearance (CL/F) of lopinavir is 6–7 L/hour.

Once-daily dosing: The pharmacokinetics of once-daily lopinavir/ritonavir were studied in HIV-infected patients who had not previously received antiretroviral therapy. Lopinavir/ritonavir 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg using a once-daily dosing regimen. Repeated administration of lopinavir/ritonavir at 800/200 mg once daily for 2 weeks without dietary restrictions (n=16) resulted in a mean Cmax of lopinavir of 14.8 ± 3.5 µg/mL (mean ± standard deviation) approximately 6 hours after administration. Mean trough concentrations of lopinavir prior to morning dosing were 5.5 ± 5.4 µg/mL. The mean AUC over 24 hours was 206.5 ± 89.7 µg·hr/mL.

Compared to the twice-daily regimen, the once-daily dosing regimen is associated with approximately a 50% reduction in Cmin/Cthrough values.

Clinical characteristics.

Indications.

Treatment of HIV-infected patients in combination with other antiretroviral agents.

Contraindications.

• Hypersensitivity to lopinavir or ritonavir or to any inactive component of the drug.
• Severe hepatic impairment.
• Aluvia® contains lopinavir and ritonavir, which are inhibitors of the CYP3A isoenzyme of cytochrome P450. Lopinavir/ritonavir must not be used concomitantly with drugs whose clearance is largely dependent on CYP3A activity and whose increased plasma concentration may lead to serious and/or life-threatening reactions. The list of such drugs includes:

Increased levels of concomitant drugs:

Alpha1-adrenoreceptor antagonists.

Alfuzosin. Plasma concentration of alfuzosin increases, potentially leading to severe arterial hypotension.

Anti-anginal agents.

Ranolazine. Plasma concentration of ranolazine increases, potentially leading to serious and/or life-threatening reactions.

Antiarrhythmic agents.

Amiodarone, dronedarone. Plasma concentrations of amiodarone and dronedarone increase, resulting in an increased risk of arrhythmias or other serious adverse reactions.

Antibiotics.

Fusidic acid. Plasma concentration of fusidic acid increases. Concomitant use with fusidic acid is contraindicated in dermatological infections.

Anticancer agents.

Apalutamide. Apalutamide is a moderate to strong CYP3A4 inducer and may lead to reduced exposure of lopinavir/ritonavir and potential loss of virological response. Additionally, increased plasma concentration of apalutamide may lead to serious adverse events, including seizures.

Neratinib. Increased plasma concentration of neratinib may increase the risk of serious and/or life-threatening reactions.

Venetoclax. Plasma concentration of venetoclax increases. Risk of tumor lysis syndrome increases during initial dosing and the ramp-up phase. For patients who have completed the ramp-up phase and are on a maintenance daily dose of venetoclax, the dose of venetoclax should be reduced by at least 75% when used with strong CYP3A inhibitors (see the venetoclax product information leaflet).

Antigout agents.

Colchicine. Plasma concentration of colchicine increases, potentially leading to serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.

Antihistamines.

Astemizole, terfenadine. Plasma concentrations of astemizole and terfenadine increase, resulting in an increased risk of serious arrhythmias caused by these substances.

Antipsychotic/neuroleptic agents.

Lurasidone. Plasma concentration of lurasidone increases, potentially leading to serious and/or life-threatening reactions.

Pimozide. Plasma concentration of pimozide increases, resulting in an increased risk of serious hematological disorders or other serious adverse events caused by this substance.

Quetiapine. Increased plasma concentration of quetiapine may lead to coma.

Blonanserin. Concomitant use with blonanserin is contraindicated.

Ergot alkaloids.

Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Increased plasma concentrations of ergot derivatives may cause acute ergot toxicity, including vascular spasm and ischemia.

Gastrointestinal motility agents.

Cisapride. Plasma concentration of cisapride increases, resulting in an increased risk of serious arrhythmias caused by this substance.

Direct-acting antiviral agents against hepatitis C virus.

Elbasvir/grazoprevir. Increased risk of elevated ALT levels.

Lipid-lowering agents.

HMG-CoA reductase inhibitors.

Lovastatin, simvastatin. Plasma concentrations of lovastatin and simvastatin increase. As a result, the risk of myopathy, including rhabdomyolysis, increases.

Inhibitor of microsomal triglyceride transfer protein.

Lomitapide. Plasma concentration of lomitapide increases.

Phosphodiesterase inhibitors (PDE5).

Avanafil. Plasma concentration of avanafil increases.

Sildenafil. Contraindicated only when used for the treatment of pulmonary arterial hypertension (PAH). Increases plasma concentration of sildenafil. Thus, increased risk of adverse reactions associated with sildenafil, including arterial hypotension and syncope.

Vardenafil. Plasma concentration of vardenafil increases.

Sedatives/hypnotics.

Oral midazolam, triazolam. Plasma concentrations of oral midazolam and triazolam increase. As a result, increased risk of excessive sedative effects and respiratory depression caused by these substances. Warnings regarding parenteral administration of midazolam are provided in the section: "Interaction with other medicinal products and other types of interactions."

Beta2-adrenergic agonists (long-acting).

Salmeterol. Increased concentrations are expected due to inhibition of CYP3A by lopinavir/ritonavir. This combination may increase the risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, tachycardia, and sinus tachycardia.

Decreased levels of lopinavir/ritonavir:

Herbal products.

St. John's wort. There is a risk that herbal products containing St. John's wort (Hypericum perforatum) may reduce the concentrations and clinical effect of lopinavir and ritonavir.

Interaction with other medicinal products and other types of interactions.

Aluvia® contains lopinavir and ritonavir, which are inhibitors of the CYP3A isoenzyme of cytochrome P450 in vitro. Concomitant administration of lopinavir/ritonavir and drugs primarily metabolized by the CYP3A system may lead to increased plasma concentrations of other drugs, potentially increasing or prolonging their therapeutic and adverse effects. Aluvia® does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6, or CYP1A2 at clinically used concentrations.

Lopinavir/ritonavir in vivo induces its own metabolism and increases the biotransformation of some drugs metabolized by the cytochrome P450 enzyme system (including CYP2C9 and CYP2C19) and via glucuronidation. This may lead to decreased plasma concentrations of drugs and possible reduction in their efficacy when co-administered with lopinavir/ritonavir.

Medicinal products contraindicated specifically due to the expected degree of interaction and potential for serious adverse events are listed in the Contraindications section.

Known and theoretical interactions with selected antiretroviral and other medicinal products are provided in the table below.

Unless otherwise stated, the studies listed below were conducted using the recommended dose of lopinavir/ritonavir (i.e., 400/100 mg twice daily).

Antiretroviral agents.

Nucleoside reverse transcriptase inhibitors (NRTIs).

