Calidavir pills 200mg+50mg, 60pcs

Composition

Active ingredient:

Lopinavir 200 mg,

Ritonavir 50 mg,

Auxiliary substances:

Each film-coated tablet contains:

The core:  hyprolose (hydroxypropyl cellulose) to 40.0 mg;

carboximetilkrahmal sodium (primogel) was 30.0 mg;

copovidone (kollidon VA 64) -11,0 mg;

silicon dioxide colloidal (Aerosil brand A-300) – 14.0 mg;

croscarmellose sodium – 20,0 mg;

lactose monohydrate – 140,0 mg;

macrogol 6000 (polyethylene glycol 6000) – 5.0 mg;

sodium fumarate – 5.0 mg;

Polysorbate 80 (tween-80) – 5.0 mg.

Film shell:

Finished water-soluble film shell -14.0 mg (Shell composition: hypromellose (hydroxypropylmethylcellulose) – 74.2%, macrogol 6000 (polyethylene glycol 6000) – 14.3%, titanium dioxide-3.5%, talc – 2.3%, iron oxide red dye-1.4%, iron oxide yellow dye-4.3%).

Pharmacological action

Antiviral [HIV] agentath:

J. 05. A. R. 10 Lopinavir + Ritonavir

J. 05. A. R Combinations of antiviral drugs active against HIV

Pharmacodynamics : Kalidavir® is a combination drug that contains lopinavir and ritonavir.

Lopinavir is an inhibitor of HIV-1 and HIV-2 proteases of the human immunodeficiency virus (HIV) and provides antiviral activity of the drug. Inhibition of HIV proteases interferes with the synthesis of viral proteins and prevents the cleavage of the gag-pol polypeptide, which leads to the formation of an immature and unable to infect virus.

Ritonavir inhibits the CYP3A-mediated metabolism of lopinavir in the liver, which leads to an increase in the concentration of lopinavir in blood plasma. Ritonavir is also an HIV protease inhibitor.

Resistance

Isolation of resistant strains in vitro

A strain of HIV-1 with reduced sensitivity to lopinavir was isolated in vitro. HIV-1 was passed in vitro separately with lopinavir and a combination of lopinavir and ritonavir at concentrations equivalent to the plasma concentrations observed during treatment with lopinavir/ritonavir. Based on genotypic and phenotypic studies of the virus subtypes isolated during passage, it can be assumed that the presence of ritonavir at these concentrations does not significantly affect the isolation of lopinavir-resistant virus subtypes.

Overall, an in vitro study of the characteristics of phenotypic cross-resistance between lopinavir and other protease inhibitors indicates that a decrease in sensitivity to lopinavir is closely related to a decrease in sensitivity to ritonavir and indinavir, but is not associated with a decrease in sensitivity to amprenavir, saquinavir and nelfinavir.

Resistance study in patients who did not have a history of antiretroviral therapy

In clinical trials with a limited number of strains studied, no selective resistance to lopinavir was observed in patients without significant resistance to protease inhibitors at baseline.

Resistance study in patients treated with protease inhibitors

The occurrence of resistance to lopinavir in patients who were unsuccessfully treated with basic protease inhibitors was studied in long-term studies involving 19 patients treated with protease inhibitors, in two Phase

II studies and one Phase III study. Patients had incomplete viral suppression or a viral recoil phenomenon resulting from a response to lopinavir/ritonavir and showing increasing resistance in vitro between baseline and recoil (defined as the occurrence of new mutations or a twofold change in phenotypic sensitivity to lopinavir).

Increasing resistance was characteristic of patients characterized by the presence of initial strains that had undergone several mutations during treatment with protease inhibitors, with no more than 40 times reduced initial sensitivity to lopinavir. Mutations V82A, I54V, and M46I occurred most frequently. Mutations of L33F, I50V, and V32I were also observed in combination with I47V/A. 19 strains showed a three-to four-fold increase in the concentration of 50% inhibition (IC50) in comparison with the original strains (from 6.2 to 43-fold, in comparison with wild types of the virus).

There is a genotypic correlation of decreased phenotypic sensitivity to lopinavir in viruses isolated after treatment with other protease inhibitors. In vitro antiviral activity of lopinavir was evaluated against 112 strains isolated from patients who were unsuccessfully treated with one or more protease inhibitors.

Within this group, the following mutations in the HIV protease were associated with reduced in vitro sensitivity to lopinavir:  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 median EC50 of lopinavir against isolates with mutations 0-3,4-5,6-7, and 8-10 at the above amino acid positions was 0.8,2.7, and 13.5, respectively, which is 44 times higher than the EC50 of wild HIV types. All 16 virus types that showed a 20-fold increase in sensitivity had mutations at positions 10,54,63 and 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20,24,46,53,71, and 90.

In addition to the above mutations, V32I and I47A mutations were observed in recurrent strains with reduced sensitivity to lopinavir in patients treated with protease inhibitors and treated with lopinavir/ritonavir.

In patients treated with lopinavir / ritonavir, mutations I47A and L76V were detected in recurrent strains with reduced sensitivity to lopinavir. The assessment of the importance of individual mutations or sets of mutations may change with additional data. It is recommended that you always consult about the current system for evaluating the results of resistance studies.

