Lopinavir/ritonavir macleods

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPINAVIR/RITONAVIR MACLEODS

Composition:

Tablets 200 mg/50 mg:

Active substances: lopinavir, ritonavir;

One tablet contains lopinavir 200 mg and ritonavir 50 mg;

Excipients: copovidone, sorbitan laurate, colloidal anhydrous silicon dioxide, anhydrous dibasic calcium phosphate, sodium stearyl fumarate; Coating Opadry II Yellow 85F520041: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172).

Tablets 100 mg/25 mg:

Active substances: lopinavir, ritonavir;

One tablet contains lopinavir 100 mg and ritonavir 25 mg;

Excipients: copovidone, sorbitan laurate, colloidal anhydrous silicon dioxide, anhydrous dibasic calcium phosphate, sodium stearyl fumarate; Coating Opadry II Yellow 85F42187: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 200 mg/50 mg

Biconvex, film-coated, capsule-shaped yellow tablets with "M 32" engraved on one side and smooth on the other side.

Tablets 100 mg/25 mg

Biconvex, film-coated, capsule-shaped pale yellow tablets with "M 31" engraved on one side and smooth on the other side.

Pharmacotherapeutic group

Antivirals for systemic use. Antivirals for the treatment of HIV infections, combinations. ATC code J05AR10.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Lopinavir provides the antiviral activity of the medicinal product "Lopinavir/Ritonavir Macleods". Lopinavir is an inhibitor of HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein, leading to production of immature, non-infectious virus particles.

Electrocardiogram Changes

The QTcF interval was evaluated in a randomized, placebo-controlled, active-controlled crossover study (moxifloxacin 400 mg once daily) in 39 healthy adult volunteers, with 10 measurements taken at 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 and supratherapeutic 800/200 mg twice daily doses of lopinavir/ritonavir, respectively. Dose-dependent QRS prolongation of up to 6–9.5 ms, induced by high doses of lopinavir/ritonavir (800/200 mg twice daily), contributes to QT prolongation. On Day 3 after administration of these regimens, exposure was approximately 1.5 and 3 times higher than that observed with the standard recommended maintenance dose of lopinavir/ritonavir (once or twice daily).

Mild PR interval prolongation was also observed on Day 3 in subjects receiving lopinavir/ritonavir in this same study. Mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms over the 12-hour interval. The maximum PR interval was 286 ms, and no second- or third-degree heart block was observed.

In vitro Antiviral Activity

The antiviral activity of lopinavir against laboratory strains and clinical isolates of HIV was evaluated in vitro using 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 absence or presence of 50% human serum, the mean EC50 of lopinavir against HIV-1IIIB in MT4 cells ranged from 17 nM to 102 nM, respectively. In the absence of human serum, the mean EC50 of lopinavir against several clinical isolates of HIV-1 was 6.5 nM.

Resistance

Selection of Resistance in vitro

HIV-1 isolates with reduced susceptibility to lopinavir were selected in vitro. HIV-1 was passaged under in vitro conditions with lopinavir alone and in combination with lopinavir and ritonavir at plasma concentrations observed during treatment with "Lopinavir/Ritonavir Macleods". Genotypic and phenotypic analysis of viruses isolated from these cultures suggests that the presence of ritonavir at these concentrations has no significant effect on the selection of lopinavir-resistant viruses. Overall, the in vitro phenotypic cross-resistance profile between lopinavir and other protease inhibitors indicates that reduced susceptibility to lopinavir is closely correlated with reduced susceptibility to ritonavir and indinavir, but not closely correlated with reduced susceptibility to amprenavir, saquinavir, or nelfinavir.

Resistance Analysis in Antiretroviral-Naïve Patients

In clinical trials with a limited number of analyzed isolates, resistance to lopinavir was not observed in antiretroviral-naïve patients without significant baseline resistance to protease inhibitors. See clinical studies section below for additional information.

Resistance Analysis in Patients Previously Treated with Protease Inhibitors (PIs)

Assessment of lopinavir resistance in patients with prior virological failure on protease inhibitor therapy was performed by analyzing longitudinal isolates from 19 patients previously treated with protease inhibitors in two Phase II and one Phase III trials. These patients experienced incomplete virological suppression or rebound in viral load after an initial response to therapy, and developed additional in vitro resistance between baseline and viral load rebound (defined as emergence of new mutations or a ≥2-fold decrease in phenotypic susceptibility to lopinavir). Gradual resistance development was most commonly observed in patients whose baseline isolates contained multiple protease inhibitor-associated mutations, with baseline lopinavir susceptibility reduced less than 40-fold. The most frequently observed mutations were V82A, I54V, and M46I. Mutations L33F, I50V, and V32I in combination with I47V/A were also detected. In the 19 isolates analyzed, EC50 increased by a mean of 4.3-fold compared to baseline isolates (range: 6.2 to 43-fold increase compared to wild-type virus).

Genotypic correlates associated with reduced phenotypic susceptibility of viruses to lopinavir are considered when selecting other protease inhibitors. The antiviral activity of lopinavir in vitro was studied against 112 clinical isolates obtained from patients with prior failure on one or more protease inhibitors. In this group, reduced in vitro susceptibility to lopinavir was associated with the following HIV protease mutations: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M. The mean EC50 of lopinavir against isolates containing 0–3, 4–5, 6–7, and 8–10 of these mutations was 0.8-, 2.7-, 13.5-, and 44.0-fold higher than the EC50 against wild-type HIV, respectively. All 16 viruses with >20-fold change in susceptibility contained mutations at positions 10, 54, 63, plus 82 and/or 84. Additionally, they contained on average 3 mutations at positions 20, 24, 46, 53, 71, and 90. In addition to the above mutations, V32I and I47A mutations were detected in isolates with reduced lopinavir susceptibility isolated after viral load rebound in patients previously treated with protease inhibitors and receiving lopinavir/ritonavir. I47A and L76V mutations were observed in isolates with reduced lopinavir susceptibility isolated after viral load rebound in patients receiving lopinavir/ritonavir therapy.

Conclusions regarding the relevance of specific mutations and mutation patterns may evolve as additional data become available; therefore, current data interpretation systems are recommended when evaluating resistance testing results.

Antiviral Activity of Lopinavir/Ritonavir in Patients with Prior Protease Inhibitor Failure

The clinical relevance of reduced in vitro susceptibility to lopinavir was assessed by evaluating virological response to lopinavir/ritonavir therapy relative to baseline viral genotype and phenotype in 56 patients with prior failure on protease inhibitor combinations. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6- to 96-fold higher than that against wild-type HIV. After 48 weeks of therapy with lopinavir/ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, plasma HIV RNA levels < 400 copies/mL were observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with baseline lopinavir susceptibility reduced less than 10-fold, 10–40 fold, and more than 40-fold, respectively. Additionally, virological response was observed in 91% (21/23), 71% (15/21), and 33% (2/6) of patients whose isolates contained 0–5, 6–7, and 8–10 of the above-mentioned HIV protease mutations associated with reduced lopinavir susceptibility in vitro. Since these patients had not previously received lopinavir/ritonavir or efavirenz, the response may be partially attributable to the antiviral activity of efavirenz, particularly in patients infected with virus exhibiting high resistance to lopinavir. The study design did not include a control group of patients not receiving lopinavir/ritonavir.

Cross-Resistance

The activity of other protease inhibitors was evaluated against isolates that developed increased resistance to lopinavir after lopinavir/ritonavir therapy in patients previously treated with protease inhibitors. Cross-resistance to other protease inhibitors was analyzed in 18 isolates obtained after viral load rebound 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 against these 18 isolates was 6.9- to 63-fold higher than against wild-type HIV at baseline and after viral load rebound, respectively. Overall, isolates obtained after viral load rebound showed either maintained cross-resistance (if present at baseline) or developed new substantial cross-resistance to indinavir, saquinavir, and atazanavir. A moderate reduction in amprenavir activity was observed, with mean EC50 increases of 3.7- to 8-fold for isolates at baseline and after viral load rebound, respectively. Isolates retained susceptibility to tipranavir, with mean EC50 increases of 1.9- and 1.8-fold for isolates at baseline and after viral load rebound, respectively, compared to wild-type HIV.

Clinical Outcomes

The effects of lopinavir/ritonavir (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4+ T-cell counts) were evaluated in controlled clinical trials of lopinavir/ritonavir lasting from 48 to 360 weeks.

Use in Adult Patients

Antiretroviral-Naïve Patients

Study M98-863 was a randomized, double-blind trial involving 653 antiretroviral-naïve patients, comparing lopinavir/ritonavir (400/100 mg twice daily) with nelfinavir (750 mg three times daily) plus stavudine and lamivudine. The mean baseline CD4+ T-cell count was 259 cells/mm³ (range: 2 to 949 cells/mm³), and the mean baseline plasma HIV-1 RNA level was 4.9 log₁₀ copies/mL (range: 2.6 to 6.8 log₁₀ copies/mL).

Table 1

Results at Week 48: Study M98-863
	Lopinavir/ritonavir (N=326)	Nelfinavir (N=327)
HIV RNA <400 copies/mL*	75%	63%
HIV RNA <50 copies/mL* ǂ	67%	52%
Mean increase in CD4+ T-cell count (cells/mm3) compared to baseline	207	195

* Analysis of the "all patients who initiated treatment" sample, in which patients with missing data were categorized as patients without virological response.

ǂ p<0.001.

