Ritovir-l

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RITOVIR-L (RITOVIR-L)

Composition:

Active substances: lopinavir, ritonavir;

One tablet contains 200 mg of lopinavir and 50 mg of ritonavir;

Excipients: copovidone, sorbitan laurate, colloidal silicon dioxide anhydrous, sodium stearyl fumarate, Opadry II Yellow 16C82767 (hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol, hydroxypropylcellulose (E 463), iron oxide yellow (E 172), talc (E 553b), colloidal silicon dioxide anhydrous (E 551), polysorbate 80 (E 433)).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: yellow, oval-shaped film-coated tablets, with the inscription "H" on one side and "70" on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Antiviral agents for the treatment of HIV infection, combinations. ATC code J05AR10.

Pharmacological Properties

Pharmacodynamics

Lopinavir is a protease inhibitor of HIV-1 and HIV-2 that prevents the 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 renders this enzyme unable to process 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 isolated from 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 suggests that reduced susceptibility to lopinavir closely correlates with reduced susceptibility to ritonavir and indinavir, but such a strong correlation is absent with reduced susceptibility to amprenavir, saquinavir, and nelfinavir.

Cross-resistance

The activity of other protease inhibitors was evaluated against isolates exhibiting increased resistance to lopinavir after lopinavir/ritonavir therapy in patients previously treated with protease inhibitors. The presence of cross-resistance to other protease inhibitors was analyzed in 18 isolates obtained after a sharp increase in viral load in patients previously treated with protease inhibitors, who demonstrated increased resistance to lopinavir within the framework of three phase II and one phase III lopinavir/ritonavir studies. On average, the EC50 of lopinavir for these 18 isolates, isolated at baseline and after a sharp increase in viral load, was 6.9–63 times higher than the EC50 against wild-type HIV, respectively. Overall, isolates obtained after a sharp increase in viral load exhibited the same cross-resistance (if such cross-resistance existed at baseline) or developed new significant cross-resistance to indinavir, saquinavir, and atazanavir. A moderate reduction in amprenavir activity was observed, with a mean increase in EC50 of isolates isolated at baseline and after a sharp increase in viral load by 3.7–8 times, respectively. Isolates retained sensitivity to tipranavir, with a mean increase in EC50 of isolates isolated at baseline and after a sharp 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 the influence 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) in 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. Prolongation of the QRS interval induced by high doses of lopinavir/ritonavir (800/200 mg twice daily), ranging from 6 msec to 9.5 msec, contributes to QT prolongation. Both regimens resulted in exposures on Day 3 approximately 1.5 and 3 times higher than those observed with the steady recommended dose of lopinavir/ritonavir (once or twice daily). No increases in QTcF > 60 msec from baseline or increases in QTcF interval exceeding the potentially clinically significant threshold of 500 msec were observed.

Mild PR interval prolongation 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 have been studied in healthy adult volunteers and in HIV-infected individuals, with no significant differences observed between parameters in these two groups. Lopinavir is almost completely metabolized by CYP3A. Ritonavir inhibits the metabolic degradation of lopinavir, thereby increasing lopinavir plasma concentrations. Comparing results across different studies, when lopinavir/ritonavir is administered at a dose of 400/100 mg twice daily to HIV-infected patients, the mean plasma concentration of lopinavir at steady state is 15–20 times higher than that of ritonavir. The plasma concentration of ritonavir is less than 7% of the concentration 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 the drug is attributable to 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 trough concentration at steady state prior to the morning dose was 8.1 ± 5.7 µg/mL. The AUC for lopinavir over 12 hours after administration averaged 113.2 ± 60.5 µg•h/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 was compared after a high-fat meal (872 kcal, 56% from fat) and under fasting conditions. No significant changes in Cmax and AUCinf values were observed. Therefore, lopinavir/ritonavir in tablet form can be administered independently of food intake.

Distribution

At steady state, approximately 98–99% of lopinavir is bound to plasma proteins. Lopinavir is capable of binding 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, the protein binding of lopinavir at steady state remains constant over a wide concentration range and does not differ between healthy volunteers and HIV-infected patients.