Stavudine and lamivudine. Plasma concentration of lopinavir does not change when lopinavir/ritonavir is co-administered with stavudine or lamivudine. Dose adjustment is not required.

Didanosine. Didanosine must be taken on an empty stomach with lopinavir/ritonavir tablets.

Zidovudine and abacavir. Lopinavir/ritonavir induces glucuronidation, thus reducing plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.

Tenofovir. Concomitant administration of lopinavir/ritonavir with tenofovir (300 mg once daily) results in a 32% increase in tenofovir levels without changes in lopinavir and ritonavir concentrations, but high tenofovir concentrations may potentiate tenofovir-related adverse reactions, including renal impairment.

Elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported with protease inhibitors, especially in combination with NRTIs.

Non-nucleoside reverse transcriptase inhibitors.

Efavirenz. Plasma concentration of lopinavir decreases by 20% when lopinavir/ritonavir (500/125 mg twice daily) is co-administered with efavirenz (600 mg once daily). The dose of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when co-administered with efavirenz. Once-daily lopinavir/ritonavir should not be used in combination with efavirenz.

Nevirapine. Plasma concentration of lopinavir decreases by 27% when co-administered with nevirapine (200 mg twice daily). The dose of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when co-administered with nevirapine. Once-daily lopinavir/ritonavir should not be used in combination with nevirapine.

Etravirine. Concomitant administration of lopinavir/ritonavir (400/100 mg twice daily) and etravirine may reduce etravirine plasma concentration by 35%, while lopinavir plasma concentration remains unchanged. Dose adjustment is not required.

Rilpivirine. Concomitant administration of lopinavir/ritonavir (400/100 mg twice daily) and rilpivirine may increase rilpivirine plasma concentration by 52%, while lopinavir plasma concentration remains unchanged. Dose adjustment is not required.

Delavirdine. Delavirdine may increase plasma concentration of lopinavir.

CCR5 receptor antagonist.

Maraviroc. Concomitant administration of maraviroc and lopinavir/ritonavir increases maraviroc plasma levels by 295%. The dose of maraviroc should be reduced to 150 mg twice daily when co-administered with lopinavir/ritonavir 400/100 mg twice daily.

Integrase inhibitors.

Raltegravir. Clinical studies showed no clinically significant interaction between lopinavir/ritonavir and raltegravir. Dose adjustment is not required.

Concomitant use with other HIV protease inhibitors.

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Amprinavir. Lopinavir/ritonavir is expected to increase concentrations of amprinavir (amprinavir 750 mg twice daily). Concomitant use of lopinavir/ritonavir and amprinavir leads to decreased lopinavir concentration. The dose of lopinavir/ritonavir may need to be increased when co-administered with amprinavir, especially in patients with extensive protease inhibitor experience or reduced viral susceptibility to lopinavir. Once-daily lopinavir/ritonavir should not be used in combination with amprinavir.

Fosamprenavir. Concomitant administration of lopinavir/ritonavir (400/100 mg twice daily) with fosamprenavir/ritonavir (700/100 mg twice daily) results in significant decreases in amprinavir concentrations. Concomitant use of higher doses of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients with prior protease inhibitor experience led to higher rates of gastrointestinal adverse events and increased triglyceride levels without enhanced virological efficacy compared to standard fosamprenavir/ritonavir doses. Concomitant use of these drugs is not recommended. Lopinavir/ritonavir should not be taken once daily in combination with amprinavir.

Indinavir. When indinavir 600 mg twice daily is co-administered with lopinavir/ritonavir, there are no changes in the area under the pharmacokinetic curve (AUC) of indinavir, its minimum concentration increases 3.5-fold, and maximum concentration decreases compared to indinavir 800 mg three times daily alone. Appropriate doses for this combination in terms of efficacy and safety have not been established.

Saqunavir. When saquinavir 1000 mg twice daily is co-administered with lopinavir/ritonavir, no further increases in saquinavir plasma concentrations are observed. Dose adjustment is not required.

Tipranavir/ritonavir. Concomitant use of these drugs is not recommended as plasma concentration of lopinavir decreases by 55%.

Nelfinavir. Lopinavir/ritonavir is expected to increase nelfinavir concentrations (nelfinavir 1000 mg twice daily). Concomitant use of lopinavir/ritonavir and nelfinavir leads to decreased lopinavir concentration. The dose of lopinavir/ritonavir may need to be increased when co-administered with nelfinavir, especially in patients with extensive protease inhibitor experience or reduced viral susceptibility to lopinavir. Once-daily lopinavir/ritonavir should not be used in combination with nelfinavir.

Ritonavir. When an additional 100 mg ritonavir is administered twice daily with lopinavir/ritonavir, AUC and Cmin of lopinavir increase by 33% and 64%, respectively.

Agents reducing gastric acidity.

Omeprazole, ranitidine. Dose adjustment of lopinavir/ritonavir is not required.

Alpha1-adrenoreceptor antagonists.

Alfuzosin. Due to CYP3A inhibition by lopinavir/ritonavir, increased alfuzosin concentrations are expected. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated due to the potential for increased alfuzosin-related toxicity, including arterial hypotension.

Analgesics.

Fentanyl. Lopinavir/ritonavir inhibits CYP3A4, thus increased plasma concentrations of fentanyl are expected. When fentanyl is co-administered with lopinavir/ritonavir, careful monitoring of therapeutic and adverse effects, including respiratory depression and sedation, is recommended.

Anti-anginal agents.

Ranolazine. Due to CYP3A inhibition by lopinavir/ritonavir, increased ranolazine concentrations are expected. Concomitant use of lopinavir/ritonavir with ranolazine is contraindicated.

Antiarrhythmic agents.

Amiodarone, dronedarone. Concentrations of amiodarone and dronedarone may increase due to CYP3A4 inhibition by lopinavir/ritonavir. Concomitant use of lopinavir/ritonavir with amiodarone or dronedarone is contraindicated, as it may increase the risk of arrhythmias or other serious adverse reactions.

Digoxin. Plasma concentrations may increase due to P-glycoprotein inhibition by lopinavir/ritonavir. Elevated digoxin levels may gradually decrease over time due to P-glycoprotein induction. When lopinavir/ritonavir and digoxin are used concomitantly, caution is advised, and digoxin plasma concentration monitoring should be performed if possible. Prescribing lopinavir/ritonavir to patients taking digoxin requires caution, as the acute inhibitory effect of ritonavir on P-glycoprotein is expected to significantly increase digoxin levels. Prescribing digoxin to patients already taking lopinavir/ritonavir is likely to result in a smaller than expected increase in digoxin concentrations.

Bepiridil, systemic lidocaine, and quinidine. Concentrations of these drugs increase when co-administered with lopinavir/ritonavir. Caution is advised, and therapeutic drug monitoring should be performed if possible.