113 patients receiving nelfinavir and 74 patients receiving lopinavir/ritonavir had HIV RNA levels above 400 copies/mL from week 24 to week 96 of treatment. Of these, resistance testing was performed on isolates from 96 patients receiving nelfinavir and 51 patients receiving lopinavir/ritonavir. Resistance to nelfinavir, defined as the presence of D30N or E90M mutations in protease, was observed in 41 of 96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary mutation or active site mutations in protease (see above), was observed in 0 of 51 (0%) patients. The absence of lopinavir resistance was confirmed by phenotypic analyses.

Study M05-730 was a randomized, open-label, multicenter trial comparing lopinavir/ritonavir 800/200 mg once daily plus tenofovir DF and emtricitabine versus lopinavir/ritonavir 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Due to the pharmacokinetic interaction between lopinavir/ritonavir and tenofovir, the results of this study should not be strictly extrapolated to other lopinavir/ritonavir-based regimens.

Patients were randomized in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 333) or lopinavir/ritonavir 400/100 mg twice daily (n = 331). Additional stratification within each group occurred in a 1:1 ratio (one part of patients received tablets, the other soft capsules). Patients received the study drug as either tablets or soft capsules for 8 weeks, after which all patients received tablets once or twice daily for the remainder of the study period. Patients received emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Protocol-defined non-inferiority of the once-daily regimen compared to the twice-daily regimen was considered demonstrated if the lower limit of the 95% confidence interval for the difference in the proportion of study participants with treatment response (once-daily minus twice-daily) excluded –12% at week 48. The median age of patients enrolled in the study was 39 years (range: 19 to 71); 75% were white, 78% were male. The median CD4+ T-cell count was 216 cells/mm³ (range: 20 to 775 cells/mm³), and the median baseline plasma HIV-1 RNA level was 5.0 log₁₀ copies/mL (range: 1.7–7.0 log₁₀ copies/mL).

Table 2

Virological response of study participants at week 48 and week 96
	Week 48			Week 96
	Once daily (QD)	Twice daily (BID)	Difference [95 % CI]	QD	BID	Difference [95 % CI]
Lack of response	257/333 (77.2 %)	251/331 (75.8 %)	1.3 % [–5.1, 7.8]	216/333 (64.9 %)	229/331 (69.2 %)	4.3 % [–11.5, 2.8]
Observed data	257/295 (87.1 %)	250/280 (89.3 %)	2.2 % [–7.4, 3.1]	216/247 (87.4 %)	229/248 (92.3 %)	4.9 % [–10.2, 0.4]
Mean increase in CD4+ T-cell count (cells/mm³) compared to baseline	186	198		238	254

At week 96, genotypic resistance testing results were available for 25 patients in the QD group and 26 patients in the BID group who had incomplete virologic response. In the QD group, no patient demonstrated resistance to lopinavir, whereas in the BID group, one patient—who already had significant resistance to protease inhibitors at baseline—developed additional resistance to lopinavir during the study.

Sustained virologic response to lopinavir/ritonavir (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) was observed in a small Phase II trial (M97-720) after 360 weeks of treatment. Initially, 100 patients were treated with lopinavir/ritonavir (51 patients received 400/100 mg twice daily, and 49 patients received either 200/100 mg twice daily or 400/200 mg twice daily). All patients were switched to open-label lopinavir/ritonavir 400/100 mg twice daily between weeks 48 and 72.

Thirty-nine patients (39%) discontinued the study, including 16 (16%) due to adverse reactions, one of which was fatal. Sixty-one patients completed the study (35 of whom received the recommended dose of 400/100 mg twice daily throughout the entire study period).

Table 3

Results at week 360: study M97-720
	Lopinavir/ritonavir (N = 100)
HIV RNA < 400 copies/ml	61%
HIV RNA < 50 copies/ml	59%
Mean increase in CD4+ T-cell count (cells/mm3) compared to baseline	501

After 360 weeks of treatment, genotypic analysis of viral isolates was successfully performed in 19 out of 28 patients with confirmed HIV RNA above 400 copies/mL and showed no primary mutations or sites of active mutations in protease (amino acid positions 8, 30, 32, 46, 47, 48, 50, 82, 84, and 90) or phenotypic resistance to protease inhibitors.

Patients previously treated with antiretroviral therapy

M06-802 was a randomized, open-label study comparing the safety, tolerability, and antiviral activity of once-daily versus twice-daily lopinavir/ritonavir tablets in 559 patients with detectable viral load while on their current antiretroviral therapy. Patients had not previously received lopinavir/ritonavir. They were randomized in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299). Patients also received at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. The study population had moderate prior experience with protease inhibitors (PIs): more than half of the patients had never previously received a PI, and approximately 80 % had virus strains with fewer than three PI mutations. The mean age of patients enrolled in the study was 41 years (range: 21 to 73); 51 % were white, and 66 % were male. The mean CD4+ T-cell count was 254 cells/mm³ (range: 4 to 952 cells/mm³), and the mean baseline plasma HIV-1 RNA level was 4.3 log₁₀ copies/mL (range: 1.7–6.6 log₁₀ copies/mL). In approximately 85 % of patients, the viral load was < 100,000 copies/mL.

Table 4

Virological response of study participants at Week 48; Study 802
	QD	BID	Difference [95% CI]
Non-response	171/300 (57%)	161/299 (53.8%)	3.2% [–4.8%, 11.1%]
Observed data	171/225 (76.0%)	161/223 (72.2%)	3.8% [–4.3%, 11.9%]
Mean increase in CD4+ T-cell count (cells/mm³) from baseline	135	122

At week 48, genotypic resistance testing results were obtained from 75 patients in the QD group and 75 patients in the BID group who had incomplete virological response. In the QD group, 6 out of 75 (8%) patients exhibited new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 84, 90), compared to 12 out of 77 (16%) patients in the BID group.

Children

Study M98-940 was an open-label study evaluating the use of the liquid formulation of lopinavir/ritonavir in 100 children, of whom 56% had previously received and 44% had not previously received antiretroviral therapy. None of the patients had been treated with nucleoside reverse transcriptase inhibitors. Patients were randomized into two treatment groups: 230 mg lopinavir / 57.5 mg ritonavir / m² or 300 mg lopinavir / 75 mg ritonavir / m². Treatment-naïve patients additionally received nucleoside reverse transcriptase inhibitors. Previously treated patients received nevirapine in combination with one or two nucleoside reverse transcriptase inhibitors. After 3 weeks, safety, efficacy, and pharmacokinetic profiles of both regimens were assessed for each patient. Subsequently, all patients continued treatment with the 300/75 mg/m² regimen. The mean age of patients was 5 years (range 6 months to 12 years); 14 patients were under 2 years of age, and 6 patients were 1 year or younger. The mean baseline CD4+ T-cell count was 838 cells/mm³, and the mean baseline plasma HIV-1 RNA concentration was 4.7 log₁₀ copies/mL.

Table 5

Results at week 48: study M98-940
	Patients who previously did not receive antiretroviral therapy (N = 44)	Patients who previously received antiretroviral therapy (N = 56)
HIV RNA < 400 copies/ml	84 %	75 %
Mean increase in CD4+ T-cell count (cells/mm3) from baseline	404	284

KONCERT/PENTA 18 — a prospective, multicenter, randomized, open-label study evaluating the pharmacokinetic profile, efficacy, and safety of lopinavir/ritonavir dosing regimens as 100 mg/25 mg tablets (weight-based) twice daily and once daily as part of combination antiretroviral therapy (cART) in HIV-1-infected children with virological suppression (n = 173). Eligible for participation were children up to 18 years of age, with body weight > 15 kg, who had been receiving cART including lopinavir/ritonavir and had HIV-1 RNA levels < 50 copies/mL for at least 24 weeks, and who were able to swallow tablets. At week 48, the efficacy and safety of the lopinavir/ritonavir 100 mg/25 mg tablet regimen twice daily (n = 87) in the pediatric population were compared with safety and efficacy results obtained from previously conducted studies using lopinavir/ritonavir twice daily in adults and children. The percentage of patients who experienced HIV-1 RNA levels > 50 copies/mL during 48 weeks was higher in children receiving lopinavir/ritonavir tablets once daily (12%) than in those receiving the twice-daily regimen (8%, p = 0.19), primarily due to lower adherence in the once-daily group. The results favor the twice-daily dosing regimen, which is further supported by pharmacokinetic parameter analyses indicating a significant advantage of this dosing schedule.

Pharmacokinetics

The pharmacokinetic properties of lopinavir when co-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 entirely metabolized by CYP3A. Ritonavir inhibits the metabolic breakdown of lopinavir, thereby increasing lopinavir plasma concentrations. Comparing data from various studies, when lopinavir/ritonavir 400/100 mg is administered twice daily to HIV-infected patients, the mean lopinavir concentration at steady state is 15–20 times higher than that of ritonavir. The plasma concentration of ritonavir is less than 7% of that observed after administration of ritonavir 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. Therefore, the antiviral activity of the medicinal product "Lopinavir/Ritonavir Macleods" is attributed to lopinavir.

Absorption

Following multiple oral doses of lopinavir/ritonavir 400/100 mg twice daily for 2 weeks without food restrictions, the Cmax of lopinavir in plasma was 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 12-hour AUC of lopinavir averaged 113.2 ± 60.5 µg·h/mL. The absolute bioavailability of lopinavir when co-administered with ritonavir in humans has not been established.

Effect of Food on Absorption Following Oral Administration

A single 400/100 mg dose of lopinavir/ritonavir tablets was administered after a high-fat meal (872 kcal, 56% fat) and under fasting conditions. No significant changes in Cmax and AUCinf were observed. Therefore, lopinavir/ritonavir tablets can be administered regardless of food intake. Additionally, lower pharmacokinetic variability related to food intake was observed compared to lopinavir/ritonavir soft capsules.