Biological transformation

In vitro experiments using human liver microsomes showed that lopinavir is primarily metabolized via oxidation. Lopinavir is extensively metabolized in the liver by the cytochrome P450 system, particularly the CYP3A isoenzyme. Ritonavir is a potent inhibitor of CYP3A activity and thereby inhibits the degradation of lopinavir, increasing its plasma concentration. Experiments with radiolabeled 14C-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 metabolic degradation and likely accelerating lopinavir metabolism. With repeated dosing, the pre-dose concentration of lopinavir decreases, and concentration stabilization is achieved approximately between 10 days and 2 weeks.

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 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 dosing, less than 3% of the administered dose of lopinavir 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/h.

Once-daily dosing: The pharmacokinetics of once-daily administration of lopinavir/ritonavir were studied in HIV-infected patients previously untreated with antiretroviral agents. Lopinavir/ritonavir 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg using a once-daily dosing regimen. Repeated administration of lopinavir/ritonavir at a dose of 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 the morning dose were 5.5 ± 5.4 µg/mL. The mean AUC over 24 hours was 206.5 ± 89.7 µg•h/mL.

Compared to the twice-daily regimen, the once-daily dosing regimen is associated with approximately a 50% reduction in Cmin/Ctrough 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.
• Ritorvir-L contains lopinavir and ritonavir, which are inhibitors of the CYP3A isoenzyme of cytochrome P450. Ritorvir-L must not be used concomitantly with drugs whose clearance is largely dependent on CYP3A activity, as increased plasma concentrations of these drugs may lead to serious and/or life-threatening reactions. The list of such drugs includes:

Increased levels of concomitant drugs:

Alpha1-adrenoreceptor antagonist

Alfuzosin. Plasma concentration of alfuzosin increases, which may lead to severe arterial hypotension.

Anti-anginal agents

Ranolazine. Plasma concentration of ranolazine increases, which may lead 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 occurrence 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 prescribing information for Venclexta).

Antigout agents

Colchicine. Plasma concentration of colchicine increases, which may lead to the development of serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.

Antihistamines

Astemizole, terfenadine. Plasma concentrations of astemizole and terfenadine increase. As a result, the risk of serious arrhythmias caused by these substances increases.

Antipsychotic/neuroleptic agents

Lurasidone. Plasma concentration of lurasidone increases, which may lead to serious and/or life-threatening reactions.

Pimozide. Plasma concentration of pimozide increases. As a result, the risk of serious hematological disorders or other serious adverse events caused by this substance increases.

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. As a result, the risk of serious arrhythmias caused by this substance increases.

Direct-acting antiviral agents against hepatitis C virus

Elbasvir/grazoprevir. Risk of increased ALT levels increases.

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir. Plasma concentration of paritaprevir increases; thus, the risk of increased ALT levels increases.

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.

Microsomal triglyceride transfer protein inhibitor

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, the risk of excessive sedative effect and respiratory depression caused by these substances increases. See section "Interaction with other medicinal products and other forms of interaction" for warnings regarding parenteral administration of midazolam.

Beta2-adrenergic agonists (long-acting)

Salmetrol. Increased concentrations are expected due to inhibition of CYP3A by lopinavir/ritonavir. This combination may lead to an increased 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 (Hypericum perforatum). 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 forms of interaction

Ritorvir-L 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, which may increase or prolong their therapeutic and adverse effects. Ritorvir-L does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6, or CYP1A2 at concentrations used in clinical practice.

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 due to the expected degree of interaction and the possibility of developing serious adverse events are listed in the "Contraindications" section.

Known and theoretical interactions with selected antiretroviral and other medicinal products are listed 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 used concomitantly 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; therefore, it reduces plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.

Tenofovir. Concomitant use 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 the occurrence of tenofovir-related adverse reactions, including renal impairment.

Elevated creatine phosphokinase levels, 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 used concomitantly with efavirenz (600 mg once daily). The dose of lopinavir/ritonavir tablets should be increased to 500/125 mg twice daily when used concomitantly with efavirenz. Lopinavir/ritonavir once daily should not be used in combination with efavirenz.