Antiviral activity of lopinavir in patients who were unsuccessfully treated with protease inhibitors

The clinical significance of reduced sensitivity to lopinavir in vitro was studied by evaluating the virological response to treatment with lopinavir/ritonavir, taking into account the initial viral genotype and phenotype, in 56 patients who did not receive a positive effect from treatment with various protease inhibitors. The EC50 value of lopinavir based on 56 source virus strains exceeded the EC50 value of wild HIV types in the range from 0.6 to 98 – fold. After 48 weeks of treatment with lopinavir / ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, the plasma level of HIV RNA was A 10-40-fold and more than 40-fold decrease in sensitivity to lopinavir, respectively, compared to baseline. Also, a virological response was observed in 91% (21/23),71% (15/21) and 33% (2/6) of patients with 0-5,6-7, and 8-10 mutations in the above-mentioned HIV protease mutations associated with reduced sensitivity to lopinavir in vitro. Since these patients have not previously taken lopinavir / ritonavir or efavirenz, part of the effect can be attributed to the antiviral activity of efavirenz, especially for patients with a highly resistant type of virus. The study does not involve a control group of patients who did not take lopinavir/ritonavir.

Cross-resistance

Efficacy of other protease inhibitors against strains that developed increasing resistance to lopinavir after treatment with lopinavir/ritonavir in patients taking protease inhibitors: the presence of cross-resistance to other prosthetic inhibitors was analyzed in 18 recurrent strains that showed increased resistance to lopinavir during three Phase II studies and one Phase II study of lopinavir/ritonavir in patients receiving protease inhibitors.

The median IC50 of lopinavir for these 18 strains in the initial state and with the phenomenon of virological impact was higher in the range from 6.9 to 63 times, respectively, compared with wild types of virus. As a rule, strains with virological impact both retain (with cross-resistance initially) and develop significant resistance to indinavir, saquinavir, and atazanavir.

A moderate decrease in amprenavir activity was observed with a median IC50 multiplicity of 3.7 to 8 for the initial and recurrent strains, respectively. The strains retained sensitivity to tipranavir with a median increase in IC50 at the initial level and with the phenomenon of virological return with a multiplicity of 1.9 to 1.8, respectively, compared with wild types of the virus. For more information on tipranavir, including genotypic response rates in the treatment of lopinavir-resistant HIV-1 infection, please refer to the tipranavir instructions for use.

Pharmacokinetics:

The pharmacokinetics of lopinavir in combination with ritonavir were studied in healthy volunteers and HIV-infected patients; no significant differences were found between the two groups. Lopinavir is almost completely metabolized by the CYP3A isoenzyme. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma concentrations.

When using lopinavir/ritonavir at a dose of 400/100 mg twice a day, the average steady-state plasma concentrations of lopinavir in HIV-infected patients were 15-20 times higher than those of ritonavir, and the plasma concentration of ritonavir was less than 7% of the concentration when taking ritonavir at a dose of 600 mg twice a day. The EC50 of lopinavir in vitro is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

Suction

In a pharmacokinetic study involving HIV-positive patients (n=19), when taking 400/100 mg of lopinavir/ritonavir twice daily with food for three weeks, the average value of the maximum plasma concentration of lopinavir (Cmax) was 9.8 ±3.7 mcg/ml, observed approximately four hours after taking the drug.

The average steady-state concentration before the morning dose was 7.1 ±2.9 mcg / ml and the minimum concentration within the dosage interval was 5.5 ± 2.7 mcg / ml. Area under the concentration-time curve (AUC) lopinavir within 12 hours after taking the drug averaged 92.6 ± 36.7 mcg-h / ml. The absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established.

Effect of pisha on oral absorption

Taking a single dose of 400/100 mg lopinavir / ritonavir in tablet dosage form after a meal (high fat content,872 kcal,56% fat) did not lead to significant changes in Cmax and AUCinf compared to fasting. Therefore, the drug Kalidavir * in tablet dosage form can be taken with or without food.

Distribution

At steady state, approximately 98-99% of lopinavir is bound to plasma proteins. Lopinavir binds to alpha-1-acid glycoprotein (AH) and albumin, but has a higher affinity for AH. At steady state, the binding of lopinavir to plasma proteins remains constant in the range of registered concentrations created after taking 400/100 mg of lopinavir / ritonavir twice a day, and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

In vitro studies have shown that lopinavir mainly undergoes oxidative metabolism involving the cytochrome P450 system of hepatocytes, mainly under the influence of the CYP3A isoenzyme. Ritonavir is a potent inhibitor of the CYP3A4 isoenzyme, which inhibits the metabolism of lopinavir, which increases the concentration of lopinavir in blood plasma. After a single dose of 400/100 mg of lopinavir / ritonavir (with labeled 14C-lopinavir),89% of radioactivity was provided by the original drug. At least 13 oxidative metabolites of lopinavir have been identified in humans. Ritonavir is able to induce cytochrome P450 isoenzymes, which leads to the induction of its own metabolism. During long-term use, lopinavir concentrations before the next dose decreased over time, stabilizing after approximately 10-16 days.

Deduction

After taking 400/100 mg of 14C-lopinavir/ritonavir after eight days, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the 14C-lopinavir dose are detected in the urine and feces, respectively. At the same time, unchanged lopinavir is 2.2% and 19.8%, respectively. After prolonged use, less than 3% of the lopinavir dose is excreted unchanged through the kidneys. The clearance (CL/F) of lopinavir when taken orally is 5,98 +/- 5,75 l/h.