Distribution

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

Biological Transformation

In vitro studies using human liver microsomes have shown 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 lopinavir metabolism, increasing its plasma concentration. Studies with radiolabeled 14C-lopinavir have shown that after a single 400/100 mg dose of lopinavir/ritonavir administered to humans, 89% of total radioactivity in plasma was attributed to the parent compound. At least 13 oxidative metabolites of lopinavir have been identified in humans. The 4-oxo and 4-hydroxy metabolite isomeric pairs are the main metabolites with antiviral activity, but they represent only minor fractions of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzyme activity, thereby accelerating its own metabolism and possibly accelerating lopinavir metabolism as well. With repeated dosing, the pre-dose concentration of lopinavir decreases, and concentration stabilization is achieved within approximately 10 days to 2 weeks.

Elimination

After administration of 14C-lopinavir/ritonavir 400/100 mg, 10.4 ± 2.3% and 82.6 ± 2.5% of the administered 14C-lopinavir dose were 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 peak to trough 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: Pharmacokinetics

The pharmacokinetics of once-daily lopinavir/ritonavir administration were studied in antiretroviral treatment-naïve HIV-infected patients. Lopinavir/ritonavir 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg once daily. After multiple doses of lopinavir/ritonavir 800/200 mg once daily for 2 weeks without food restrictions (n = 16), the mean Cmax of lopinavir was 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 24-hour AUC 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.

Pharmacokinetics in Children

Dose 200/50 mg

Pharmacokinetic data in children under 2 years of age are limited. The pharmacokinetics of lopinavir/ritonavir oral solution administered at doses of 300/75 mg/m² twice daily and 230/57.5 mg/m² twice daily were studied in 53 children aged 6 months to 12 years. Steady-state mean AUC, Cmax, and Cmin values were 72.6 ± 31.1 µg·h/mL, 8.2 ± 2.9 µg/mL, and 3.4 ± 2.1 µg/mL, respectively, after administration of lopinavir/ritonavir oral solution at 230/57.5 mg/m² without nevirapine (n = 12), and 85.8 ± 36.9 µg·h/mL, 10.0 ± 3.3 µg/mL, and 3.6 ± 3.5 µg/mL, respectively, after administration at 300/75 mg/m² with nevirapine (n = 12). The 230/57.5 mg/m² twice-daily regimen without nevirapine and the 300/75 mg/m² twice-daily regimen with nevirapine achieved lopinavir plasma concentrations similar to those observed in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.

Dose 100/25 mg

Pharmacokinetic data in children under 2 years of age are limited. The pharmacokinetics of "Lopinavir/Ritonavir Macleods" 100/25 mg administered twice daily without nevirapine were studied in 53 children. For lopinavir, the mean AUC, Cmax, and C12 at steady state ± standard deviation were 112.5 ± 37.1 µg·h/mL, 12.4 ± 3.5 µg/mL, and 5.71 ± 2.99 µg/mL, respectively. The weight-based twice-daily regimen without nevirapine achieved lopinavir plasma concentrations similar to those observed in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.

Sex, Race, and Age

The pharmacokinetics of lopinavir/ritonavir in elderly individuals have not been studied. In adult patients, pharmacokinetics are not influenced by age or sex. Clinically significant differences in pharmacokinetics related to race have not been established.

Pregnancy and Postpartum Period

In an open-label pharmacokinetic study, 12 HIV-infected women with gestational age up to 20 weeks, receiving combination antiretroviral therapy, initially received lopinavir/ritonavir 400 mg/100 mg (two 200/50 mg tablets) twice daily until week 30 of gestation. At week 30 of pregnancy, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) twice daily, and women continued this regimen until the end of the second week postpartum. Lopinavir plasma concentrations were measured during four 12-hour periods in the second trimester (20–24 weeks of gestation), third trimester before dose escalation (30th week of gestation), third trimester after dose escalation (32nd week of gestation), and eight weeks postpartum. Dose escalation did not result in a significant increase in lopinavir plasma concentrations.

In another open-label pharmacokinetic study, 19 pregnant HIV-infected women received lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy initiated prior to conception. Serial blood samples were collected predose and at 12-hour intervals during the second and third trimesters, at delivery, and 4–6 weeks postpartum (in women who continued treatment after childbirth) for pharmacokinetic analysis of total plasma lopinavir concentrations and unbound drug concentrations.

Pharmacokinetic data obtained in HIV-1-infected pregnant women receiving lopinavir/ritonavir tablets 400/100 mg twice daily are presented in Table 6.

Table 6

Steady-state pharmacokinetic parameters of lopinavir in HIV-infected pregnant women, mean (% CV)
Pharmacokinetic parameter	2nd trimester n = 17*	3rd trimester n = 23	Postpartum n = 17**
AUC0–12, μg·h/mL	68.7 (20.6)	61.3 (22.7)	94.3 (30.3)
Cmax, μg/mL	7.9 (21.1)	7.5 (18.7)	9.8 (24.3)
Cpredose, μg/mL	4.7 (25.2)	4.3 (39.0)	6.5 (40.4)
* n = 18 for Cmax ** n = 16 for Cpredose

Renal impairment

The pharmacokinetics of lopinavir/ritonavir have not been studied in patients with renal impairment; however, renal clearance of lopinavir is minimal, and a reduction in total clearance in patients with renal impairment is not expected.

Hepatic impairment

Steady-state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared to those in HIV-infected patients with normal hepatic function. The dose of lopinavir/ritonavir 400 mg/100 mg twice daily was administered repeatedly. A limited increase in total lopinavir concentrations of approximately 30% was observed, which was not considered clinically significant.

Clinical characteristics.

Indications

"Lopinavir/Ritonavir Macleods" is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus type 1 (HIV-1) infected adults and children aged 2 years and older.

The selection of "Lopinavir/Ritonavir Macleods" for treatment of HIV-1 infected patients, together with other protease inhibitors, should be based on individual viral resistance testing results and treatment history.

Contraindications

Hypersensitivity to lopinavir or ritonavir or to any of the excipients of the medicinal product.

Severe hepatic impairment.

"Lopinavir/Ritonavir Macleods" contains lopinavir and ritonavir, which are inhibitors of the CYP3A isoenzyme of the cytochrome P450 system.

Lopinavir/ritonavir must not be used concomitantly with medicinal products whose clearance is largely dependent on CYP3A activity, as increased plasma concentrations of these agents may lead to serious or life-threatening reactions.

The list of such medicinal products includes:

Medicinal products whose plasma levels increase when co-administered

Alpha1-adrenoceptor antagonist

Alfuzosin. Increased plasma concentration of alfuzosin may lead to severe hypotension.

Anti-anginal agents

Ranolazine. Increased plasma concentration of ranolazine may lead to serious or life-threatening reactions.

Antiarrhythmic agents

Amiodarone, dronedarone. Increased plasma concentrations of amiodarone and dronedarone may increase the risk of arrhythmias or other serious adverse reactions.

Antibiotics

Fusidic acid. Increased plasma concentration of fusidic acid. Concomitant use with fusidic acid is contraindicated in dermatological infections.

Anticancer agents

Neratinib. Increased plasma concentration of neratinib increases the likelihood of serious and/or life-threatening reactions.

Venetoclax. Plasma concentration of venetoclax increases. Risk of tumor lysis syndrome increases during initiation and dose escalation phases. For patients who have completed the dose escalation phase and are on maintenance daily dosing of venetoclax, the dose of venetoclax should be reduced by at least 75% when co-administered with strong CYP3A inhibitors.

Antigout agents

Colchicine. Increased plasma concentration of colchicine may lead to serious or life-threatening reactions in patients with renal and/or hepatic impairment.

Antihistamines

Astemizole, terfenadine. Increased plasma concentrations of astemizole and terfenadine. As a result, increased risk of serious arrhythmias caused by these agents.

Antipsychotic/neuroleptic agents

Lurasidone. Increased plasma concentration of lurasidone may lead to serious or life-threatening reactions.

Pimozide. Increased plasma concentration of pimozide. As a result, increased risk of serious hematological disorders or other serious adverse events.

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. Increased plasma concentration of cisapride. As a result, increased risk of serious arrhythmias caused by this agent.

Direct-acting antiviral agents against hepatitis C virus

Elbasvir/grazoprevir. Increased risk of elevated alanine aminotransferase (ALT) levels.

Ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Increased plasma concentration of paritaprevir. As a result, increased risk of elevated ALT levels.

HMG-CoA reductase inhibitors

Lovastatin, simvastatin. Increased plasma concentrations of lovastatin and simvastatin. As a result, increased risk of myopathy, including rhabdomyolysis.

Microsomal triglyceride transfer protein (MTTP) inhibitor

Lomitapide. Increased plasma concentration of lomitapide.

Phosphodiesterase inhibitors (PDE5)

Avanafil. Increased plasma concentration of avanafil.

Sildenafil. Contraindicated only when used for the treatment of pulmonary arterial hypertension (PAH). Increased plasma concentration of sildenafil. As a result, increased risk of sildenafil-related adverse reactions, including hypotension and syncope.

Vardenafil. Increased plasma concentration of vardenafil.

Sedatives/hypnotics

Oral midazolam, triazolam. Increased plasma concentrations of oral midazolam and triazolam. As a result, increased risk of excessive sedation and respiratory depression caused by these agents.

Medicinal products that reduce plasma levels of lopinavir/ritonavir when co-administered

Herbal products

St. John’s wort (Hypericum perforatum). 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

"Lopinavir/Ritonavir Macleods" contains lopinavir and ritonavir, which are inhibitors of the CYP3A isoenzyme of the cytochrome P450 system in vitro. Concomitant administration of lopinavir/ritonavir with medicinal products that are primarily metabolized by the CYP3A system may result in increased plasma concentrations of these other agents, potentially increasing or prolonging their therapeutic and adverse effects. "Lopinavir/Ritonavir Macleods" does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6, or CYP1A2 at clinically relevant concentrations.