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

Etravirine. Concomitant use of lopinavir/ritonavir (400/100 mg twice daily) and etravirine may reduce plasma concentration of etravirine by 35%; plasma concentration of lopinavir does not change. Dose adjustment is not required.

Rilpivirine. Concomitant use of lopinavir/ritonavir (400/100 mg twice daily) and rilpivirine may increase plasma concentration of rilpivirine by 52%; plasma concentration of lopinavir does not change. Dose adjustment is not required.

Delavirdine. Delavirdine may increase plasma concentration of lopinavir.

CCR5 antagonist

Maraviroc. Concomitant use of maraviroc and lopinavir/ritonavir increases maraviroc plasma levels by 295%. The dose of maraviroc should be reduced to 150 mg twice daily during concomitant use with lopinavir/ritonavir 400/100 mg twice daily.

Integrase inhibitors

Raltegravir. Clinical studies have shown 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.

Atazanavir. Lopinavir/ritonavir is expected to increase atazanavir concentrations (atazanavir 750 mg twice daily). Concomitant use of lopinavir/ritonavir and atazanavir leads to decreased lopinavir concentrations. The dose of lopinavir/ritonavir may need to be increased during concomitant use with atazanavir, especially in patients with extensive protease inhibitor experience or reduced viral susceptibility to lopinavir. Lopinavir/ritonavir once daily should not be used in combination with atazanavir.

Fosamprenavir. Concomitant use of lopinavir/ritonavir (400/100 mg twice daily) with fosamprenavir/ritonavir (700/100 mg twice daily) results in significant reduction in atazanavir concentrations. Concomitant use of higher doses of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients with protease inhibitor experience led to a higher frequency of gastrointestinal adverse events and increased triglyceride levels with no increase in virological efficacy compared to standard doses of fosamprenavir/ritonavir. Concomitant use of these drugs is not recommended. Lopinavir/ritonavir should not be taken once daily in combination with atazanavir.

Indinavir. When indinavir 600 mg twice daily is taken concomitantly 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 taking indinavir alone at 800 mg three times daily. Appropriate doses for this combination in terms of efficacy and safety have not been established.

Saqunavir. When saquinavir 1000 mg twice daily is used concomitantly with lopinavir/ritonavir, no further increase in saquinavir plasma concentrations is 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 concentrations. The dose of lopinavir/ritonavir may need to be increased during concomitant use with nelfinavir, especially in patients with extensive protease inhibitor experience or reduced viral susceptibility to lopinavir. Lopinavir/ritonavir once daily should not be used in combination with nelfinavir.

Ritonavir. When an additional 100 mg of ritonavir twice daily is taken concomitantly 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 inhibition of CYP3A by lopinavir/ritonavir, increased concentrations of alfuzosin are expected. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated due to possible increased alfuzosin-related toxicity, including arterial hypotension.

Analgesics

Fentanyl. Lopinavir/ritonavir inhibits CYP3A4, resulting in expected increased plasma concentrations of fentanyl. When fentanyl is used concomitantly with lopinavir/ritonavir, careful monitoring of therapeutic and adverse effects, including respiratory depression and sedation, is recommended.

Anti-anginal agents

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

Antiarrhythmic agents

Amiodarone, dronedarone

Concentrations of amiodarone and dronedarone may increase due to inhibition of CYP3A4 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 inhibition of P-glycoprotein by lopinavir/ritonavir. Elevated digoxin levels may sometimes decrease with increased induction of P-glycoprotein. When lopinavir/ritonavir and digoxin are used concomitantly, caution is advised, and monitoring of digoxin blood concentrations should be performed if possible. Caution is advised when prescribing lopinavir/ritonavir to patients taking digoxin, as 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 less than expected increase in digoxin concentrations.

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

Antibiotics

Clarithromycin. Moderate increase in AUC of clarithromycin is expected due to inhibition of CYP3A by lopinavir/ritonavir. In patients with renal impairment (creatinine clearance < 30 mL/min), consider reducing the dose of clarithromycin. Caution is advised when prescribing clarithromycin concomitantly with lopinavir/ritonavir to 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 prescribing information for abemaciclib. Careful monitoring for possible adverse reactions associated with abemaciclib 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, which may cause serious adverse events, including seizures. Concomitant use of lopinavir/ritonavir and apalutamide is contraindicated.