Antibiotics.

Clarithromycin. A moderate increase in clarithromycin AUC is expected due to CYP3A inhibition by lopinavir/ritonavir. In patients with renal impairment (creatinine clearance <30 mL/min), consider reducing the clarithromycin dose. Caution is advised when prescribing clarithromycin concomitantly with lopinavir/ritonavir in patients with hepatic or renal impairment.

Antineoplastic agents.

Abemaciclib. Serum concentration of abemaciclib may increase due to CYP3A inhibition by ritonavir. Concomitant use of abemaciclib and lopinavir/ritonavir should be avoided. If concomitant use cannot be avoided, refer to the abemaciclib product information leaflet. Close monitoring for possible abemaciclib-related adverse reactions is required.

Apalutamide. Apalutamide is a moderate to strong CYP3A4 inducer and may lead to reduced exposure of lopinavir/ritonavir and potential loss of virological response. Serum concentration of apalutamide may increase due to CYP3A inhibition by lopinavir/ritonavir, potentially causing serious adverse events, including seizures. Concomitant use of lopinavir/ritonavir and apalutamide is contraindicated.

Afatinib. Increased AUC of afatinib plasma concentration is expected. The extent of increase depends on the timing of ritonavir administration. This is associated with inhibition of BCRP (breast cancer resistance protein/ABCG2) and acute P-glycoprotein inhibition by lopinavir/ritonavir. Caution is advised when prescribing afatinib in combination with lopinavir/ritonavir. Refer to the afatinib product information leaflet before use. Monitor for possible afatinib-related adverse reactions.

Ceritinib. Serum concentrations may increase due to CYP3A and P-glycoprotein inhibition by lopinavir/ritonavir. Caution is advised when prescribing ceritinib in combination with lopinavir/ritonavir. Refer to the ceritinib product information leaflet before use. Monitor for possible ceritinib-related adverse reactions.

Most tyrosine kinase inhibitors, such as dasatinib, nilotinib, vinblastine, vincristine. Serum concentrations increase when co-administered due to CYP3A inhibition by lopinavir/ritonavir. Close monitoring for tolerability of these anticancer agents is required.

Encorafenib and ivosidenib. Serum concentrations of these drugs may increase due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use potentially increases the risk of adverse reactions such as QT interval prolongation.

Ibrutinib. Lopinavir/ritonavir inhibits CYP3A. Concomitant use of ibrutinib and lopinavir/ritonavir may increase ibrutinib exposure, potentially increasing the risk of toxicity, including tumor lysis syndrome. Concomitant use of ibrutinib and lopinavir/ritonavir should be avoided.

If benefit outweighs risk, the ibrutinib dose should be reduced to 140 mg, and the patient should be closely monitored for signs of toxicity.

Neratinib. Neratinib serum concentration may increase due to CYP3A inhibition by ritonavir. Concomitant use of neratinib and lopinavir/ritonavir is contraindicated due to the potential for serious and/or life-threatening reactions, including hepatotoxicity.

Venetoclax. Lopinavir/ritonavir inhibits CYP3A. Concomitant use of venetoclax and lopinavir/ritonavir may increase venetoclax exposure. Risk of tumor lysis syndrome increases during initial dosing and the ramp-up phase. For patients who have completed the ramp-up phase and are on a maintenance daily dose of venetoclax, the venetoclax dose should be reduced by at least 75% when used with strong CYP3A inhibitors. Patients should be closely monitored for any venetoclax-related toxicity.

For dosing recommendations for venetoclax, nilotinib, and dasatinib, refer to the product information leaflets of these drugs.

Anticoagulants.

Warfarin. Concomitant use with lopinavir/ritonavir may alter concentrations due to CYP2C9 induction. Monitoring of INR (international normalized ratio) is recommended.

Rivaroxaban. Concomitant use of lopinavir/ritonavir and rivaroxaban may increase rivaroxaban exposure, leading to an increased risk of bleeding. Rivaroxaban use is not recommended in patients receiving concomitant lopinavir/ritonavir therapy.

Dabigatran etexilate, edoxaban. Serum concentration may increase due to P-glycoprotein inhibition by lopinavir/ritonavir. When Aluvia® is used concomitantly with direct oral anticoagulants (DOACs) transported by P-glycoprotein but not metabolized by CYP3A4, including dabigatran etexilate and edoxaban, consider the need for clinical monitoring and/or DOAC dose reduction.

Vorapaxar. Serum concentration may increase by 153% due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of vorapaxar with lopinavir/ritonavir is not recommended.

Antiepileptic drugs.

Phenytoin. Steady-state phenytoin concentration moderately decreases due to CYP2C9 and CYP2C19 induction by lopinavir/ritonavir. Lopinavir concentration decreases due to CYP3A induction by phenytoin. Caution is advised when prescribing phenytoin in combination with lopinavir/ritonavir. Phenytoin levels should be monitored when used concomitantly with lopinavir/ritonavir. Increased lopinavir/ritonavir dose may be anticipated when co-administered with phenytoin. Dose escalation has not been evaluated in clinical practice.

Lopinavir/ritonavir should not be taken once daily in combination with phenytoin.

Carbamazepine and phenobarbital. Carbamazepine serum concentration may increase due to CYP3A inhibition by lopinavir/ritonavir.

Lopinavir concentration may decrease due to CYP3A induction by carbamazepine and phenobarbital. Caution is advised when prescribing carbamazepine or phenobarbital in combination with lopinavir/ritonavir. Carbamazepine and phenobarbital levels should be monitored when co-administered with lopinavir/ritonavir. Increased lopinavir/ritonavir dose may be anticipated when co-administered with carbamazepine or phenobarbital. Dose escalation has not been evaluated in clinical practice. Lopinavir/ritonavir should not be taken once daily in combination with carbamazepine and phenobarbital.

Lamotrigine and valproate. Concomitant use of lopinavir/ritonavir and lamotrigine was associated with a 50% reduction in lamotrigine AUC due to induction of lamotrigine glucuronidation. Close monitoring is required for reduced valproic acid efficacy when used concomitantly with lopinavir/ritonavir and valproic acid. For patients starting or discontinuing lopinavir/ritonavir while on maintenance lamotrigine: dose increase of lamotrigine may be needed when lopinavir/ritonavir is added, or dose reduction when lopinavir/ritonavir is discontinued. Thus, lamotrigine plasma concentration monitoring should be performed, especially before starting concomitant lopinavir/ritonavir and during the first 2 weeks after starting or discontinuing lopinavir/ritonavir, to determine the need for lamotrigine dose adjustment. For patients already taking lopinavir/ritonavir and starting lamotrigine, no adjustment of the recommended lamotrigine dose escalation regimen should be necessary.