Once-daily

use The pharmacokinetics of lopinavir/ritonavir with a frequency of once-daily use were evaluated in HIV-infected patients who had not previously received antiretroviral therapy. Lopinavir / ritonavir 800/200 mg was used in combination with emtricitabine 200 mg and tenofovir 300 mg once daily.

With long-term use of 800/200 mg of lopinavir/ritonavir once a day for 4 weeks during meals, the average maximum plasma concentration of lopinavir (Cmax) was 11.8 ± 3.7 mcg/ml and reached approximately 6 hours after use. The average steady-state concentration of lopinavir before the morning dose was 3.2 ± 2.1 mcg / ml, the minimum concentration within the dosage interval was 1.7 ± 1.6 mcg/ml. The AUC of lopinavir at the 24-hour interval of use averaged 154.1 ± 61.4 mcg-h / ml.

Special patient groups

Gender, race and age

The pharmacokinetics of lopinavir have not been studied in elderly patients. No gender-dependent pharmacokinetic differences were observed in adult patients. No clinically significant race-dependent pharmacokinetic differences were found.

Children

The pharmacokinetics of lopinavir / ritonavir at 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily were studied in a total of 53 patients under 12 years of age. The dosage regimen of 230/57.5 mg/m2 twice daily without nevirapine and 300/75 mg/m2 twice daily with nevirapine provided plasma concentrations of lopinavir similar to those obtained in adult patients taking 400/100 mg twice daily (without nevirapine). Taking lopinavir/ritonavir once daily in children has not been studied.

Mean steady-state AUC, Cmax, and Cmin of lopinavir after taking lopinavir/ritonavir 230/57.5 mg/m2 twice daily without nevirapine (n=12) were 72.6 ±31.1 mcg/ml; 8.2 ± 2.9 and 3.4 ± 2.1 mcg/ml, respectively; and 85.8 ± 36.9 mcg/ml,10.0 ±3.3 and 3.6 ± 3.5 mcg/ml, respectively, after taking 300/75 mg/m2 twice daily with nevirapine (n=12). The nevirapine regimen was 7 mg/kg twice daily (in patients from six months to eight years) or 4 mg / kg twice daily (in patients over eight years of age).

Renal insufficiency

The pharmacokinetics of lopinavir have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is insignificant, a decrease in total clearance in patients with renal insufficiency is not expected.

Liver failure

Lopinavir is primarily metabolized and excreted by the liver. Combined dosing of lopinavir / ritonavir 400/100 mg twice daily in patients simultaneously infected with HIV and hepatitis C virus with moderate to mild hepatic impairment resulted in a 30% increase in lopinavir AUC and a 20% increase in Cmax compared to HIV-infected patients with normal liver function.

The binding of lopinavir to plasma proteins was lower in mild and moderate hepatic insufficiency compared to the control groups (99.09% compared to 99.31%, respectively). Lopinavir / ritonavir has not been studied in patients with severe hepatic insufficiency.

Pregnancy and postpartum

Pharmacokinetic data show that there is a slight decrease in the AUC and Cmax of lopinavir in pregnant women in the third trimester of pregnancy compared to the second trimester of pregnancy.

Indications

Treatment of HIV infection in adults and children over 3 years of age as part of combination therapy.

Use during pregnancy and lactation

Pregnancy

The effects of lopinavir/ritonavir were evaluated in 3366 women during pregnancy. Available data indicate that lopinavir/ritonavir does not increase the risk of common serious congenital malformations compared to the baseline incidence of congenital malformations. If necessary, lopinavir/ritonavir can be used during pregnancy.

Breast-feeding period

Studies in rats have shown that lopinavir is excreted in the mother’s milk. It is not known whether this drug is excreted in human milk. Women should stop breastfeeding.

Contraindications

-Hypersensitivity to lopinavir, ritonavir or to the auxiliary components of the drug.

– Severe liver failure.

– Concomitant use of drugs whose clearance is significantly dependent on metabolism by the CYP3A isoenzyme. These drugs include: astemizole, blonanserin, terfenadine, midazolam (for oral use), triazolam, cisapride, pimozide, salmeterol, sildenafil (only if used for the treatment of pulmonary hypertension, see “Interaction with other drugs”), tadalafil (only if used for the treatment of pulmonary hypertension, see “Interaction with other drugs”), vardenafil, avanafil, voriconazole, ergot alkaloids (for example, ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine.

– Simultaneous use with St. John’s wort, boceprevir, simeprevir.

– Concomitant use of a standard dose of Kalidavir with rifampicin.

– Concomitant use of Kalidavir and tipranavir with a low dose of ritonavir.

– Children under 3 years of age (for this dosage form).

– Use of Kalidavir once daily in combination with carbamazepine, phenobarbital or phenytoin.

– Use Kalidavir once daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

– Use of Kalidavir once daily in children (under 18 years of age).

– Use Kalidavir once daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

– Concomitant use with ketoconazole and itraconazole in high doses (more than 200 mg / day).

– Simultaneous use with dronedarone.

– Concomitant use with colchicine in patients with renal and/or hepatic insufficiency.

– Use of lopinaviThere were no changes in the pharmacokinetics of lopinavir when lopinavir/ritonavir was co-administered with stavudine and lamivudine compared to lopinavir/ritonavir monotherapy.

Didanosine

Didanosine is recommended to be taken on an empty stomach; therefore, in combination with didanosine, lopinavir/ritonavir tablets should be taken one hour before or two hours after a meal.

Zidovudine and abacavir

Lopinavir / ritonavir induces glucuronidation, so the drug can reduce the plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.