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

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

Most tyrosine kinase inhibitors, such as dasatinib, nilotinib, vinblastine, vincristine When used concomitantly, their serum concentrations increase due to inhibition of CYP3A by lopinavir/ritonavir. Careful 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 may potentially increase the risk of adverse reactions, such as QT 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 dose of ibrutinib should be reduced to 140 mg, and the patient should be closely monitored for signs of toxicity.

Neratinib. Serum concentration of neratinib may increase due to CYP3A inhibition by ritonavir. Concomitant use of neratinib and lopinavir/ritonavir is contraindicated due to the possibility of 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 dose of venetoclax should be reduced by at least 75% when used with strong CYP3A inhibitors. Patients should be closely monitored for signs of venetoclax-related toxicity.

For dosing recommendations for venetoclax, nilotinib, and dasatinib, refer to the prescribing information for these medicinal products.

Anticoagulants

Warfarin. Concomitant use with lopinavir/ritonavir may alter concentrations due to induction of CYP2C9. 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. Use of rivaroxaban is not recommended in patients receiving concomitant therapy with lopinavir/ritonavir.

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

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

Antiepileptic agents

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

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

Carbamazepine and phenobarbital. Serum concentration of carbamazepine may increase due to inhibition of CYP3A by lopinavir/ritonavir.

Lopinavir concentration may decrease due to induction of CYP3A 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 used concomitantly with lopinavir/ritonavir. Increased dose of lopinavir/ritonavir may be anticipated when used concomitantly with carbamazepine or phenobarbital. Dose increase 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 has been associated with a 50% reduction in lamotrigine AUC due to induction of lamotrigine glucuronidation. Close monitoring is required for reduced effect of valproic acid when lopinavir/ritonavir and valproic acid are used concomitantly. For patients starting or discontinuing lopinavir/ritonavir during maintenance lamotrigine dosing: dose increase of lamotrigine may be needed when lopinavir/ritonavir is added, or dose reduction of lamotrigine when lopinavir/ritonavir is discontinued. Thus, monitoring of lamotrigine plasma concentration is recommended, especially before starting concomitant use of 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 need is expected for adjustment of the recommended lamotrigine dose escalation regimen.

Antidepressants and anxiolytics

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

Antifungal agents

Ketoconazole and itraconazole. Lopinavir/ritonavir may increase plasma concentrations of ketoconazole and itraconazole due to inhibition of CYP3A 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 Ritorvir-L should be avoided unless benefit-risk assessment favors voriconazole use.

Agents for gout treatment

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

Antihistamine medicinal products

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

Antibacterial agents

Fusidic acid. Fusidic acid concentration may increase due to inhibition of CYP3A 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 treatment of bone and joint infections, where concomitant use of these drugs 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 used concomitantly for 24 days, bedaquiline plasma concentration (AUC) increases by 22% due to inhibition of CYP3A4 by lopinavir/ritonavir. Bedaquiline should be used cautiously concomitantly with ritonavir and only if benefit outweighs risk. More frequent ECG and transaminase level monitoring is recommended.

Delamanid. When delamanid (100 mg twice daily) is used concomitantly 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 used concomitantly with lopinavir/ritonavir for 10 days, Cmax and AUC of rifabutin increase 3.5 and 5.7 times, respectively. When used concomitantly with lopinavir/ritonavir, the recommended dose of rifabutin 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 expected increased AUC of rifabutin. For patients who do not tolerate the dose of 150 mg three times weekly, further reduction of rifabutin dose to 150 mg twice weekly is recommended. It should be noted that the dose of 150 mg twice weekly may not provide optimal AUC of rifabutin, thus leading to the risk of rifabutin resistance and, consequently, ineffective treatment. Dose adjustment of lopinavir/ritonavir is not required.