Antidepressants and anxiolytics.

Trasodone. Single-dose co-administration of ritonavir (200 mg twice daily) and trazodone led to increased trazodone plasma concentration (AUC increased 2.4-fold). Adverse events such as nausea, dizziness, arterial hypotension, and syncope were observed after co-administration of trazodone and ritonavir. It is unknown whether lopinavir/ritonavir causes a similar increase in trazodone exposure. This combination should be used with caution, and dose reduction of trazodone should be considered.

Antifungal agents.

Ketoconazole and itraconazole. Lopinavir/ritonavir may increase ketoconazole and itraconazole plasma concentrations due to CYP3A inhibition by lopinavir/ritonavir. High doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.

Voriconazole. Voriconazole concentration may decrease. Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) contained in Aluvia® should be avoided unless benefit-risk assessment favors voriconazole use.

Agents for gout treatment.

Colchicine. Colchicine concentration is expected to increase 3-fold when used with lopinavir/ritonavir due to P-glycoprotein and/or CYP3A4 inhibition by ritonavir. Concomitant use of lopinavir/ritonavir with colchicine in patients with renal and/or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening colchicine-related reactions, such as neuromuscular toxicity (including rhabdomyolysis). For patients with normal renal and hepatic function recommended lopinavir/ritonavir therapy, colchicine dose reduction or discontinuation is recommended. Refer to the colchicine product information leaflet.

Antihistamine medicinal products.

Astemizole, terfenadine. Lopinavir/ritonavir inhibits CYP3A, thus increased plasma concentrations of astemizole and terfenadine are expected. Concomitant use of these drugs is contraindicated due to the risk of serious arrhythmia.

Antibacterial agents.

Fusidic acid. Fusidic acid concentration may increase due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of lopinavir/ritonavir with fusidic acid is contraindicated in dermatological practice due to increased risk of fusidic acid-related adverse events, especially rhabdomyolysis. When used for bone and joint infections where concomitant use cannot be avoided, close monitoring for possible muscle-related adverse events is recommended.

Antituberculosis agents.

Bedaquiline. When bedaquiline 400 mg single dose and lopinavir/ritonavir 400/100 mg twice daily are co-administered for 24 days, bedaquiline plasma concentration (AUC) increases by 22% due to CYP3A4 inhibition by lopinavir/ritonavir. Bedaquiline should be used cautiously with ritonavir and only if benefit outweighs risk. More frequent ECG and transaminase level monitoring are recommended.

Delamanid. When delamanid (100 mg twice daily) is co-administered with lopinavir/ritonavir (400/100 mg twice daily), delamanid and its active metabolite DM-6705 concentrations increase by 22% and 30%, respectively. Due to the risk of QTc prolongation associated with DM-6705, if concomitant use of delamanid with lopinavir/ritonavir is necessary, ECG monitoring is recommended throughout delamanid treatment.

Rifabutin. When rifabutin (150 mg once daily) is co-administered with lopinavir/ritonavir for 10 days, Cmax and AUC of rifabutin increase 3.5 and 5.7 times, respectively. When co-administered with lopinavir/ritonavir, the recommended rifabutin dose is 150 mg three times weekly (e.g., Monday, Wednesday, Friday). Enhanced monitoring for rifabutin-related adverse reactions, including neutropenia and uveitis, is required due to the expected increase in rifabutin AUC. For patients unable to tolerate 150 mg three times weekly, further reduction of rifabutin dose to 150 mg twice weekly is recommended. Note that 150 mg twice weekly may not provide optimal rifabutin AUC, potentially leading to rifabutin resistance and ineffective treatment. Lopinavir/ritonavir dose adjustment is not required.

Rifampicin. Concomitant use of lopinavir/ritonavir with rifampicin is not recommended due to significant reduction in lopinavir concentrations due to CYP3A induction by rifampicin. Adjusting lopinavir/ritonavir dose to 400 mg/400 mg (i.e., lopinavir/ritonavir 400/100 mg + ritonavir 300 mg) twice daily can overcome the inductive effect of rifampicin on CYP3A4. However, this dose adjustment may be associated with increased ALT/AST levels and gastrointestinal disorders. Therefore, this combination should be avoided unless clearly necessary. If concomitant use cannot be avoided, increased lopinavir/ritonavir doses of 400 mg/400 mg twice daily may be prescribed with rifampicin under careful safety and plasma concentration monitoring. Lopinavir/ritonavir dose should be increased gradually only after starting rifampicin.

Antipsychotic agents.

Lurasidone. Increased lurasidone concentrations are expected due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use with lurasidone is contraindicated.

Pimozide. Lopinavir/ritonavir inhibits CYP3A, thus increased pimozide blood concentration is expected. Concomitant use of these drugs may increase the risk of serious hematological disorders and other serious adverse reactions.

Quetiapine. Due to CYP3A inhibition by lopinavir/ritonavir, increased quetiapine concentrations are expected. Concomitant use of lopinavir/ritonavir and quetiapine is contraindicated as it may increase quetiapine-related toxicity.

Benzodiazepines.

Midazolam. Lopinavir/ritonavir should not be prescribed in combination with oral midazolam or should be used with caution with parenteral midazolam due to a 13-fold increase in midazolam AUC with oral administration and a 4-fold increase with parenteral administration. If lopinavir/ritonavir is prescribed with parenteral midazolam, this combination should be administered in an intensive care unit or similar setting allowing close clinical monitoring and treatment in case of respiratory depression and/or prolonged sedative effect. Dose adjustment of midazolam should be considered, especially if more than one midazolam dose is administered.

Beta2-adrenergic agonists (long-acting).

Salmeterol. Concomitant use with lopinavir/ritonavir is contraindicated (see section "Contraindications").

Calcium channel blockers.

Felodipine, nifedipine, nicardipine. Lopinavir/ritonavir may increase their plasma concentrations due to CYP3A inhibition. Clinical monitoring of therapeutic effect and adverse events is recommended when these drugs are co-administered with lopinavir/ritonavir.

Corticosteroids.

Dexamethasone. Lopinavir concentration may decrease due to CYP3A induction by dexamethasone. Clinical monitoring of antiviral effect is recommended when lopinavir/ritonavir is co-administered with dexamethasone.

Fluticasone propionate (inhaled, intranasal, or injectable), budesonide, triamcinolone. When fluticasone propionate intranasal 50 mcg four times daily is co-administered with lopinavir/ritonavir, increased fluticasone propionate plasma concentration and 86% reduction in cortisol levels are observed. Greater effects are expected with inhaled fluticasone propionate. Adverse events related to systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate. This may also apply to other corticosteroids metabolized via CYP3A4, such as budesonide and triamcinolone. Therefore, concomitant use of lopinavir/ritonavir and glucocorticoids is not recommended unless potential benefit outweighs the risks of systemic corticosteroid effects. Consider dose reduction of glucocorticoids with close monitoring of local and systemic effects or switching to glucocorticoids not substrates of CYP3A4 (e.g., beclomethasone). Additionally, tapering glucocorticoids may require a longer than usual gradual dose reduction.