Tenofovir

The study showed that lopinavir / ritonavir increases the concentration of tenofovir in blood plasma. The mechanism of this interaction is unknown. Patients taking lopinavir / ritonavir and tenofovir should be monitored for tenofovir-related side effects, including impaired renal function.

Other NRTs

Increased creatine phosphokinase (CPK) activity, myalgia, myositis and, rarely, rhabdomyolysis have been reported with HIV protease inhibitors, especially in combination with NRTIs.

Non-nucleoside reverse transcriptase inhibitors(NNRTIs)

Nevirapine

There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. The results of a study involving HIV-positive children showed a decrease in lopinavir concentrations during concomitant use with nevirapine. It is believed that the effect of nevirapine on HIV-positive adult patients may be similar to that in children, which may lead to a decrease in the concentration of lopinavir. The clinical significance of this pharmacokinetic interaction is unknown.

In patients who have previously received antiretroviral therapy or who have phenotypic or genotypic signs of a significant decrease in sensitivity to lopinavir, when lopinavir / ritonavir is co-administered with nevirapine, it may be necessary to increase the dose of lopinavir / ritonavir to 500/125 mg twice daily. Lopinavir / ritonavir in combination with nevirapine is contraindicated once a day.

Efavirenz

Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg (two tablets of 200/50 mg + one tablet of 100/25 mg) twice a day does not affect the concentration of lopinavir in blood plasma in comparison with the use of lopinavir/ritonavir 400/100 mg twice a day without efavirenz. Increasing the dose of lopinavir/ritonavir tablets to 600/150 mg (three (3) 200/50 mg tablets) twice daily when co-administered with efavirenz increased the plasma concentration of lopinavir by approximately 36% and the concentration of ritonavir by approximately 56-92% compared to the dose of lopinavir/ritonavir 400/100 mg (two (2) 200/50 mg tablets) when taken twice daily without efavirenz (see section “Dosage and use”).

Efavirenz and nevirapine induce the CYP3A isoenzyme and, thus, can reduce the plasma concentrations of other viral protease inhibitors when used in combination with lopinavir/ritonavir.

Concomitant use of lopinavir / ritonavir with both efavirenz and nevirapine once daily is contraindicated.

Delavirdin

Delavirdine is able to increase the concentration of lopinavir in blood plasma.

Rilpivirine

When rilpivirine is co-administered with lopinavir/ritonavir, it is possible to increase the concentration of rilpivirine, but changes in the dose of lopinavir/ritonavir are not required. use and selection of the dose of rilpivirine should be made in accordance with its instructions for use.

Etravirine

Concomitant use of etravirine with lopinavir/ritonavir may increase the concentration of etravirine, but changes in the dose of lopinavir/ritonavir are not required. Prescribing and selecting the dose of etravirine should be done in accordance with its instructions for use.

HIV protease inhibitors

Amprenavir

Lopinavir / ritonavir may increase plasma concentrations of amprenavir (taking amprenavir at a dose of 750 mg twice daily plus lopinavir / ritonavir leads to an increase in AUC, a similar Cmax, an increase in Cmin relative to amprenavir at a dose of 1200 mg twice daily). Concomitant use of lopinavir / ritonavir and amprenavir reduces the concentration of lopinavir (see section “Dosage and use”). Concomitant use of lopinavir / ritonavir with amprenavir once daily is contraindicated.

Fosamprenavir

The study showed that concomitant use of lopinavir / ritonavir with fosamprenavir reduces the concentrations of fosamprenavir and lopinavir. Adequate safety and efficacy doses of fosamprenavir and lopinavir/ritonavir in combination have not been established.

Co-use of an increased dose of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients who had previously taken HIV protease inhibitors resulted in an increase in the frequency of gastrointestinal (GI) side effects and an increase in blood triglyceride concentrations without enhancing the antiviral effect, compared with the standard dose of fosamprenavir/ritonavir.

Indinavir

Lopinavir/ritonavir may increase indinavir concentrations (when combined with indinavir at a dose of 600 mg 2 times a day with simultaneous use of lopinavir/ritonavir, there is a decrease in Cmax, an increase in Cmin compared to taking indinavir three times a day at a dose of 800 mg, while AUC is similar). The indinavir dose may need to be reduced when lopinavir/ritonavir is co-administered 400/100 mg twice daily. use of lopinavir / ritonavir in combination with indinavir once daily has not been studied.

Nelfinavir

Lopinavir / ritonavir may increase the concentrations of nelfinavir and the nelfinavir metabolite M8 (when taking nelfinavir 1000 mg twice daily and lopinavir / ritonavir compared to taking nelfinavir 1250 mg twice daily, similar AUC, similar Cmax and increased Cmin are observed). Concomitant use of lopinavir / ritonavir and nelfinavir leads to a decrease in lopinavir concentrations (see section “Dosage and use”).

Concomitant use of lopinavir / ritonavir with nelfinavir once daily is contraindicated.

Ritonavir

When lopinavir/ritonavir was co-administered with an additional 100 mg of ritonavir twice daily, the AUC of lopinavir increased by 33% and Cmin increased by 64% compared to lopinavir/ritonavir 400/100 mg twice daily.

Saquinavir

Lopinavir / ritonavir increases saquinavir concentrations (saquinavir 800 mg twice daily in combination with lopinavir / ritonavir leads to an increase in AUC, Cmax and Cmin compared to saquinavir 1200 mg three times daily). The dose of saquinavir co-administered with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. use of lopinavir / ritonavir in combination with saquinavir once daily has not been studied.