"Lopinavir/Ritonavir Macleods" in vivo induces its own metabolism and enhances the biotransformation of certain medicinal products metabolized by the cytochrome P450 enzyme system (including CYP2C9 and CYP2C19) as well as by glucuronidation. This may lead to decreased plasma concentrations of co-administered drugs and reduced efficacy when used concomitantly with lopinavir/ritonavir.

All interaction studies, unless otherwise specified, were conducted using lopinavir/ritonavir capsules, which result in approximately 20% lower lopinavir exposure compared to the 200/50 mg tablets.

The table below presents interactions between "Lopinavir/Ritonavir Macleods" and other concurrently administered medicinal products (increased concentration is indicated by "↑", decreased by "↓", no change by "↔").

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

Table 7

Medicinal product within each therapeutic group	Effect on the concentration of the drug Mean geometric change (%) AUC, Cmax, Cmin, mechanisms of interaction	Clinical recommendations for concomitant use with the medicinal product "Lopinavir/Ritonavir Macleods"
Antiretroviral drugs
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Stavudine, lamivudine	Lopinavir: ↔	No dose adjustment required.
Abacavir, zidovudine	Abacavir, zidovudine: concentrations may decrease due to increased glucuronidation induced by lopinavir/ritonavir	The clinical significance of decreased abacavir and zidovudine concentrations is unknown.
Tenofovir disoproxil fumarate 300 mg once daily (equivalent to 245 mg tenofovir disoproxil)	Tenofovir: AUC: ↑ 32% Cmax: ↔ Cmin: ↑ 51% Lopinavir: ↔	No dose adjustment required. Increased tenofovir concentrations may enhance tenofovir-related adverse effects, including renal function impairment.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz, 600 mg once daily	Lopinavir: AUC: ↓ 20% Cmax: ↓13% Cmin: ↓ 42%	The dose of "Lopinavir/Ritonavir Macleods" tablets should be increased to 500 mg / 125 mg twice daily when used concomitantly with efavirenz. "Lopinavir/Ritonavir Macleods" should not be taken once daily in combination with efavirenz.
Efavirenz, 600 mg once daily (lopinavir/ ritonavir 500 mg / 125 mg twice daily)	Lopinavir: ↔ (applies to 400 mg / 100 mg twice daily dose taken separately)
Nevaripine, 200 mg twice daily	Lopinavir: AUC: ↓ 27% Cmax: ↓ 19% Cmin: ↓ 51%	The dose of "Lopinavir/Ritonavir Macleods" tablets should be increased to 500/125 mg twice daily when used concomitantly with nevirapine. "Lopinavir/Ritonavir Macleods" should not be taken once daily in combination with nevirapine.
Etravirine (lopinavir/ ritonavir 400 mg / 100 mg twice daily)	Etravirine: AUC: ↓ 35% Cmin: ↓ 45% Cmax: ↓ 30% Lopinavir: AUC: ↔ Cmin: ↓ 20% Cmax: ↔	No dose adjustment required
Rilpivirine (lopinavir/ ritonavir, capsules 400 mg/100 mg twice daily)	Rilpivirine: AUC: ↑ 52% Cmin: ↑ 74% Cmax: ↑ 29% Lopinavir: AUC: ↔ Cmin: ↓ 11% Cmax: ↔ (inhibition of CYP3A enzymes)	Concomitant use of "Lopinavir/Ritonavir Macleods" with rilpivirine leads to increased plasma concentrations of rilpivirine, however, no dose adjustment is required.
HIV CCR5 chemokine receptor antagonist
Maraviroc	Maraviroc: AUC: ↑ 295% Cmax: ↑ 97% Due to CYP3A inhibition by lopinavir/ritonavir	The dose of maraviroc should be reduced to 150 mg twice daily during concomitant use with "Lopinavir/Ritonavir Macleods" at a dose of 400 mg / 100 mg twice daily.
Integrase inhibitor
Raltegravir	Raltegravir: AUC: ↔ Cmax: ↔ C12:↓30% Lopinavir: ↔	No dose adjustment required.
Concomitant use with other HIV protease inhibitors (PIs) According to current treatment guidelines, dual protease inhibitor therapy is generally not recommended
Fosamprenavir/ ritonavir (700/100 mg twice daily) (lopinavir/ ritonavir 400 mg / 100 mg twice daily) or Fosamprenavir (1400 mg twice daily) (lopinavir/ ritonavir 533 mg / 133 mg twice daily)	Fosamprenavir: amprenavir concentrations significantly decrease	Concomitant use of higher doses of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients previously treated with protease inhibitors resulted in a higher frequency of gastrointestinal adverse events and increased triglyceride levels without enhanced virological efficacy compared to standard fosamprenavir/ritonavir doses. Concomitant use of these medicinal products is not recommended. "Lopinavir/Ritonavir Macleods" should not be taken once daily in combination with amprenavir.
Indinavir 600 mg twice daily	Indinavir: AUC: ↔ Cmin: ↑ 3.5 times Cmax: ↓ (applies to indinavir 800 mg three times daily taken separately) Lopinavir: ↔ (Based on historical data comparison)	Optimal doses for this combination in terms of efficacy and safety have not been established.
Saquinavir 1000 mg twice daily	Saquinavir: ↔	No dose adjustment required.
Tipranavir/ ritonavir (500/100 mg twice daily)	Lopinavir: AUC: ↓ 55 % Cmin: ↓ 70 % Cmax: ↓47 %	Concomitant use of these medicinal products is not recommended.
Drugs that reduce gastric acidity
Omeprazole (40 mg once daily)	Omeprazole: ↔ Lopinavir: ↔	No dose adjustment required.
Ranitidine (150 mg single dose)	Ranitidine: ↔	No dose adjustment required.
Alpha1-adrenergic blockers
Alfuzosin	Alfuzosin: increased concentrations expected due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of "Lopinavir/Ritonavir Macleods" and alfuzosin is contraindicated due to possible increased alfuzosin-related toxicity, including arterial hypotension.
Analgesics
Fentanyl	Fentanyl: increased risk of adverse reactions (respiratory depression, sedation) due to higher plasma concentrations resulting from CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Close monitoring for adverse reactions (mainly respiratory depression and sedation) is recommended when fentanyl is used concomitantly with "Lopinavir/Ritonavir Macleods".
Anti-anginal agents
Ranolazine	Concentrations expected to increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of "Lopinavir/Ritonavir Macleods" and ranolazine is contraindicated.
Antiarrhythmic agents
Amiodarone Dronedarone	Amiodarone, dronedarone: concentrations may increase due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Concomitant use of "Lopinavir/Ritonavir Macleods" with amiodarone or dronedarone is contraindicated, as it increases the risk of arrhythmias or other serious adverse reactions.
Digoxin	Digoxin: plasma concentrations may increase due to P-glycoprotein inhibition by "Lopinavir/Ritonavir Macleods". Elevated digoxin levels may gradually decrease over time due to P-glycoprotein induction.	Care should be taken when using "Lopinavir/Ritonavir Macleods" concomitantly with digoxin, and therapeutic drug monitoring of digoxin concentrations should be performed if possible. Particular caution is advised when prescribing "Lopinavir/Ritonavir Macleods" to patients taking digoxin, 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 Macleods" is likely to result in a smaller than expected increase in digoxin concentrations.
Bepridil, systemic lidocaine, quinidine	Bepridil, systemic lidocaine, quinidine: concentrations may increase when used concomitantly with "Lopinavir/Ritonavir Macleods"	Caution is advised, and therapeutic drug monitoring should be performed if possible.
Antibiotics
Clarithromycin	Clarithromycin: moderate increase in AUC of clarithromycin expected due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Dose reduction of clarithromycin should be considered in patients with renal impairment (creatinine clearance < 30 mL/min). Caution is advised when prescribing clarithromycin concomitantly with "Lopinavir/Ritonavir Macleods" to patients with hepatic or renal impairment.
Anticancer agents and kinase inhibitors
Abemaciclib	Serum concentrations may increase due to CYP3A inhibition by ritonavir	Concomitant use of abemaciclib and "Lopinavir/Ritonavir Macleods" should be avoided. Monitor for possible abemaciclib-related adverse reactions.
Apalutamide	Apalutamide is a moderate or strong CYP3A4 inducer, which may lead to reduced effect of lopinavir/ritonavir. Serum concentrations of apalutamide may increase due to CYP3A inhibition by lopinavir/ritonavir.	Reduced effect of "Lopinavir/Ritonavir Macleods" may lead to loss of virological response. In addition, concomitant use of apalutamide and "Lopinavir/Ritonavir Macleods" may lead to serious adverse effects, including seizures due to increased apalutamide levels. Concomitant use of "Lopinavir/Ritonavir Macleods" with apalutamide is not recommended.
Afatinib (Ritonavir 200 mg twice daily)	Afatinib: AUC: ↑ Cmax: ↑ The degree of increase depends on the timing of ritonavir administration. Related to inhibition of BCRP (breast cancer resistance protein/ABCG2) and acute P-glycoprotein inhibition by "Lopinavir/Ritonavir Macleods"	Caution is advised when prescribing afatinib in combination with "Lopinavir/Ritonavir Macleods". Monitor for possible afatinib-related adverse reactions.
Ceritinib	Serum concentrations may increase due to CYP3A and P-glycoprotein inhibition by "Lopinavir/Ritonavir Macleods"	Caution is advised when prescribing ceritinib in combination with "Lopinavir/Ritonavir Macleods". Monitor for possible ceritinib-related adverse reactions.
Most tyrosine kinase inhibitors, e.g., dasatinib, nilotinib, vincristine, and vinblastine	Most tyrosine kinase inhibitors, e.g., dasatinib, nilotinib, as well as vincristine and vinblastine: risk of increased adverse events due to higher serum concentrations resulting from CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Close monitoring for tolerability of these anticancer agents is recommended.
Encorafenib	Serum concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of encorafenib with "Lopinavir/Ritonavir Macleods" may increase encorafenib exposure, increasing the risk of toxicity, including serious adverse effects such as QT interval prolongation. Concomitant use of encorafenib and "Lopinavir/Ritonavir Macleods" should be avoided. If benefit outweighs risk and use of "Lopinavir/Ritonavir Macleods" is necessary, the patient should be closely monitored.
Fostamatinib	Increased exposure of the metabolite R406 of fostamatinib	Concomitant use of fostamatinib with "Lopinavir/Ritonavir Macleods" may increase exposure to the metabolite R406 of fostamatinib, leading to dose-dependent adverse effects such as hepatotoxicity, neutropenia, arterial hypertension, or diarrhea.