Phosphodiesterase inhibitors.

Avanafil. Concomitant use of ritonavir 600 mg twice daily with avanafil increases avanafil plasma concentration (AUC) 13-fold due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of avanafil with lopinavir/ritonavir is contraindicated.

Tadalafil. Concomitant use of lopinavir/ritonavir with tadalafil for treatment of pulmonary arterial hypertension is contraindicated, as tadalafil blood concentration increases 2-fold due to CYP3A inhibition by lopinavir/ritonavir.

Sildenafil. Concomitant use of lopinavir/ritonavir with sildenafil for treatment of pulmonary arterial hypertension is contraindicated, as tadalafil blood concentration increases 11-fold due to CYP3A inhibition by lopinavir/ritonavir.

Sildenafil and tadalafil for erectile dysfunction should be used cautiously in patients taking lopinavir/ritonavir, with close monitoring for adverse events, including arterial hypotension, syncope, vision changes, and prolonged erection. When co-administered with lopinavir/ritonavir, sildenafil doses should not exceed 25 mg every 48 hours, and tadalafil doses should not exceed 10 mg every 72 hours.

Vardenafil. Concomitant use of lopinavir/ritonavir with vardenafil is contraindicated, as vardenafil blood concentration increases 49-fold due to CYP3A inhibition by lopinavir/ritonavir.

Gonadotropin-releasing hormone receptor antagonists.

Elagolix. Concomitant use of elagolix with lopinavir/ritonavir may increase elagolix exposure due to inhibition of OATP, CYP3A, and P-gp. Serious adverse reactions with elagolix use, such as suicidal ideation and increased liver transaminases, are known. Additionally, elagolix is a weak/moderate CYP3A inducer, which may reduce lopinavir/ritonavir exposure. Refer to the elagolix product information leaflet for dosing when used with strong CYP3A4 inhibitors.

Kinase inhibitors (also see Antineoplastic agents above).

Fostamatinib. Concomitant use of fostamatinib with lopinavir/ritonavir may increase exposure to the fostamatinib metabolite R406, leading to dose-dependent adverse reactions such as hepatotoxicity and neutropenia.

Ergot alkaloids.

Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Plasma concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of these drugs is contraindicated as it may lead to acute ergot toxicity, including vasospasm and ischemia.

Agents affecting gastrointestinal motility (GI).

Cisapride. Cisapride plasma concentration may increase due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of these drugs is contraindicated as it may increase the risk of serious arrhythmia.

Direct-acting antiviral agents against hepatitis C virus.

Elbasvir/grazoprevir. Plasma concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir. Concomitant use of these drugs is contraindicated.

Glecaprevir/pibrentasvir. Serum concentration may increase due to inhibition of P-gp, BCRP, and OATP1B by lopinavir/ritonavir. Concomitant use of glecaprevir/pibrentasvir and lopinavir/ritonavir is not recommended due to the risk of increased ALT associated with elevated glecaprevir plasma concentration.

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir. For paritaprevir, AUC increases 2.17-fold, Cmax 2.04-fold, Cmin 2.36-fold. Paritaprevir exposure may increase when co-administered with lopinavir/ritonavir. Concomitant use is not recommended.

Sofosbuvir/velpatasvir/voxilaprevir. Serum concentrations of sofosbuvir, velpatasvir, and voxilaprevir may increase due to inhibition of P-gp, BCRP, and OATP1B1/3 by lopinavir/ritonavir. However, only increased voxilaprevir exposure is considered clinically significant. Concomitant use of lopinavir/ritonavir and sofosbuvir/velpatasvir/voxilaprevir is not recommended.

Hepatitis C virus protease inhibitor.

Boceprevir. Concomitant use of boceprevir (800 mg three times daily) and lopinavir/ritonavir resulted in a 45% decrease in boceprevir AUC and a 34% decrease in lopinavir AUC. Concomitant use of lopinavir/ritonavir and boceprevir is not recommended.

Telaprevir. Concomitant use of telaprevir 750 mg three times daily and lopinavir/ritonavir leads to a 54% decrease in telaprevir AUC, with maximum and minimum plasma concentrations decreasing by 53% and 52%, respectively, while lopinavir concentrations remain unchanged. Concomitant use of lopinavir/ritonavir and telaprevir is not recommended.

Simprevir. Concomitant use of lopinavir/ritonavir and simprevir may increase simprevir plasma concentration (AUC) 7.2-fold. Concomitant use of lopinavir/ritonavir and simprevir is not recommended.

Herbal products.

St. John's wort (Hypericum perforatum). Patients receiving lopinavir/ritonavir therapy should not use herbal products containing St. John's wort (Hypericum perforatum) due to the risk of reduced plasma concentrations of protease inhibitors due to CYP3A induction by St. John's wort, potentially leading to reduced clinical efficacy and development of resistance to lopinavir or the protease inhibitor class. If a patient is already taking St. John's wort, it should be discontinued, and viral load levels should be checked if possible. After discontinuation of St. John's wort, lopinavir and ritonavir levels may increase. Dose adjustment of lopinavir/ritonavir may be needed. The inductive effect may persist for at least 2 weeks after discontinuation of St. John's wort. Therefore, lopinavir/ritonavir can be safely initiated 2 weeks after discontinuation of St. John's wort.

Immunosuppressants.

Cyclosporine, sirolimus (rapamycin), and tacrolimus. Concomitant use with lopinavir/ritonavir may increase their blood concentrations due to CYP3A induction by lopinavir/ritonavir. More frequent therapeutic concentration monitoring of these drugs is recommended until plasma levels stabilize.

Lipid-lowering agents.

Lovastatin and simvastatin. Combination of these substances with lopinavir/ritonavir is contraindicated, as their plasma concentrations significantly increase due to CYP3A induction by lopinavir/ritonavir, potentially causing myopathy, including rhabdomyolysis.

Lomitapide. Strong CYP3A4 inhibitors increase lomitapide exposure approximately 27-fold. CYP3A4 inhibition by lopinavir/ritonavir is expected to increase lomitapide concentration. Concomitant use of lopinavir/ritonavir with lomitapide is contraindicated.

Atorvastatin is less dependent on CYP3A metabolism. When co-administered with atorvastatin, Cmax and AUC of atorvastatin increased on average 4.7 and 5.9 times, respectively. Combination of lopinavir/ritonavir with atorvastatin is not recommended. If atorvastatin use is absolutely necessary, the lowest possible atorvastatin dose should be used with careful safety monitoring.