Tipranavir

When tipranavir (500 mg twice daily) is co-administered with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily), the AUC and Cmin of lopinavir decrease by 55% and 70%, respectively. Concomitant use of lopinavir / ritonavir and tipranavir with a low dose of ritonavir is contraindicated.

Hepatitis C virus protease inhibitors

Telaprevir

Concomitant use of lopinavir / ritonavir with telaprevir leads to a decrease in the steady-state concentration of telaprevir without changing the steady-state concentration of lopinavir. Concomitant use of telaprevir and lopinavir / ritonavir is not recommended.

Boceprevir

Concomitant use of lopinavir / ritonavir with boceprevir leads to a decrease in the steady-state concentrations of boceprevir and lopinavir. Concomitant use of lopinavir / ritonavir with boceprevir is contraindicated.

Simeprevir

Concomitant use of simeprevir with lopinavir / ritonavir may increase the concentration of simeprevir. Concomitant use of lopinavir / ritonavir and simeprevir is contraindicated.

Antiviral drugs – inhibitors of the CCR5 chemokine receptor

Maravirok

Simultaneous use of maraviroc with lopinavir / ritonavir leads to an increase in the concentration of maraviroc in blood plasma. When used concomitantly with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced. The dosage of maraviroc should be selected in accordance with its instructions for use.

Integrase inhibitors

Raltegravir

When lopinavir / ritonavir is co-administered with raltegravir, the AUC and Cmax of raltegravir do not change. There was a 30% reduction from 12 raltegravir. The pharmacokinetic parameters of lopinavir did not change. When lopinavir / ritonavir is co-administered with raltegravir, no dose adjustment of lopinavir/ritonavir is required.

Other medications

Narcotic analgesics

Fentanyl

Since lopinavir / ritonavir inhibits the CYP3A4 isoenzyme, it is possible to increase the concentration of fentanyl in blood plasma.

Therapeutic and side effects (including respiratory depression) should be carefully monitored when lopinavir/ritonavir and fentanyl are co-administered.

Antiarrhythmic drugs

Bepridil, lidocaine and quinidine

Concomitant use with lopinavir / ritonavir may increase the concentrations of these drugs. Caution should be exercised when using these drugs and monitoring therapeutic concentrations, if possible.

Dronedaron

Dronedarone concentrations may increase when used concomitantly with lopinavir/ritonavir.Concomitant use with lopinavir / ritonavir is contraindicated.

Digoxin

An analysis of the literature showed that concomitant use of ritonavir (300 mg every 12 hours) and digoxin resulted in a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin, while monitoring the concentration of digoxin in the blood serum. Special care should be taken when prescribing lopinavir/ritonavir in patients taking digoxin, due to the strong inhibitory effect of ritonavir on P-glycoprotein and the resulting significant increase in digoxin concentrations.

In those patients who started digoxin during lopinavir/ritonavir therapy, a less significant increase in digoxin concentrations should be expected.

Medications that extend the QT interval

Under the influence of lopinavir / ritonavir, concentrations of phenyramine, quinidine, erythromycin, clarithromycin may increase, followed by prolongation of the QT interval and the development of cardiac side effects. Special care should be taken when using lopinavir/ritonavir concomitantly with drugs that prolong the QT interval. Anticancer agents (e. g. dasatinib, nilotinib, vincristine, vinblastine)

It is possible to increase the serum concentrations of these drugs when used simultaneously with lopinavir / ritonavir, which may lead to increased side effects usually associated with taking these antitumor drugs.

The dosage of nilotinib and dasatinib should be selected in accordance with the instructions for use of these drugs.

Anticoagulants

Possible effect on warfarin concentrations when used concomitantly with lopinavir / ritonavir. It is recommended to monitor the INR (International Normalized ratio).

Rivaroxaban

Concomitant use of rivaroxaban with lopinavir / ritonavir may increase the concentration of rivaroxaban, which may lead to an increased risk of bleeding. Concomitant use of rivaroxaban with lopinavir / ritonavir is not recommended.

Antidepressants

Bupropion

Concomitant use of bupropion with lopinavir/ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, then it should be carried out under close clinical monitoring of the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.

Trazodone

Concomitant use of ritonavir and trazodone may lead to an increase in the concentration of trazodone in the blood plasma. Side effects were observed: nausea, dizziness, hypotension and fainting. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, should be used with caution and reduce the dose of trazodone.

Antipsychotic drugs

Quetiapine, blonanserin and pimozide

Since lopinavir / ritonavir is an inhibitor of the CYP3A isoenzyme, the concentration of quetiapine, blonanserin and pimozide in blood plasma may increase. Concomitant use of lopinavir / ritonavir and quetiapine, blonanserin and pimozide is contraindicated. Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

It is known that these drugs can induce the CYP3A4 isoenzyme and, thus, reduce the concentration of lopinavir. Concomitant use of lopinavir / ritonavir once daily in combination with phenobarbital, phenytoin or carbamazepine is contraindicated.

In addition, the concomitant use of phenytoin and lopinavir / ritonavir leads to a moderate decrease in steady-state concentrations of phenytoin.

Concentrations of phenobarbital, phenytoin, and carbamazepine should be monitored when administered concomitantly with lopinavir / ritonavir.