Ibrutinib	Serum concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of ibrutinib and "Lopinavir/Ritonavir Macleods" may increase ibrutinib exposure, increasing the risk of toxicity, including tumor lysis syndrome. Concomitant use of ibrutinib and "Lopinavir/Ritonavir Macleods" should be avoided. If benefit outweighs risk and use of "Lopinavir/Ritonavir Macleods" is necessary, the ibrutinib dose should be reduced to 140 mg and the patient should be closely monitored for toxicity.
Neratinib	Serum concentrations may increase due to CYP3A inhibition by ritonavir	Concomitant use of neratinib with "Lopinavir/Ritonavir Macleods" is contraindicated due to serious and/or potentially life-threatening reactions, including hepatotoxicity.
Venetoclax	Serum concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Lopinavir/ritonavir inhibits CYP3A. Concomitant use of venetoclax and lopinavir/ritonavir may increase venetoclax exposure, posing a serious risk of tumor lysis syndrome. For patients who have completed the ramp-up phase and are on a stable 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 signs of venetoclax toxicity.
Anticoagulants
Warfarin	Warfarin: concomitant use with "Lopinavir/Ritonavir Macleods" may alter concentrations due to CYP2C9 induction	Monitoring of INR (International Normalized Ratio) is recommended.
Rivaroxaban (Ritonavir 600 mg twice daily)	Rivaroxaban: AUC: ↑ 153 % Cmax: ↑ 55 % Due to CYP3A and P-glycoprotein inhibition by lopinavir/ritonavir	Concomitant use of rivaroxaban and "Lopinavir/Ritonavir Macleods" may increase rivaroxaban concentration, thereby increasing the risk of bleeding. Use of rivaroxaban is not recommended in patients receiving concomitant therapy with "Lopinavir/Ritonavir Macleods".
Dabigatran etexilate, Edoxaban	Dabigatran etexilate, Edoxaban: Plasma concentrations may increase due to P-glycoprotein inhibition by "Lopinavir/Ritonavir Macleods".	Clinical monitoring and/or dose reduction of direct oral anticoagulants (DOACs) should be considered if DOACs are transported by P-glycoproteins but not metabolized by CYP3A4, including dabigatran etexilate and edoxaban, when used concomitantly with "Lopinavir/Ritonavir Macleods".
Vorapaxar	Serum concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of vorapaxar with lopinavir/ritonavir is not recommended.
Anticonvulsants
Phenytoin	Phenytoin: steady-state concentrations moderately decreased due to CYP2C9 and CYP2C19 induction by "Lopinavir/Ritonavir Macleods" Lopinavir: concentrations decrease due to CYP3A induction by phenytoin	Caution is advised when prescribing phenytoin in combination with "Lopinavir/Ritonavir Macleods". Dose increase of "Lopinavir/Ritonavir Macleods" may be anticipated with concomitant use of phenytoin. Dose increase has not been evaluated in clinical practice. "Lopinavir/Ritonavir Macleods" should not be taken once daily in combination with phenytoin.
Carbamazepine and phenobarbital	Carbamazepine: serum concentrations may increase due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods" Lopinavir: concentrations may decrease due to CYP3A induction by carbamazepine and phenobarbital	Caution is advised when prescribing carbamazepine or phenobarbital in combination with "Lopinavir/Ritonavir Macleods". Carbamazepine and phenobarbital levels should be monitored when used concomitantly with lopinavir/ritonavir. Dose increase of "Lopinavir/Ritonavir Macleods" may be anticipated with concomitant use of carbamazepine or phenobarbital. Dose increase has not been evaluated in clinical practice. "Lopinavir/Ritonavir Macleods" should not be taken once daily in combination with carbamazepine and phenobarbital.
Lamotrigine and valproate	Lamotrigine: AUC: ↓ 50 % Cmax: ↓ 46 % Cmin: ↓56 % Due to induction of lamotrigine glucuronidation Valproate: ↓	Close monitoring is required for reduced efficacy of valproic acid when "Lopinavir/Ritonavir Macleods" is used concomitantly with valproic acid. For patients starting or discontinuing "Lopinavir/Ritonavir Macleods" while on maintenance lamotrigine, dose adjustment of lamotrigine may be required—increasing the dose when starting or decreasing the dose when discontinuing "Lopinavir/Ritonavir Macleods". Therefore, plasma lamotrigine concentration monitoring should be performed, especially before initiating concomitant use with "Lopinavir/Ritonavir Macleods" and during the first 2 weeks after starting or discontinuing "Lopinavir/Ritonavir Macleods", to determine the need for lamotrigine dose adjustment. For patients already taking "Lopinavir/Ritonavir Macleods" who start lamotrigine, dose adjustment prior to the recommended lamotrigine dose increase is not required.
Antidepressants and anxiolytics
Trazodone, single dose (Ritonavir 200 mg twice daily)	Trazodone: AUC: ↑ 2.4 times Adverse events such as nausea, dizziness, arterial hypotension, and syncope were observed after concomitant use of trazodone and ritonavir	It is unknown whether the combination of 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	Ketoconazole, itraconazole: serum concentrations may increase due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	High doses of ketoconazole and itraconazole (> 200 mg/day) are not recommended.
Voriconazole	Voriconazole: concentrations may decrease	Concomitant use of voriconazole and low-dose ritonavir (100 mg twice daily) contained in "Lopinavir/Ritonavir Macleods" should be avoided unless benefit outweighs risk.
Drugs for the treatment of gout
Colchicine, single dose (Ritonavir 200 mg twice daily)	Colchicine: AUC: ↑ 3 times Cmax: ↑ 1.8 times Due to P-glycoprotein and/or CYP3A4 inhibition by ritonavir	Concomitant use of "Lopinavir/Ritonavir Macleods" with colchicine in patients with impaired renal and/or hepatic function is contraindicated due to possible development of serious or life-threatening colchicine-related reactions, such as neuromuscular toxicity (including rhabdomyolysis). For patients with normal renal and hepatic function requiring lopinavir/ritonavir therapy, colchicine dose reduction or discontinuation is recommended.
Antihistamine drugs
Astemizole, terfenadine	Lopinavir/ritonavir inhibits CYP3A, leading to expected increased plasma concentrations of astemizole and terfenadine	Concomitant use of these drugs is contraindicated due to the risk of serious arrhythmia.
Antibacterial agents
Fusidic acid	Fusidic acid: concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of "Lopinavir/Ritonavir Macleods" with fusidic acid is contraindicated in dermatological practice due to increased risk of fusidic acid-related adverse effects, especially rhabdomyolysis. For treatment of bone and joint infections, where concomitant use cannot be avoided, close monitoring for possible muscle-related adverse effects is strongly recommended.
Antituberculosis drugs
Bedaquiline (single dose) (lopinavir/ ritonavir 400 mg / 100 mg twice daily, multiple doses)	Bedaquiline: AUC: ↑ 22 % Cmax: ↔ Greater effect on bedaquiline plasma levels may be observed with concomitant use of lopinavir/ritonavir. CYP3A4 inhibition is likely related to lopinavir/ritonavir.	Due to the risk of bedaquiline-related adverse effects, combination of bedaquiline and "Lopinavir/Ritonavir Macleods" should be avoided. If benefit outweighs risk, extreme caution is advised when using bedaquiline concomitantly with "Lopinavir/Ritonavir Macleods". More frequent ECG and transaminase level monitoring is recommended.
Delamanid (100 mg twice daily) (lopinavir/ ritonavir 400 mg / 100 mg twice daily)	Delamanid: AUC: ↑ 22 % DM-6705 (active metabolite of delamanid): AUC: ↑ 30 % Greater effect on DM-6705 levels may be observed with prolonged concomitant use with lopinavir/ritonavir	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 the delamanid treatment period.
Rifabutin, 150 mg once daily	Rifabutin (parent drug and active metabolite 25-O-desacetyl): AUC: ↑ 5.7 times Cmax: ↑ 3.5 times	When used concomitantly with "Lopinavir/Ritonavir Macleods", the recommended dose of rifabutin is 150 mg three times weekly on pre-specified days (e.g., Monday, Wednesday, Friday). Enhanced monitoring for rifabutin-related adverse reactions, including neutropenia and uveitis, is required due to expected increased rifabutin exposure. For patients who do not tolerate the 150 mg dose three times weekly, further reduction of rifabutin dose to 150 mg twice weekly is recommended. It should be noted that a dose of 150 mg twice weekly may not provide optimal rifabutin exposure, thus risking rifabutin resistance and ineffective treatment. Dose adjustment of "Lopinavir/Ritonavir Macleods" is not required.
Rifampicin	Lopinavir: significant decrease in lopinavir concentrations may occur due to CYP3A induction by rifampicin	Concomitant use of "Lopinavir/Ritonavir Macleods" with rifampicin is not recommended, as decreased lopinavir concentration may significantly reduce the therapeutic effect of lopinavir. Dose adjustment of "Lopinavir/Ritonavir Macleods" to 400 mg / 400 mg (i.e., "Lopinavir/Ritonavir Macleods" 400 mg / 100 mg + ritonavir 300 mg) twice daily can compensate for the inducing effect of rifampicin on CYP3A4. However, such dose adjustment may be associated with increased ALT (alanine aminotransferase) / AST (aspartate aminotransferase) 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 Macleods" 400 mg / 400 mg twice daily may be prescribed in combination with rifampicin, provided careful safety monitoring and therapeutic drug monitoring. The dose of "Lopinavir/Ritonavir Macleods" should be increased gradually only after starting rifampicin.
Antipsychotic agents
Lurasidone	Increased lurasidone concentrations expected due to CYP3A inhibition by lopinavir/ ritonavir	Concomitant use with lurasidone is contraindicated.
Pimozide	Lopinavir/ritonavir inhibits CYP3A, leading to expected increased pimozide blood concentration	Concomitant use of these drugs increases the risk of serious hematological disorders and other serious adverse reactions.
Quetiapine	Increased quetiapine concentrations expected due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of "Lopinavir/Ritonavir Macleods" and quetiapine is contraindicated, as it may lead to increased quetiapine-related toxicity.
Benzodiazepines