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

Antipsychotic agents

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

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

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

Benzodiazepines

Midazolam. Lopinavir/ritonavir should not be prescribed in combination with oral midazolam or should be prescribed 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. When lopinavir/ritonavir is prescribed in combination with parenteral midazolam, such combination should be administered in an intensive care unit or similar facility providing the possibility of careful clinical monitoring and treatment in case of respiratory depression and/or prolonged sedative effect. Dose adjustment of midazolam should be considered, especially when more than one dose of midazolam is prescribed.

Beta2-adrenergic agonists (long-acting)

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

Calcium channel blockers

Felodipine, nifedipine, nicardipine. Lopinavir/ritonavir may increase their plasma concentrations due to inhibition of CYP3A. When these drugs are used concomitantly with lopinavir/ritonavir, clinical monitoring of therapeutic effect and adverse events is recommended.

Corticosteroids

Dexamethasone. Lopinavir concentration may decrease due to induction of CYP3A by dexamethasone. When lopinavir/ritonavir is used concomitantly with dexamethasone, clinical monitoring of antiviral effect is recommended.

Fluticasone propionate (inhaled, intranasal, or injectable), budesonide, triamcinolone. When fluticasone propionate 50 mcg four times daily intranasally is used concomitantly with lopinavir/ritonavir, increased plasma concentration of fluticasone propionate and 86% reduction in cortisol levels were observed. Greater effect is expected with inhaled fluticasone propionate. Adverse events associated with systemic corticosteroid action, including Cushing's syndrome and adrenal suppression, have been reported in patients receiving ritonavir and fluticasone propionate in inhaled or intranasal form. This may also be characteristic of 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 action. Dose reduction of glucocorticoids with careful monitoring of local and systemic effects or switching to glucocorticoids not substrates of CYP3A4 (e.g., beclomethasone) should be considered. Additionally, tapering of glucocorticoids after discontinuation may require a longer duration than usual.

Phosphodiesterase inhibitors

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

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

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

Sildenafil and tadalafil should be used cautiously for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir, with careful monitoring for adverse events, including arterial hypotension, syncope, vision changes, and prolonged erection. When used concomitantly with lopinavir/ritonavir, sildenafil doses should not exceed 25 mg within 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 inhibition of CYP3A 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 are known, such as suicidal ideation and increased liver transaminase levels. Additionally, elagolix is a weak/moderate CYP3A inducer, which may cause reduced exposure of lopinavir/ritonavir. Refer to the prescribing information for elagolix for dosing recommendations 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 metabolite R406 of fostamatinib, leading to dose-dependent adverse reactions, such as hepatotoxicity and neutropenia.

Ergot alkaloids

Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Plasma concentrations may increase due to inhibition of CYP3A 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

Cisapride. Plasma concentration of cisapride may increase due to inhibition of CYP3A 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 inhibition of CYP3A 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 increased plasma concentration of glecaprevir.

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 used concomitantly with lopinavir/ritonavir. Concomitant use is not recommended.

Sofosbuvir/velpatasvir/voxilaprevir. Serum concentration of sofosbuvir, velpatasvir, and voxilaprevir may increase due to inhibition of P-gp, BCRP, and OATP1B1/3 by lopinavir/ritonavir. However, only increased exposure to voxilaprevir 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 led to a 45% reduction in boceprevir AUC and a 34% reduction 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% reduction in telaprevir AUC, maximum and minimum plasma concentrations decrease by 53% and 52%, respectively, while lopinavir concentration parameters do not change. 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 induction of CYP3A by St. John's wort products, which may lead 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 started 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 induction of CYP3A by lopinavir/ritonavir. More frequent determination of therapeutic concentration of these drugs is recommended until plasma levels of these drugs stabilize.

Lipid-lowering agents

Lovastatin and simvastatin. Combination of these substances with lopinavir/ritonavir is contraindicated, as concomitant use significantly increases plasma concentrations of lovastatin and simvastatin due to induction of CYP3A by lopinavir/ritonavir, which may cause 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 metabolized by CYP3A. When used concomitantly 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 there is an absolute need for atorvastatin use, the lowest possible dose of atorvastatin should be taken with careful safety monitoring.