Lamotrigine and valproic acid

Concomitant use of these drugs with lopinavir/ritonavir resulted in a decrease in lamotrigine and valproic acid concentrations. The decrease in lamotrigine concentration reached 50%. These drug combinations should be used with caution. When these drugs are co-administered with lopinavir/ritonavir, especially during the dose selection period, it may be necessary to increase the dose of lamotrigine or valproic acid, as well as monitor their plasma concentrations.

For patients who start or stop taking Kalidavir® during lamotrigine therapy, the plasma lamotrigine concentration should be monitored before starting co-use with Kalidavir®, during the first 2 weeks of co-use, or within 2 weeks after discontinuation of Kalidavir® to determine whether lamotrigine dosage changes are necessary.

No lamotrigine dose adjustment is required for patients who are already taking Kalidavir and are starting to take lamotrigine.

Sleeping pills

Midazolam for oral use and triazolam

Since lopinavir / ritonavir inhibits the CYP3A isoenzyme, the concentration of midazolam and triazolam in blood plasma may increase, while the risk of severe sedation and respiratory failure increases. Concomitant use of lopinavir / ritonavir and triazolam is contraindicated.

Concomitant oral use of midazolam in combination with lopinavir / ritonavir is contraindicated. It is allowed to use midazolam parenterally with caution in combination with lopinavir / ritonavir. In the latter case, the patient should be admitted to the intensive care unit and carefully monitored. In case of respiratory depression and/or prolonged sedation, appropriate treatment should be prescribed. Timely dose adjustment of midazolam is necessary, especially with repeated use.

Ergot alkaloids

Dihydroergotamine, ergonovine, ergotamine and methylergonovine

An increase in the plasma concentration of ergot derivatives leads to an increase in its toxicity, including vasospasm and ischemia. Concomitant use with lopinavir / ritonavir is contraindicated.

Drugs that regulate the motor function of the gastrointestinal tract

Cisapride

An increase in the plasma concentration of cisapride increases the risk of severe arrhythmia. Concomitant use with lopinavir / ritonavir is contraindicated.

Antihistamines

Astemizole and terfenadine

Increased plasma concentrations of astemizole and terfenadine increase the risk of severe arrhythmia. Concomitant use with lopinavir / ritonavir is contraindicated.

Beta-2-adrenomimetics

Salmeterol

Since lopinavir / ritonavir inhibits the CYP3A isoenzyme, the concentration of salmeterol in blood plasma may increase. Concomitant use of lopinavir / ritonavir and salmeterol may increase the risk of cardiovascular side effects associated with salmeterol, including prolongation of the QT interval, palpitation sensation, and sinus tachycardia.

Concomitant use of lopinavir / ritonavir and salmeterol is contraindicated.

Alfa-1-adrenoblockers

Alfuzosin

Since lopinavir / ritonavir inhibits the CYP3A isoenzyme, the concentration of alfuzosin in blood plasma may increase, while increasing the risk of developing severe arterial hypotension. Concomitant use of lopinavir / ritonavir and alfuzosin is contraindicated.

Antiarrhythmic drugs

Amiodarone

Since lopinavir / ritonavir inhibits the CYP3A isoenzyme, the concentration of amiodarone in blood plasma may increase, while increasing the risk of arrhythmias and other adverse reactions associated with the use of amiodarone. Concomitant use of lopinavir / ritonavir and amiodarone is contraindicated.

Antifungal products

Serum concentrations of ketoconazole and itraconazole may increase under the influence of lopinavir/ritonavir. The use of ketoconazole and itraconazole in high doses (more than 200 mg/day) together with lopinavir / ritonavir is contraindicated.

Voriconazole

The study showed that concomitant use of ritonavir at a dose of 100 mg every 12 hours reduces the steady-state AUC of voriconazole by an average of 39%; concomitant use of lopinavir/ritonavir and voriconazole is contraindicated.

Medications for the treatment of gout

Concomitant use of lopinavir / ritonavir with colchicine in patients with renal and/or hepatic insufficiency is contraindicated due to the possible increased risk of colchicine-related side effects, such as neuromuscular toxicity (including rhabdomyolysis). It is necessary to reduce the dose of colchicine or discontinue colchicine therapy in patients with normal renal or hepatic function, if therapy with lopinavir/ritonavir is required. For more information, see the instructions for use on colchicine.

Antibacterial agents

Lopinavir/ritonavir may cause a moderate increase in clarithromycin AUC. In patients with hepatic impairment, the dose of clarithromycin should be reduced when administered concomitantly with lopinavir / ritonavir. In patients with renal insufficiency (with creatinine clearance Therefore, caution should be exercised when concomitantly using clarithromycin and lopinavir/ritonavir in patients with impaired liver and kidney function.

Fusidic acid

Concomitant use of lopinavir / ritonavir with fusidic acid leads to an increase in the concentration of fusidic acid in blood plasma.The use of fusidic acid for the treatment of skin infections while taking lopinavir/ritonavir is contraindicated.

When using fusidic acid for the treatment of osteoarticular infections, where co-use with Kalidavir® is unavoidable, it is recommended to monitor musculoskeletal and connective tissue side effects.