Rosuvastatin. When co-administered with rosuvastatin 20 mg once daily, Cmax and AUC of rosuvastatin increased on average 5 and 2 times, respectively. Although rosuvastatin is weakly metabolized by CYP3A4, increased plasma concentrations were observed. The mechanism of this interaction may involve transporter protein inhibition. Caution is required when co-administering lopinavir/ritonavir and rosuvastatin, and consideration should be given to using reduced doses.

Fluvastatin or pravastatin. Clinically significant interaction is not expected. Pravastatin is not metabolized by CYP450 isoenzymes. Fluvastatin is partially metabolized by CYP2C9. When treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Opioids.

Buprenorphine. 16 mg once daily. Dose adjustment is not required.

Methadone. Lopinavir/ritonavir reduces methadone plasma concentration. Monitoring of methadone plasma concentration is recommended.

Oral contraceptives.

Ethinylestradiol. Additional contraceptive measures may be required when lopinavir/ritonavir is co-administered with contraceptives containing ethinylestradiol (regardless of contraceptive form, e.g., oral contraceptive or patch), as ethinylestradiol concentration may decrease.

Smoking cessation aids.

Bupropion. In healthy volunteers, AUC and Cmax of bupropion and its active metabolite hydroxybupropion decreased by approximately 50% when co-administered with lopinavir/ritonavir. This effect may be due to induction of bupropion metabolism. Therefore, if concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be under close clinical monitoring of bupropion efficacy without exceeding the recommended dose, despite the observed induction.

Thyroid hormone replacement therapy.

Levothyroxine. Interaction between ritonavir-containing drugs and levothyroxine has been reported. Patients receiving levothyroxine should have thyroid-stimulating hormone (TSH) levels monitored for at least one month after starting and/or stopping lopinavir/ritonavir therapy.

Vasodilators.

Bosentan. When bosentan and lopinavir/ritonavir are co-administered, Cmax and AUC of bosentan increase 6 and 5 times, respectively, and Cmin increases 48 times at the start of concomitant use due to CYP3A4 induction by lopinavir/ritonavir. Plasma concentrations of lopinavir/ritonavir may decrease due to CYP3A4 induction by bosentan. Caution is advised when prescribing lopinavir/ritonavir with bosentan. When these drugs are co-administered, HIV therapy efficacy should be monitored, and patients should be closely observed for bosentan toxicity, especially during the first week of concomitant use.

Riociguat. Serum concentrations may increase due to CYP3A and P-glycoprotein inhibition by lopinavir/ritonavir. Concomitant use of these drugs is not recommended.

Antiparasitic agents.

Atovaquone. When lopinavir/ritonavir and atovaquone are co-administered, therapeutic atovaquone concentration may decrease, so atovaquone dose increase may be necessary.

Other medicinal products.

Based on known metabolic profiles, clinically significant interactions between lopinavir/ritonavir and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole (in patients with normal renal and hepatic function) are not expected.

Special precautions for use.

Patients with concomitant diseases.

Hepatic impairment.

The safety and efficacy of lopinavir/ritonavir in patients with significant hepatic impairment have not been established. Lopinavir/ritonavir is contraindicated in patients with severe hepatic impairment.

In patients with chronic hepatitis B or C who are treated with a combination of antiretroviral agents, there is an increased risk of developing severe and potentially life-threatening hepatic adverse reactions. In cases of concomitant antiviral therapy for hepatitis B or C, refer to the Instructions for Medical Use of the respective medicinal products.

In patients with pre-existing hepatic dysfunction, including chronic hepatitis, increased frequency of hepatic events may occur during combination antiretroviral therapy; such patients should be closely monitored according to standard practice. If symptoms of worsening liver disease occur in these patients, interruption or discontinuation of treatment should be considered.

Elevated transaminase activity, with or without concomitant increases in bilirubin levels, has been reported in HIV-1 mono-infected patients or in patients receiving post-exposure prophylaxis as early as 7 days after initiation of lopinavir/ritonavir in combination with other antiretroviral agents. In some cases, hepatic dysfunction was severe.

Appropriate laboratory tests should be performed prior to starting lopinavir/ritonavir, and careful monitoring of patients during treatment is required.

Renal impairment.

Since renal clearance of lopinavir and ritonavir is minimal, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein-bound, it is unlikely that they will be removed by hemodialysis or peritoneal dialysis.

Haemophilia.

There have been reports of increased bleeding, including spontaneous skin bruising and hemarthrosis, in patients with haemophilia type A and B who were treated with protease inhibitors. Some patients required additional factor VIII. In more than half of the reported cases, treatment with protease inhibitors was continued or restarted after interruption. A causal relationship was presumed, although the mechanism of action was not explained. Therefore, patients with haemophilia should be aware of the possibility of increased bleeding.

Pancreatitis.

Cases of pancreatitis have been reported in patients receiving the medicinal product Aluvia®, including patients who developed hypertriglyceridemia. In most cases, patients had a prior history of pancreatitis and/or were taking other medicinal products that could contribute to the development of pancreatitis. Marked elevation of triglyceride levels is a risk factor for pancreatitis. In patients with progressive HIV infection, the risk of increased triglyceride concentrations and development of pancreatitis may be increased.

The possibility of pancreatitis should be considered in the presence of clinical symptoms (nausea, vomiting, abdominal pain) or changes in laboratory parameters (elevated serum lipase or amylase). Patients who exhibit these signs or symptoms should be evaluated, and if pancreatitis is diagnosed, lopinavir/ritonavir therapy must be discontinued.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immune deficiency, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur upon initiation of combination antiretroviral therapy (cART), leading to severe clinical conditions or worsening of symptoms. Such reactions are usually observed within the first few weeks or months after starting cART. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. All inflammatory symptoms should be evaluated, and appropriate treatment should be initiated if necessary.

Autoimmune disorders (e.g., Graves' disease) have also been reported in the context of immune reconstitution, although the time of onset varied and they could manifest many months after initiation of treatment.

Osteonecrosis.

Although the etiology is multifactorial (including corticosteroid use, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported more frequently in patients with advanced HIV disease and/or long-term combination antiretroviral therapy (cART). Patients should be advised to seek medical attention if they experience joint pain, stiffness, or difficulty in movement.

PR interval prolongation.

Lopinavir/ritonavir has caused mild asymptomatic PR interval prolongation in some patients. Rare cases of second- or third-degree atrioventricular block have been reported in patients with underlying structural heart disease and pre-existing conduction disorders, or in patients receiving medicinal products known to prolong the PR interval (e.g., verapamil or atazanavir) while on lopinavir/ritonavir. Lopinavir/ritonavir should be used with caution in such patients.

Weight and metabolic parameters.