Rosuvastatin. When used concomitantly 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 be explained by inhibition of transport proteins. Caution is required when lopinavir/ritonavir and rosuvastatin are used concomitantly, and use of reduced doses should be considered.

Fluvastatin or pravastatin. Clinically significant interaction is not expected. Pravastatin is not metabolized by CYP450 isoenzyme. 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. When lopinavir/ritonavir is used concomitantly with contraceptives containing ethinylestradiol (regardless of contraceptive form, e.g., oral contraceptive or patch), additional contraceptive measures may be needed, 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 used concomitantly 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 medicinal products 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 used concomitantly, Cmax and AUC of bosentan increase 6 and 5 times, respectively, and Cmin increases 48 times at the beginning of concomitant use due to induction of CYP3A4 by lopinavir/ritonavir. Plasma concentrations of lopinavir/ritonavir may decrease due to induction of CYP3A4 by bosentan. Caution is advised when prescribing lopinavir/ritonavir with bosentan. When these drugs are used concomitantly, monitoring of anti-HIV therapy efficacy is required, and patients should be closely monitored for bosentan toxicity, especially during the first week of concomitant use.

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

Antiparasitic agents

Atovaquone. When lopinavir/ritonavir and atovaquone are used concomitantly, therapeutic concentration of atovaquone may decrease, so dose increase of atovaquone 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 impairment of liver function 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 case 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 function abnormalities 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, consideration should be given to interrupting or discontinuing treatment.

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 initiating 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 in patients with renal impairment are not expected. Because lopinavir and ritonavir are highly protein-bound, it is unlikely that they will be removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in patients with haemophilia 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 reinitiated after interruption. A causal relationship was suspected, 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 lopinavir/ritonavir, including patients who developed hypertriglyceridaemia. 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 should be discontinued.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency, an inflammatory response to asymptomatic or residual opportunistic microorganisms may occur during 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 initiation of combination antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. All inflammatory symptoms should be evaluated, and appropriate treatment initiated if necessary.

Autoimmune disorders (e.g., Graves' disease and autoimmune hepatitis) have also been reported in the context of immune reconstitution; however, the time to onset varied, and these conditions may manifest many months after initiation of treatment.

Osteonecrosis

Although the aetiology is multifactorial (including corticosteroid use, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have occurred 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, joint stiffness, or difficulty in movement.

PR interval prolongation

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

Body weight and metabolic parameters

During antiretroviral therapy, increases in body weight and levels of lipids and glucose in blood may occur. These changes may be partially related to disease control and lifestyle. Regarding lipids, there is evidence that in some cases this is a result of treatment, while no convincing evidence has been obtained linking increased body weight to a specific treatment regimen. Monitoring of lipid and glucose levels should be performed according to established guidelines for HIV infection management. Lipid abnormalities should be managed according to clinical practice.

Diabetes mellitus/hyperglycaemia

New-onset diabetes mellitus, hyperglycaemia, or exacerbation of pre-existing diabetes mellitus have been reported in patients receiving protease inhibitors. In some cases, hyperglycaemia 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 hyperglycaemia. Blood glucose levels should be monitored.

Redistribution of adipose tissue and metabolic disturbances

Combination antiretroviral therapy in HIV-infected patients has been associated with redistribution of adipose tissue (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 with 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.

Elevated lipid levels

Treatment with lopinavir/ritonavir leads to increases, sometimes substantial, in plasma concentrations of total cholesterol and triglycerides, which should be measured before initiation and at regular intervals during therapy with lopinavir/ritonavir. 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 did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently 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 paediatric practice

Lopinavir/ritonavir should be administered to children in the form of oral solution. In HIV-infected patients aged 14 days to 12 years, the adverse reaction profile observed 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 to children once daily.

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. Administration of lopinavir/ritonavir may increase the concentration of concurrently administered agents and cause corresponding cardiac adverse reactions.

Ritovir-L is not a medicinal product for definitive cure of HIV infection or AIDS. Although effective viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, residual transmission risk cannot be excluded. Preventive measures should be taken according to national guidelines to avoid transmission. Individuals taking lopinavir/ritonavir remain at risk of developing HIV- and AIDS-associated infections.