Anti-tuberculosis drugs

Rifabutin

When rifabutin and lopinavir / ritonavir were co-administered for ten days, the cmax and AUC of rifabutin (unchanged drug and active 25-O-deacetyl metabolite) increased 3.5-fold and 5.7-fold, respectively. Based on these data, it is recommended to reduce the dose of rifabutin by 75% (i. e. 150 mg every other day or three times a week) when used with lopinavir/ritonavir. Further dose reduction of rifabutin may be required. Rifabutin-associated side effects (including neutropenia and uveitis) should be carefully monitored due to possible increased rifabutin activity. Further dose reduction of rifabutin may be required. Reducing the dose of rifabutin to 150 mg 2 times a week is recommended for patients who do not tolerate a dose of 150 mg 3 times a week. It should be borne in mind that the dosage regimen of 150 mg 2 times a week may not provide the optimal therapeutic effect of rifabutin, which may lead to the development of resistance and ineffectiveness of treatment. No dose adjustment is required for Kalidavir.

Rifampicin

Concomitant use of the drug Kalidavir® in a standard dose with rifampicin is contraindicated, since a decrease in the concentration of lopinavir can lead to a significant decrease in its therapeutic effect.

It is allowed to adjust the dose of lopinavir / ritonavir 400 mg / 400 mg (i. e. Kalidavir® at a dose of 400/100 mg + ritonavir at a dose of 300 mg) twice a day in order to compensate for the SURZA 4 isoenzyme – inducing effect of rifampicin. However, such dose adjustment may be accompanied by increased ALT/AST activity and gastrointestinal disorders. Therefore, it is recommended to avoid using this combination of medications unless absolutely necessary. When using lopinavir / ritonavir at an adjusted dose of 400 mg / 400 mg twice daily simultaneously with rifampicin, careful monitoring of safety and efficacy is necessary. An increase in the dose of Kalidavir® should be performed after the start of rifampicin use.

Bedaquiline

A study in healthy volunteers used 400 mg of bedaquiline once and 400/100 mg of lopinavir/ritonavir twice daily for 24 days, which resulted in a 22% increase in the AUC of bedaquiline. Bedaquiline should be used with caution together with lopinavir/ritonavir, and only if the benefit of combined use exceeds the potential risk of adverse reactions (see section “Special Instructions” and “With caution”).

Delamanid

Studies on the interaction of delamanid with ritonavir alone have not been conducted. Studies in healthy volunteers used delamanide 100 mg twice daily and lopinavir / ritonavir 400/100 mg twice daily for 14 days, with a slight increase in the concentrations of delamanide and the delamanide metabolite (DM-6705). If the use of delamanide and ritonavir is really necessary, the ECG should be monitored more frequently throughout the duration of treatment with delamanide due to the risk of prolongation of the QTc interval associated with the DM-6705 metabolite. It is necessary to monitor the activity of transaminases in the blood.

Antiparasitic agents

It is possible to reduce the therapeutic concentration of atovahone when used simultaneously with lopinavir / ritonavir. It may be necessary to increase the dose of atovahone.

Glucocorticosteroids (corticosteroids)

Dexamethasone may cause an increase in the activity of the CYP3A4 isoenzyme and a decrease in lopinavir concentrations. Antiviral activity should be monitored during the use of dexamethasone and lopinavir / ritonavir.

Fluticasone

Concomitant use of lopinavir / ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum cortisol concentrations. It is recommended to consider alternatives to fluticasone, especially for long-term use.

Systemic effects of glucocorticosteroids, including Itsenko-Cushing syndrome and adrenal suppression, have been reported when ritonavir is co-administered with intranasal and inhaled forms of fluticasone and budesonide.

Concomitant use of lopinavir/ritonavir and fluticasone, as well as other CORTICOSTEROIDS that are metabolized by the CYP3A4 isoenzyme, such as budesonide, is not recommended unless the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Special caution should be exercised when lopinavir/ritonavir is co-administered with any of the inhaled or nasal glucocorticosteroids. Consideration should be given to reducing the dose of glucocorticosteroid with careful monitoring of local and general reactions, or switching to a glucocorticosteroid that is not a substrate for the CYP3A4 isoenzyme (for example, Beclomethasone). Also, in case of discontinuation of glucocorticoid therapy, a gradual dose reduction should be carried out over a long period. Slow calcium channel blockers (e. g. felodipine, nifedipine, nicardipine)

There may be an increase in serum concentrations of these drugs when used concomitantly with lopinavir/ritonavir. It is recommended to monitor the therapeutic effects and side effects of concomitant use of drugs in this group with lopinavir / ritonavir.

PDE5 inhibitors

Special care should be taken when using sildenafil and tadalafil for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir, since when taking these drugs simultaneously, you can expect a significant increase in their concentrations and the development of side effects, such as hypotension and prolonged erection.

Sildenafil

Use sildenafil for the treatment of erectile dysfunction should be used with caution in reduced doses (25 mg every 48 hours) and more often monitor side effects. The use of sildenafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.

Tadalafil

Use tadalafil for the treatment of erectile dysfunction should be used with caution in reduced doses (no more than 10 mg every 72 hours) and more often monitor side effects. The use of tadalafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.

Vardenafil

Concomitant use of vardenafil with lopinavir / ritonavir is contraindicated.

Avanafil

When avanafil and lopinavir/ritonavir are co-administered, avanafil concentrations may significantly increase. Concomitant use of avanafil and lopinavir / ritonavir is contraindicated.

Medicinal products based on medicinal plants

Concomitant use of drugs containing St. John’s wort is contraindicated in patients receiving treatment with lopinavir/ritonavir, as this combination may reduce the concentrations of lopinavir/ritonavir in blood plasma. This effect may occur due to the induction of the CYP3A4 isoenzyme and may lead to a loss of therapeutic effect and the development of resistance.