Midazolam	Oral midazolam: AUC: ↑ 13 times Parenteral midazolam: AUC: ↑ 4 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	"Lopinavir/Ritonavir Macleods" should not be prescribed in combination with oral midazolam, and caution is advised when prescribing "Lopinavir/Ritonavir Macleods" concomitantly with parenteral midazolam. If "Lopinavir/Ritonavir Macleods" is prescribed in combination with parenteral midazolam, treatment should occur in an intensive care unit (ICU) or similar facility allowing close clinical monitoring and treatment in case of respiratory depression and/or prolonged sedation. Dose adjustment of midazolam should be considered, especially if more than one dose of midazolam is administered.
Beta-2-adrenergic agonists (long-acting)
Salmeterol	Salmeterol: concentrations may increase due to CYP3A inhibition by lopinavir/ritonavir	Combined use increases the risk of cardiovascular adverse effects associated with salmeterol, including QT prolongation, tachycardia, and sinus tachycardia. Therefore, concomitant use of "Lopinavir/Ritonavir Macleods" and salmeterol is not recommended.
Calcium channel blockers
Felodipine, nifedipine, and nicardipine	Felodipine, nifedipine, and nicardipine: concentrations may increase due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Clinical monitoring of therapeutic effect and adverse events is recommended when these drugs are used concomitantly with "Lopinavir/Ritonavir Macleods".
Corticosteroids
Dexamethasone	Lopinavir: concentrations may decrease due to CYP3A induction by dexamethasone	Clinical monitoring of antiviral effect is recommended when these drugs are used concomitantly with "Lopinavir/Ritonavir Macleods".
Fluticasone propionate (inhaled, intranasal, or injectable), budesonide, triamcinolone	Fluticasone propionate: plasma concentrations ↑ cortisol levels ↓ 86 %	More pronounced effects may be expected with inhaled fluticasone propionate. 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 Macleods" and glucocorticoids is not recommended unless potential benefit outweighs the risks of systemic corticosteroid effects. Dose reduction of glucocorticoids with close monitoring of local and systemic effects should be considered, or switching to glucocorticoids not metabolized by CYP3A4 (e.g., beclomethasone). Additionally, tapering of glucocorticoids after discontinuation may require a longer duration than usual.
Phosphodiesterase inhibitors (PDE5)
Avanafil (Ritonavir 600 mg twice daily)	Avanafil: AUC: ↑ 13 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Concomitant use of avanafil and "Lopinavir/Ritonavir Macleods" is contraindicated.
Tadalafil	Tadalafil: AUC: ↑ 2 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	For pulmonary hypertension treatment: concomitant use of "Lopinavir/Ritonavir Macleods" and sildenafil is contraindicated. Concomitant use of "Lopinavir/Ritonavir Macleods" and tadalafil is not recommended. For erectile dysfunction treatment: use with caution and close monitoring for adverse effects, including arterial hypotension, syncope, visual disturbances, and prolonged erection. When used concomitantly with "Lopinavir/Ritonavir Macleods", sildenafil doses should not exceed 25 mg within 48 hours, and tadalafil doses should not exceed 10 mg within 72 hours.
Sildenafil	Sildenafil: AUC: ↑ 11 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"
Vardenafil	Vardenafil: AUC: ↑ 49 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Concomitant use of vardenafil and "Lopinavir/Ritonavir Macleods" is contraindicated.
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.
Drugs affecting gastrointestinal (GI) motility
Cisapride	Plasma concentration of cisapride may increase due to CYP3A inhibition by lopinavir/ritonavir	Concomitant use of these drugs is contraindicated, as it increases the risk of serious arrhythmia.
Direct-acting antiviral drugs against hepatitis C virus
Elbasvir/ Grazoprevir 50/200 mg once daily	Elbasvir: AUC: ↑ 2.71 times Cmax: ↑ 1.87 times C24: ↑ 3.58 times Grazoprevir AUC: ↑ 11.86 times Cmax: ↑ 6.31 times C24: ↑ 20.70 times (combination of mechanisms, including CYP3A inhibition) Lopinavir: ↔	Concomitant use of these drugs is contraindicated.
Glecaprevir/ pibrentasvir	Serum concentrations may increase due to P-glycoprotein, BCRP, and OATP1B inhibition by lopinavir/ritonavir.	Concomitant use of glecaprevir/pibrentasvir and "Lopinavir/Ritonavir Macleods" is not recommended due to increased risk of ALT elevation associated with increased glecaprevir exposure.
Orthobitevir/ paritaprevir/ ritonavir with dasabuvir (25/150/100 mg + 400 mg twice daily) Lopinavir/ritonavir 400/100 mg twice daily	Orthobitevir: ↔ Paritaprevir: AUC: ↑ 2.17 times Cmax: ↑ 2.04 times Ctrough: ↑ 2.36 times (CYP3A inhibition) Dasabuvir: ↔ Lopinavir: ↔	Concomitant use of these drugs is contraindicated. Lopinavir/ritonavir 800/200 mg once daily was administered with orthobitevir/paritaprevir/ ritonavir, with or without dasabuvir. The effect on direct-acting antivirals and lopinavir was similar to that observed with lopinavir/ritonavir 400/100 mg twice daily.
Orthobitevir/ paritaprevir/ ritonavir (25/150/100 mg twice daily) Lopinavir/ritonavir 400/100 mg twice daily	Orthobitevir: ↔ Paritaprevir: AUC: ↑ 6.10 times Cmax: ↑ 4.76 times Ctrough: ↑ 12.33 times (CYP3A inhibition) Lopinavir: ↔
Sofosbuvir/ velpatasvir/ voxilaprevir	Serum concentrations of sofosbuvir, velpatasvir, and voxilaprevir may increase due to P-glycoprotein, BCRP, and OATP1B1/3 inhibition by lopinavir/ritonavir. However, only increased exposure to voxilaprevir is considered clinically significant.	Concomitant use of these drugs and "Lopinavir/Ritonavir Macleods" is not recommended.
Hepatitis C virus protease inhibitors
Simeprevir 200 mg daily (Ritonavir 100 mg twice daily)	Simeprevir: AUC: ↑ 7.2 times Cmax: ↑ 4.7 times Cmin: ↑ 14.4 times	Concomitant use of these drugs and "Lopinavir/Ritonavir Macleods" is not recommended.
Herbal products
St. John's wort (Hypericum perforatum)	Lopinavir: concentrations may decrease due to CYP3A induction by St. John's wort herbal product	Herbal products containing St. John's wort (Hypericum perforatum) should not be combined with lopinavir/ritonavir. If a patient is already taking St. John's wort, it should be discontinued and, if possible, viral load levels should be checked. After discontinuation of St. John's wort, lopinavir and ritonavir levels may increase. Dose adjustment of "Lopinavir/Ritonavir Macleods" may be required. The inducing effect may persist for at least 2 weeks after stopping St. John's wort. Therefore, "Lopinavir/Ritonavir Macleods" can be safely initiated 2 weeks after discontinuation of St. John's wort.
Immunosuppressants
Cyclosporine, sirolimus (rapamycin), tacrolimus	Cyclosporine, sirolimus (rapamycin), tacrolimus: concentrations may increase due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Close monitoring of therapeutic drug concentrations is recommended until plasma levels stabilize.
Lipid-lowering drugs
Lovastatin, simvastatin	Lovastatin, simvastatin: marked increase in plasma concentrations due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, combination of these drugs with "Lopinavir/Ritonavir Macleods" is contraindicated.
Lipid-modifying agent
Lomitapide	CYP3A4 inhibitors increase lomitapide exposure, and strong inhibitors increase exposure approximately 27-fold. Increased lomitapide concentrations are expected due to CYP3A inhibition by lopinavir/ritonavir.	Concomitant use of "Lopinavir/Ritonavir Macleods" with lomitapide is contraindicated.
Atorvastatin	Atorvastatin: AUC: ↑ 5.9 times Cmax: ↑ 4.7 times Due to CYP3A inhibition by "Lopinavir/Ritonavir Macleods"	Concomitant use of "Lopinavir/Ritonavir Macleods" with atorvastatin is not recommended. If atorvastatin use is deemed essential, the lowest possible atorvastatin dose should be used with careful safety monitoring.
Rosuvastatin 20 mg once daily	Rosuvastatin: AUC: ↑ 2 times Cmax: ↑ 5 times Although rosuvastatin is weakly metabolized by CYP3A4, increased plasma concentrations have been observed. The mechanism of this interaction may be explained by transporter protein inhibition.	Caution is advised when using "Lopinavir/Ritonavir Macleods" concomitantly with rosuvastatin, and consideration should be given to using lower doses.
Fluvastatin or pravastatin	Fluvastatin or pravastatin: No clinically significant interaction expected. Pravastatin is not metabolized by CYP450. 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	Buprenorphine: ↔	No dose adjustment required
Methadone	Methadone: ↓	Plasma methadone level monitoring is recommended.
Oral contraceptives
Ethinylestradiol	Ethinylestradiol: ↓	Additional contraceptive measures may be required when "Lopinavir/Ritonavir Macleods" is used concomitantly with contraceptives containing ethinylestradiol (regardless of contraceptive formulation, e.g., oral contraceptive or patch).
Drugs for nicotine dependence treatment
Bupropion	Bupropion and its active metabolite hydroxybupropion: AUC and Cmax: ↓ ~ 50 % This effect may be related to induction of bupropion metabolism	If concomitant use of "Lopinavir/Ritonavir Macleods" and bupropion cannot be avoided, careful clinical monitoring of bupropion efficacy is required, without exceeding the recommended dose, regardless of the observed induction.
Hormone replacement therapy for thyroid disorders
Levothyroxine	Interactions reported between ritonavir-containing drugs and levothyroxine	In patients receiving levothyroxine, thyroid-stimulating hormone (TSH) levels should be monitored for at least one month after starting and/or stopping lopinavir/ritonavir therapy.
Vasodilators
Bosentan	Lopinavir/ritonavir: plasma concentrations of lopinavir/ritonavir may decrease due to CYP3A4 induction by bosentan. Bosentan: AUC: ↑ 5 times Cmax: ↑ 6 times At the beginning of bosentan therapy: Cmin: ↑ ~ 48 times Related to inhibition by lopinavir/ritonavir	Caution is advised when prescribing "Lopinavir/Ritonavir Macleods" with bosentan. When these drugs are used concomitantly, monitoring of anti-HIV therapy efficacy is required, and close observation for bosentan toxicity should be performed, especially during the first week of concomitant drug use.
Riociguat	Riociguat. Serum concentrations may increase due to CYP3A and P-glycoprotein inhibition by "Lopinavir/Ritonavir Macleods"	Concomitant use of these drugs is not recommended.
Other medicinal products
Based on known metabolic profiles, clinically significant interactions between "Lopinavir/Ritonavir Macleods" and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole are not expected