Increases in body weight and blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to disease control and lifestyle. Regarding lipids, evidence suggests that in some cases this is a result of treatment, while no convincing evidence links weight gain to a specific treatment regimen. Monitoring of lipid and glucose levels should be performed according to established HIV treatment guidelines. Lipid abnormalities should be managed according to clinical practice.

Diabetes mellitus/Hyperglycemia.

New-onset diabetes mellitus, hyperglycemia, or exacerbation of pre-existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some cases, hyperglycemia was severe and occasionally associated with ketoacidosis. Many patients had concomitant diseases, some of which required treatment with agents that could lead to the development of diabetes or hyperglycemia. Blood glucose levels should be monitored.

Redistribution of body fat and metabolic disturbances.

Combination antiretroviral therapy in HIV-infected patients has been associated with redistribution of body fat (lipodystrophy), including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy, and dorsocervical fat accumulation (buffalo hump). The mechanism of this effect is not fully understood. A higher risk of lipodystrophy has been associated with individual factors such as older age, and drug-related factors such as longer duration of antiretroviral therapy and associated metabolic disturbances. Clinical evaluation should include assessment of physical signs of fat redistribution and measurement of plasma lipid and glucose concentrations during treatment.

Resistance/Cross-resistance.

Various degrees of cross-resistance have been observed among protease inhibitors. The efficacy of lopinavir/ritonavir in patients previously treated with protease inhibitors as part of antiretroviral therapy is under investigation.

Increased lipid levels.

Treatment with lopinavir/ritonavir has led to increases, sometimes substantial, in plasma concentrations of total cholesterol and triglycerides. These levels should be measured before starting and at regular intervals during lopinavir/ritonavir therapy. Particular attention should be paid to patients with high baseline values and a history of lipid metabolism disorders.

Use in elderly patients.

Clinical trials of lopinavir/ritonavir have not included sufficient numbers of patients aged 65 years and older to determine differences from younger patients. In general, caution should be exercised when administering lopinavir/ritonavir to elderly patients, who more frequently have decreased hepatic, renal, or cardiac function, concomitant diseases, or other drug interactions.

Use in pediatric practice.

Lopinavir/ritonavir oral solution is used for such children. In HIV-infected patients aged 14 days to 12 years, the adverse reaction profile during clinical trials was similar to that in adult patients. Evaluation of the antiviral activity of lopinavir/ritonavir in children is ongoing in clinical trials. Lopinavir/ritonavir should not be administered once daily to children.

Other.

Particular caution should be exercised when prescribing lopinavir/ritonavir concomitantly with medicinal products that prolong the QT interval, such as chlorpheniramine, quinidine, erythromycin, clarithromycin. The use of lopinavir/ritonavir may increase the concentration of co-administered agents and cause corresponding cardiac adverse reactions.

The medicinal product Aluvia® is not a medicinal product for definitive cure of HIV infection or AIDS. In individuals receiving lopinavir/ritonavir, development of infections or other conditions associated with HIV and AIDS is still possible.

Sodium.

The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Generally, when deciding on the prescription of antiretroviral agents for the treatment of HIV infection in pregnant women and thus for reducing the risk of vertical transmission of HIV to the newborn, data from animal studies and clinical experience in pregnant women should be considered to characterize fetal safety.

Lopinavir/ritonavir has been evaluated in more than 3000 pregnant women, including over 1000 women in the first trimester of pregnancy.

In the post-marketing "Antiretroviral Pregnancy Registry", established in 1989, there were no reports of congenital defects in children born to over 1000 women who took lopinavir/ritonavir during the first trimester of pregnancy. The prevalence of congenital defects after lopinavir exposure in any trimester is comparable to that in the general population. No specific pattern of congenital defects with a common etiology has been identified. Animal studies demonstrated reproductive toxicity. Based on these data, the risk of developmental defects in humans is considered unlikely. If clinically indicated, lopinavir may be used during pregnancy.

Breastfeeding.

Animal studies in rats have shown that lopinavir is excreted in breast milk. It is not known whether this medicinal product is excreted in human milk. The general recommendation is that HIV-infected women should not breastfeed their infants to avoid transmission of HIV.

Fertility.

Animal studies did not demonstrate any effect on fertility. Data on the effect of lopinavir/ritonavir on human fertility are lacking.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Patients should be warned that nausea, drowsiness, and dizziness have been reported during treatment with lopinavir/ritonavir.

Method of administration and dosing.

Lopinavir/ritonavir should be prescribed by physicians experienced in the management of HIV infection.

Tablets should be swallowed whole and must not be chewed, broken, or crushed.

Adults.

• 400/100 mg (2 tablets of 200/50 mg) twice daily, regardless of food intake or
• 800/200 mg (4 tablets of 200/50 mg) once daily, regardless of food intake, in patients with fewer than three lopinavir-associated mutations. There are insufficient data to recommend once-daily administration in adult patients with three or more lopinavir-associated mutations.

Lopinavir/ritonavir once daily should not be used in combination with phenobarbital, phenytoin, or carbamazepine.

Concomitant therapy:

Omeprazole and ranitidine. Aluvia® may be used in combination with agents that reduce gastric acidity (omeprazole and ranitidine) without dose adjustment.

Efavirenz, nevirapine, amprenavir, or nelfinavir. Consider increasing the lopinavir/ritonavir dose to 500/125 mg twice daily (2 tablets of 200/50 mg and 1 tablet of 100/25 mg) when used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir in treatment-experienced patients in whom reduced susceptibility to lopinavir can be anticipated (based on prior treatment history or laboratory data). Lopinavir/ritonavir once daily should not be used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir.

Children aged 2 years and older

Lopinavir/ritonavir once daily should not be used in children.

For children with body weight ≥40 kg or body surface area (BSA)* ≥1.4 m², the adult dose of 400/100 mg twice daily should be administered. Recommended doses for children with body weight <40 kg or BSA between 0.5 and 1.4 m² who are able to swallow tablets whole are provided in Table 1 and Table 2 below. For children unable to swallow tablets, lopinavir/ritonavir (Kaletra) oral solution should be used.

Table 1

Dosing of Aluvia® according to body weight and BSA

(without concomitant use of efavirenz, nevirapine, nelfinavir, or amprenavir)

* Body surface area (BSA) can be calculated using the following formula:

Children under 2 years of age: The safety and efficacy of Aluvia® in children under 2 years of age have not been established. There are limited data on the pharmacokinetics of lopinavir/ritonavir in this population, and therefore no dosage recommendations can be made.