Use during pregnancy or breastfeeding

Pregnancy

When deciding on the use 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 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 exposure to lopinavir in any trimester is comparable to that in the general population. No specific pattern of congenital defects with a common aetiology has been identified. Animal studies demonstrated reproductive toxicity. Based on these data, the risk of developmental defects in humans is considered unlikely. Lopinavir/ritonavir may be used during pregnancy if clinically indicated.

Breastfeeding

Studies in rats have shown that lopinavir is excreted in breast milk. It is unknown whether this medicinal product is excreted in human breast milk. HIV-infected women must not breastfeed under any circumstances 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 vehicles or operating machinery

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

Dosage and Administration

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

Tablets should be swallowed whole and not 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 less than three lopinavir-associated mutations. There are insufficient data to recommend once-daily administration of lopinavir/ritonavir in adult patients with three or more lopinavir-associated mutations.

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

Concomitant therapy

Omeprazole and ranitidine. Ritonavir-L can be used in combination with agents that reduce gastric acidity (omeprazole and ranitidine) without dose adjustment.

Efavirenz, nevirapine, amprenavir, or nelfinavir. Consider increasing the dose of lopinavir/ritonavir 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 should not be administered once daily in children.

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

Table 1

Dosing based on body weight and BSA

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

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

Concomitant use with efavirenz, nevirapine, nelfinavir, or amprenavir

Table 2

Dosing depending on ART

(when co-administered with efavirenz, nevirapine, nelfinavir, or amprenavir)

** Administer the medicinal product containing the active substance lopinavir / ritonavir at the appropriate dosage.

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 these 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. As 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

The safety and efficacy of lopinavir / ritonavir in children under 2 years of age have not been established. There are limited pharmacokinetic data on lopinavir / ritonavir in this population, but dosing recommendations cannot be made; therefore, use of this formulation is not recommended in children under 2 years of age.

Overdose

Clinical experience with acute overdose of lopinavir / ritonavir in humans is limited to date. There is no specific antidote for lopinavir / ritonavir in case of overdose. Management of overdose with the medicinal product Rytovir-L 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 the unabsorbed active substance. Administration of activated charcoal may also be used as an adjunctive measure to eliminate the unabsorbed active substance. Because lopinavir / ritonavir are highly bound to plasma proteins, dialysis is unlikely to result in significant removal of the active substances from the body.

Adverse Reactions

The safety of lopinavir/ritonavir has been evaluated in more than 2600 patients in clinical trials, of whom over 700 patients received the dose of 800/200 mg (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 associated with lopinavir/ritonavir therapy were commonly reported during clinical trials: diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. The risk of developing diarrhea may be higher when lopinavir/ritonavir is administered once daily. Diarrhea, nausea, and vomiting may occur at the beginning of treatment, while hypertriglyceridemia and hypercholesterolemia may develop later. Adverse events that occurred during treatment led to premature discontinuation from the study in 7% of cases.

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

Adverse reactions observed in clinical trials and post-marketing period in adult patients and children

Adverse reactions reported were of moderate to severe intensity, regardless of the assessment of causality in individual cases. The adverse reactions listed below are categorized by system organ class 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 phlegmon, 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.

Metabolism and nutrition disorders: common – blood glucose abnormalities, including diabetes; hypertriglyceridemia, hypocholesterolemia, weight loss, decreased appetite; uncommon – weight gain, 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 change in 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 elevated AST, ALT, and GGT; uncommon – fatty liver degeneration, 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, capillary fragility, 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.

Elevated levels of creatine phosphokinase (CPK), myalgia, myositis, and rarely rhabdomyolysis have been reported with protease inhibitors, particularly when used in combination with nucleoside reverse transcriptase inhibitors (NRTIs).

Metabolic parameters

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

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

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

Children

In children, the adverse reaction profile and tolerability of the drug were similar to those in adult patients.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging

120 tablets in a container, 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Hetero Labs Limited, India.

Manufacturer’s location and address of place of business

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.