Special precautions for use

Hepatic impairment

The safety and efficacy of lopinavir/ritonavir in patients with severe 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. When antiretroviral combination therapy is administered to patients with hepatitis B or C, refer to the appropriate instructions for use of these medicinal products.

In patients with pre-existing hepatic impairment, including chronic hepatitis, increased frequency of hepatic toxicity 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.

Elevations in transaminases, with or without concomitant increases in bilirubin, have been observed in HIV-1 monoinfected patients and patients receiving post-exposure prophylaxis, within 7 days after starting lopinavir/ritonavir in combination with other antiretroviral agents. In some cases, hepatic disorders were serious.

Appropriate laboratory tests should be performed prior to initiating lopinavir/ritonavir, and patients should be closely monitored during treatment.

Renal impairment

Since renal clearance of lopinavir and ritonavir is minimal, increased plasma concentrations are not expected in patients with renal impairment. As 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 either 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 "Lopinavir/Ritonavir Macleods", 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 increases in triglyceride levels are a risk factor for pancreatitis. In patients with progressive HIV infection, the risk of increased triglyceride concentrations and development of pancreatitis is increased.

Pancreatitis should be considered in the presence of clinical symptoms (nausea, vomiting, abdominal pain) or laboratory abnormalities (elevated serum lipase or amylase). Patients presenting with these signs or symptoms should be evaluated, and if pancreatitis is diagnosed, treatment with "Lopinavir/Ritonavir Macleods" should be discontinued.

Immune Reconstitution Syndrome

In HIV-infected patients with severe immune deficiency, inflammatory reactions to asymptomatic or residual opportunistic pathogens may occur during combination antiretroviral therapy (cART). These reactions may result in severe clinical conditions or worsening of symptoms. Such reactions are generally 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 jiroveci 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 to occur during immune reconstitution, although these may 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, particularly 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 several healthy volunteers. Isolated reports of second- or third-degree atrioventricular block have been observed in patients receiving lopinavir/ritonavir who have underlying structural heart disease and pre-existing conduction disorders, or who are taking medicinal products that prolong the PR interval (e.g., verapamil or atazanavir). "Lopinavir/Ritonavir Macleods" should be used with caution in such patients.

Weight and metabolic parameters

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to improved control of the disease and lifestyle factors. Regarding increased lipid levels, there is evidence that in some cases this is a result of treatment, whereas convincing evidence linking weight gain to a specific treatment regimen is lacking. Monitoring of lipid and glucose levels should be performed according to established guidelines for the management of HIV infection. Abnormal lipid levels should be managed according to clinical practice.

Interaction with other medicinal products

The medicinal product "Lopinavir/Ritonavir Macleods" contains the active substances lopinavir and ritonavir, both of which are inhibitors of the CYP3A isoenzyme.

"Lopinavir/Ritonavir Macleods" may increase plasma concentrations of medicinal products that are primarily metabolized by CYP3A. These increased plasma concentrations of concomitantly administered drugs may enhance or prolong their therapeutic and adverse effects.

Potent inhibitors of the CYP3A4 isoenzyme, such as protease inhibitors, may enhance the effect of bedaquiline, increasing the risk of bedaquiline-related adverse reactions. Therefore, co-administration of bedaquiline and lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline and lopinavir/ritonavir may be permitted with caution. More frequent ECG monitoring and transaminase level checks are recommended.

Concomitant use of delamanid with another potent CYP3A inhibitor (lopinavir/ritonavir) may increase the amount of delamanid metabolites associated with QTc interval prolongation. Thus, if concomitant use of delamanid with lopinavir/ritonavir is necessary, frequent ECG monitoring is recommended throughout the delamanid treatment period.

Drug interactions with life-threatening consequences and fatal outcomes have been reported in patients receiving colchicine and potent CYP3A inhibitors such as ritonavir. Concomitant use with colchicine in patients with hepatic and/or renal disease is contraindicated.

The use of "Lopinavir/Ritonavir Macleods" in combination with the following agents is not recommended:

• Tadalafil for the treatment of pulmonary arterial hypertension;
• Riociguat;
• Vorapaxar;
• Fusidic acid for the treatment of bone and joint infections;
• Salmeterol;
• Rivaroxaban.

The use of "Lopinavir/Ritonavir Macleods" in combination with atorvastatin is not recommended. If there are clear indications for atorvastatin use, the lowest possible dose of atorvastatin should be prescribed, with careful safety monitoring. When using "Lopinavir/Ritonavir Macleods" in combination with rosuvastatin, caution should be exercised and low doses should be used. If HMG-CoA reductase inhibitor therapy is required, pravastatin or fluvastatin are the preferred agents.

PDE5 inhibitors

Sildenafil or tadalafil for the treatment of erectile dysfunction should be used with caution in patients taking "Lopinavir/Ritonavir Macleods". Concomitant use of "Lopinavir/Ritonavir Macleods" with these agents is expected to significantly increase their plasma concentrations and may lead to associated adverse reactions such as arterial hypotension, syncope, visual disturbances, and prolonged erection. Concomitant use of avanafil or vardenafil with lopinavir/ritonavir is contraindicated. Concomitant use of sildenafil for the treatment of pulmonary arterial hypertension and "Lopinavir/Ritonavir Macleods" is contraindicated.

Particular caution should be exercised when prescribing "Lopinavir/Ritonavir Macleods" concomitantly with medicinal products that prolong the QT interval, such as chlorpheniramine, quinidine, erythromycin, clarithromycin. Use of "Lopinavir/Ritonavir Macleods" may increase the concentration of co-administered agents and cause corresponding cardiac adverse reactions. Cardiac effects have been reported in preclinical studies of "Lopinavir/Ritonavir Macleods", thus a cardiac effect of the medicinal product cannot be excluded.

Concomitant use of the medicinal product with rifampicin is not recommended. Rifampicin in combination with "Lopinavir/Ritonavir Macleods" causes a significant reduction in lopinavir concentration, which may in turn lead to a marked reduction in its therapeutic effect. This phenomenon may be avoided by increasing the dose of "Lopinavir/Ritonavir Macleods", but this increases the risk of hepatotoxicity and gastrointestinal toxicity. Therefore, this combination should not be used unless absolutely necessary.

Concomitant use of "Lopinavir/Ritonavir Macleods" with fluticasone or other glucocorticoids metabolized by CYP3A4, such as budesonide, requires caution due to the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Other

"Lopinavir/Ritonavir Macleods" is not a medicinal product that directly treats HIV 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. Appropriate preventive measures should be followed to avoid transmission of infection. In individuals taking "Lopinavir/Ritonavir Macleods", infections associated with HIV and AIDS may still occur.

Use during pregnancy or breastfeeding

Pregnancy

When deciding on the use of antiretroviral agents for the treatment of HIV infection in pregnant women and, accordingly, for reducing the risk of "vertical" transmission of HIV from mother to newborn, data from animal studies and clinical experience in pregnant women should be considered to determine fetal safety.