Concomitant use with efavirenz, nevirapine, nelfinavir, or amprenavir:

Table 2

Dosing of Aluvia® depending on ART

(when used concomitantly with efavirenz, nevirapine, nelfinavir, or amprenavir)

Patients with hepatic impairment: In HIV-infected patients with mild to moderate hepatic impairment, plasma concentrations of lopinavir increase by approximately 30%, which is not clinically significant. Data in patients with severe hepatic impairment are lacking – lopinavir/ritonavir should not be used in such patients.

Patients with renal impairment: Since renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations in patients with renal impairment are not expected. Because lopinavir and ritonavir are highly bound to plasma proteins, removal by hemodialysis or peritoneal dialysis is unlikely.

Pregnancy and postpartum period: Dose adjustment is not required. Once-daily administration of lopinavir/ritonavir is not recommended in pregnant women due to lack of pharmacokinetic and clinical data.

Children.

This formulation is not recommended for use in children under 2 years of age.

Overdose.

To date, clinical experience with acute overdose of the medicinal product Aluvia® in humans has been limited. There is no specific antidote for Aluvia® in case of overdose. Management of overdose with Aluvia® should include general supportive treatment with monitoring of vital functions and the patient's clinical status. If indicated, gastric lavage should be performed to remove unabsorbed active substance. Administration of activated charcoal may also be used as an adjunctive measure to eliminate unabsorbed active substance. Since Aluvia® is highly protein-bound, dialysis is unlikely to result in significant removal of the active substance from the body.

Adverse Reactions

The safety of lopinavir/ritonavir has been evaluated in more than 2,600 patients in Phase II–IV clinical trials, of whom more than 700 patients received the 800/200 mg dose (4 tablets) once daily. In combination with nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir was used in some studies together with efavirenz or nevirapine. The following adverse reactions were commonly reported during clinical trials with lopinavir/ritonavir therapy: diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. The risk of diarrhea may be higher when lopinavir/ritonavir is administered once daily. Diarrhea, nausea, and vomiting may occur early in treatment, while hypertriglyceridemia and hypercholesterolemia may develop later. Adverse events led to premature discontinuation from the studies in Phase II–IV in 7% of cases.

It is important to note that pancreatitis, including cases in patients who developed hypertriglyceridemia, has been reported in patients receiving lopinavir/ritonavir. In addition, isolated reports of PR interval prolongation during lopinavir/ritonavir therapy have been received.

Adverse reactions observed in clinical trials and post-marketing experience in adult and pediatric patients.

Reported adverse reactions were of mild to severe intensity, regardless of the assessment of causal relationship in individual cases. The adverse reactions listed below are categorized by organ system and frequency of occurrence: very common (≥10%), common (1–10%), uncommon (0.1–1%), rare (0.01–0.1%).

Infections and infestations: very common – upper respiratory tract infection; common – lower respiratory tract infection, skin infections including cellulitis, folliculitis, and furunculosis.

Blood and lymphatic system disorders: common – anemia, leukopenia, neutropenia, lymphadenopathy; rare – splenomegaly.

Immune system disorders: common – hypersensitivity, including urticaria and angioedema; uncommon – immune reconstitution syndrome.

Endocrine disorders: uncommon – male hypogonadism.

M metabolism and nutrition disorders: common – disturbances in blood glucose levels, including diabetes, hypertriglyceridemia, hypocholesterolemia, weight decrease, decreased appetite; uncommon – weight increase, increased appetite, lactic acidosis.

Psychiatric disorders: common – anxiety; uncommon – decreased libido, unusual dreams.

Nervous system disorders: common – headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia; uncommon – seizures, loss or alteration of taste sensation, tremor, cerebral infarction.

Eye disorders: uncommon – visual disturbances.

Ear and labyrinth disorders: uncommon – tinnitus, hyperacusis, dizziness.

Cardiac disorders: uncommon – myocardial infarction due to atherosclerosis, atrioventricular block, tricuspid valve insufficiency, palpitations, atrial flutter, orthostatic hypotension, vasodilation, angina pectoris.

Vascular disorders: common – arterial hypertension; uncommon – deep vein thrombosis.

Gastrointestinal disorders: very common – diarrhea, nausea; common – pancreatitis, gastroesophageal reflux, gastroenteritis and colitis, vomiting, abdominal pain (upper and lower), bloating, dyspepsia, hemorrhoids, flatulence, gastrointestinal discomfort; uncommon – gastrointestinal hemorrhage, including gastric and intestinal ulceration, duodenitis, gastritis, rectal bleeding, stomatitis and oral mucosal ulcers, fecal incontinence, constipation, dry mouth.

Hepatobiliary disorders: common – hepatitis, including elevations in AST, ALT, and GGT; uncommon – hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia; frequency not known – jaundice.

Skin and subcutaneous tissue disorders: common – rash, including maculopapular rash, rash/dermatitis including eczema and seborrheic dermatitis, night sweats, pruritus; uncommon – alopecia, capillaritis, vasculitis; frequency not known – Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders: common – myalgia, musculoskeletal pain including arthralgia and back pain, muscle disorders such as weakness and spasms; uncommon – rhabdomyolysis, osteonecrosis.

Renal and urinary disorders: uncommon – decreased creatinine clearance, nephritis, hematuria, renal failure; frequency not known – nephrolithiasis.

Reproductive system and breast disorders: common – erectile dysfunction, menstrual disorders – amenorrhea, menorrhagia.

General disorders and administration site conditions: common – fatigue, including asthenia.

Description of selected adverse reactions.

Cases of Cushing's syndrome have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate. This is also characteristic for other corticosteroids metabolized via the P450 3A pathway, such as budesonide.

Elevations in creatine phosphokinase (CPK), myalgia, myositis, and rarely rhabdomyolysis have been reported during protease inhibitor therapy, particularly when used in combination with nucleoside reverse transcriptase inhibitors (NRTIs).

Metabolic parameters.

During antiretroviral therapy, increases in body weight as well as in levels of lipids and blood glucose may occur.

In HIV-infected patients with severe immune deficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur at the initiation of combination antiretroviral therapy (cART). Autoimmune disorders (e.g., Graves' disease) have also been reported; however, the time to onset has been variable, and these conditions may manifest many months after initiation of treatment.

Cases of osteonecrosis have also been reported, particularly in patients with well-recognized risk factors, at advanced stages of HIV disease, or with long-term use of combination antiretroviral therapy (cART). The frequency of such events is unknown.

Pediatric population.

The adverse reaction profile and tolerability of the drug in children were similar to those in adults.

Shelf life.

3 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 30°C.

Packaging.

Aluvia® 200 mg/50 mg. 120 tablets in bottles closed with caps. One bottle per cardboard box.

Aluvia® 100 mg/25 mg. 60 tablets in bottles closed with caps. One bottle per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

AbbVie Deutschland GmbH & Co. KG

Manufacturer's location and address of business operations.

Knollstrasse, 67061 Ludwigshafen, Germany