The effect of lopinavir/ritonavir has been evaluated in over 3000 pregnant women, including over 1000 during the first trimester of pregnancy.

Based on post-marketing reports included in the Antiretroviral Pregnancy Registry since January 1989, no increased risk of congenital developmental defects has been observed in more than 1000 pregnant women treated during the first trimester. The frequency of congenital defects after lopinavir use in any trimester of pregnancy is comparable to that in the general population. No congenital defects suggesting a common etiology have been reported. Animal studies have demonstrated reproductive toxicity. Based on these data, the risk of developmental defects in humans is considered unlikely. Lopinavir may be used during pregnancy if clinically indicated.

Breastfeeding

Animal studies in rats have shown that lopinavir is excreted in breast milk. It is unknown whether this medicinal product is excreted in human milk. The general recommendation is that 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 affect reaction speed when driving 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 has been reported during treatment with lopinavir/ritonavir.

Method of Administration and Dosage

"Lopinavir/Ritonavir Macleods" should be prescribed by physicians experienced in the treatment of HIV infection.

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

Dosage

Adults and adolescents

The recommended standard dose of "Lopinavir/Ritonavir Macleods" tablets is 400/100 mg (2 tablets of 200/50 mg) twice daily, independent of food intake, or 800/200 mg (4 tablets of 200/50 mg) once daily, independent of food intake. For patients with fewer than three lopinavir-associated resistance mutations, once-daily dosing may be considered, taking into account the risk of reduced durability of virological suppression (see section "Pharmacodynamics") and an increased risk of diarrhea (see section "Adverse Reactions"), compared to the recommended standard twice-daily regimen.

Children from 2 years of age

"Lopinavir/Ritonavir Macleods" 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.

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

BSA (m²) = √ (height [cm] × body weight [kg] / 3600).

For children with body weight <40 kg or body surface area (BSA)* between 0.5 and 1.4 m² who are able to swallow tablets whole, "Lopinavir/Ritonavir Macleods" 100 mg/25 mg tablets should be used. For children unable to swallow tablets, lopinavir/ritonavir should be administered as an oral solution.

Before prescribing "Lopinavir/Ritonavir Macleods" 100/25 mg tablets to infants and young children, their ability to swallow the tablets whole should be assessed.

Dosage recommendations for "Lopinavir/Ritonavir Macleods" 100/25 mg tablets based on body weight and BSA in children.

Table 8

For pediatric patients (without concomitant use of efavirenz or nevirapine)*
Body weight (kg)	Body surface area (m²)	Recommended dose of lopinavir/ritonavir (mg) twice daily. The required dose can be achieved by using two formulations of Lopinavir/Ritonavir Mylan: 100/25 mg and 200/50 mg
From 15 to 25 kg	≥ 0.5 to <0.9	200/50 mg
> 25 to 35 kg	≥ 0.9 to <1.4	300/75 mg
Greater than 35 kg	≥ 1.4	400/100 mg

*Dosing recommendations based on body weight are derived from limited data.

If convenient for patients, Lopinavir/Ritonavir Macleods 200/50 mg tablets may be used alone or in combination with Lopinavir/Ritonavir Macleods 100/25 mg tablets to achieve the recommended dose.

Children under 2 years of age

The safety and efficacy of Lopinavir/Ritonavir Macleods in children under 2 years of age have not been established. Dosing recommendations cannot be made.

Concomitant therapy: efavirenz, nevirapine

Dosing recommendations for Lopinavir/Ritonavir Macleods 100/25 mg tablets according to ART regimens when co-administered with efavirenz or nevirapine in children.

Table 9

BSA (m²)	Recommended dose of lopinavir/ritonavir (mg) twice daily. The required dose can be achieved by using two formulations of the medicinal product "Lopinavir/Ritonavir Macleods": 100/25 mg and 200/50 mg
≥ 0.5 to < 0.8	200/50 mg
≥ 0.8 to < 1.2	300/75 mg
≥ 1.2 to < 1.4	400/100 mg
≥ 1.4	500/125 mg

If convenient for patients, Lopinavir/Ritonavir Macleods 200/50 mg tablets may be used alone or in combination with Lopinavir/Ritonavir Macleods 100/25 mg tablets to achieve the recommended dose.

Hepatic impairment

In HIV-infected patients with mild to moderate hepatic impairment, lopinavir exposure is increased by approximately 30%; however, this increase is not considered clinically significant. There is no data available in patients with severe hepatic impairment. Lopinavir/Ritonavir Macleods tablets are not recommended for use in these patients.

Renal impairment

Renal clearance of lopinavir and ritonavir is negligible; therefore, increased plasma concentrations are not expected in patients with renal impairment. Since 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 during pregnancy and in the postpartum period.
• Once-daily administration of lopinavir/ritonavir is not recommended in pregnant women due to lack of pharmacokinetic and clinical data.

Children

Lopinavir/Ritonavir Macleods medicinal product is indicated for use in children aged 2 years and older. The safety and efficacy of lopinavir/ritonavir in children under 2 years of age have not been established.

Overdose

To date, clinical experience with acute overdose of Lopinavir/Ritonavir Macleods tablets in humans is limited.

Symptoms of overdose observed in dogs included salivation, vomiting, and diarrhea/defecation disorders.

Signs of toxic effects observed in mice, rats, and dogs included decreased activity, ataxia, lethargy, dehydration, and tremor.

There is no specific antidote for overdose of Lopinavir/Ritonavir Macleods. Management of overdose 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 Lopinavir/Ritonavir Macleods 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 2600 patients in Phase II–IV clinical trials, of whom more than 700 patients received the 800/200 mg dose (6 capsules or 4 tablets) once daily. In combination with nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir was used in some studies in conjunction with efavirenz or nevirapine.

The most commonly reported adverse reactions associated with lopinavir/ritonavir therapy during clinical trials were diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. The risk of diarrhea may be higher when "Lopinavir/Ritonavir Macleods" 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 studies in Phase II–IV 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 during lopinavir/ritonavir therapy have been received.

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

The events listed below were identified as adverse reactions. The frequency category includes all reported adverse reactions of moderate to severe intensity, regardless of the assessment of causality in individual cases. Adverse reactions are listed by system organ class and classified by frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity. Events listed as "not known" were identified during post-marketing surveillance.

Infections and infestations

Very common: upper respiratory tract infection.

Common: lower respiratory tract infections, skin infections including phlegmon, folliculitis, and furuncles.

Blood and lymphatic system disorders

Common: anemia, leukopenia, neutropenia, lymphadenopathy.

Immune system disorders

Common: hypersensitivity, including urticaria and angioedema.

Uncommon: immune reconstitution syndrome.

Endocrine disorders

Uncommon: hypogonadism.

Metabolism and nutrition disorders

Common: changes in plasma glucose concentration, including diabetes mellitus; hypertriglyceridemia, hypercholesterolemia, weight loss, decreased appetite.

Uncommon: weight gain, increased appetite.

Psychiatric disorders

Common: anxiety.

Uncommon: sleep disorders, decreased libido.

Nervous system disorders

Common: headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia.

Uncommon: cerebrovascular disorders, seizures, dysgeusia, ageusia, tremor.

Eye disorders

Uncommon: visual disturbances.

Ear and labyrinth disorders

Uncommon: tinnitus, vertigo.

Cardiac disorders

Uncommon: atherosclerosis (including cases complicated by myocardial infarction), atrioventricular block, tricuspid valve insufficiency.

Vascular disorders

Common: arterial hypertension.

Uncommon: deep vein thrombosis.

Gastrointestinal disorders

Very common: nausea, diarrhea.

Common: pancreatitis, vomiting, gastroesophageal reflux disease, gastroenteritis and colitis, abdominal pain (upper and lower), bloating, dyspepsia, hemorrhoids, flatulence.

Uncommon: gastrointestinal hemorrhage, including gastric and duodenal ulcer, duodenitis, gastritis and rectal bleeding, stomatitis and oral ulcers, fecal incontinence, constipation, dry mouth.

Hepatobiliary disorders

Common: hepatitis (including increased activity of AST, ALT, and GGT [gamma-glutamyl transferase]).

Uncommon: jaundice, hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia.

Skin and subcutaneous tissue disorders

Common: rash, including maculopapular rash, dermatitis (including eczema and seborrheic dermatitis), night sweats, pruritus.

Uncommon: alopecia, capillary fragility, vasculitis.

Rare: Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders

Common: myalgia, musculoskeletal pain including arthralgia and back pain, muscle cramps, muscle weakness.

Uncommon: rhabdomyolysis, osteonecrosis.

Renal and urinary disorders

Uncommon: decreased creatinine clearance, nephritis, hematuria.

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 general malaise.

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 CYP3A4, 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

Body weight and levels of lipids and glucose in blood may increase during antiretroviral therapy.

In HIV-infected patients with advanced immunosuppression at the start of combination antiretroviral therapy (cART), inflammatory reactions to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (e.g., Graves' disease and autoimmune hepatitis) have also been reported; however, these may manifest many months after initiation of treatment.

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

Children

In children aged 2 years and older, the safety profile is similar to that observed in adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at temperatures not exceeding 30 °C in a dry, light-protected place.

Keep out of reach of children.

Packaging

Tablets 200 mg / 50 mg
120 tablets in a plastic bottle with a polypropylene child-resistant closure, containing two sachets of silica gel.

Tablets 100 mg / 25 mg
60 tablets in a plastic bottle with a polypropylene child-resistant closure, containing two sachets of silica gel.

Prescription status. Prescription only.

Manufacturer. MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer’s address and place of business

Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.