If the patient is already taking St. John’s wort preparations and is prescribed lopinavir / ritonavir, then it is necessary to cancel St. John’s wort preparations and check the level of viral load. When drugs containing St. John’s wort are discontinued, the concentration of lopinavir/ritonavir in the blood plasma may increase. It may be necessary to change the dose of lopinavir/ritonavir. The inducing effect may persist for at least 2 weeks after discontinuation of treatment with St. John’s wort. Lopinavir / ritonavir is recommended to be administered 2 weeks after discontinuation of St. John’s wort preparations.

HMG-CoA reductase inhibitors

Lopinavir/ritonavir may cause a significant increase in plasma concentrations of HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme, such as lovastatin and simvastatin. Increased concentrations of these drugs can lead to the development of myopathy, including rhabdomyolysis, so their combination with lopinavir / ritonavir is contraindicated.

Rosuvastatin, whose metabolism is less dependent on the CYP3A4 isoenzyme, should be used together with ritonavir/lopinavir with caution in minimal doses. Concomitant use of atorvastatin with lopinavir / ritonavir is contraindicated. No clinically significant interaction of lopinavir / ritonavir with pravastatin was detected. The metabolism of pravastatin and fluvastatin is independent of the CYP3A4 isoenzyme, so they should not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated during the use of lopinavir/ritonavir, it is recommended to use pravastatin or fluvastatin.

Immunosuppressants

Concentrations of these drugs (e. g. cyclosporine, tacrolimus, and sirolimus) may increase when used concomitantly with lopinavir / ritonavir. More frequent monitoring of therapeutic concentrations is recommended until the concentrations of these drugs in the blood are stabilized.

Methadone

Lopinavir/ritonavir has been shown to reduce plasma concentrations of methadone.Monitoring of methadone plasma concentrations is recommended.

Buprenorphine

Buprenorphine at a dose of 16 mg once a day does not require a dose change.

Oral contraceptives or contraceptives in the form of a patch

Since plasma concentrations of ethinyl estradiol may be reduced by concomitant use of lopinavir / ritonavir and estrogen-containing oral contraceptives or contraceptives in the form of a patch, alternative or additional contraceptive measures should be used.

Vasodilators

When bosentan was co-administered with lopinavir/ritonavir, the Cmax and AUC of bosentan increased by 6 and 5 times, respectively. Caution should be exercised when bosentan and lopinavir/ritonavir are co-administered. Bosentan should be prescribed and selected in accordance with its instructions for use.

It is also necessary to monitor the effectiveness of antiviral therapy and side effects characteristic of bosentan, especially during the first week of co-use.

No clinically significant interaction is expected

No clinically significant interactions of lopinavir / ritonavir with desipramine, raltegravir, omeprazole, or ranitidine have been reported. Based on the data on metabolism, no clinically significant interaction of lopinavir/ritonavir with fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole is expected in patients with normal renal and hepatic function.

How to take, course of use and dosage

Inside, regardless of food intake. Kalidavir tablets should be swallowed whole, without chewing, breaking or crushing.

Adults

The recommended oral dose of Kalidavir is:

400/100 mg (four tablets of Kalidavir ® 100/25 mg or two tablets of Kalidavir® 200/50 mg) twice a day, regardless of food intake.

800/200 mg (eight tablets of Kalidavir ® 100/25 mg or four tablets of Kalidavir® 200/50 mg) once a day, regardless of food intake, for patients with less than 3 mutations associated with the development of resistance to lopinavir. There are insufficient data for the use of lopinavir / ritonavir once daily in adult patients with 3 or more mutations associated with the development of resistance to lopinavir.

Concomitant therapy

The use of Kalidavir tablets in combination with omeprazole and ranitidine does not require dose adjustment.

In patients with suspected low sensitivity to lopinavir (clinically or in the laboratory) who have previously received antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir or nelfinavir, the dose of Kalidavir tablets should be increased to 500/125 mg (5 tablets of 100/25 mg) twice daily. When used concomitantly with these drugs, Kalidavir tablets are contraindicated once a day.

Children

The use of Kalidavir once a day in paediatric patients is contraindicated. An adult dose of Kalidavir ® tablets (400/100 mg twice daily) without concomitant use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children with a body weight of 35 kg or more or with a body surface area of 1.4 m2 or more. It is recommended to use the following tables to determine the dose for children with a body weight of less than 35 kg or with a BMI of 0.6 to 1.4 m2.

For children with a PTA of less than 0.6 m2 or for children under 3 years of age, it is necessary to use lopinavir / ritonavir in dosage form-an oral solution.

Overdose

Currently, the clinical experience of acute overdose with lopinavir/ritonavir in humans is limited. There is no special antidote.

Treatment should include general supportive care, including monitoring of vital signs and monitoring the patient’s clinical status. If necessary, remove the unabsorbed drug by gastric lavage and prescribe activated charcoal. Since lopinavir/ritonavir is highly bound to plasma proteins, the use of dialysis is impractical.

Description

Film-coated tablets, oval, biconvex, light brown to brown in color.

On the fracture, the core is white or white with a yellowish tinge of color.

Special instructions

Impaired liver function

Lopinavir/ritonavir is mainly metabolized in the liver. Therefore, caution should be exercised when prescribing Kalidavir to patients with mild to moderate hepatic impairment. The use of lopinavir/ritonavir is contraindicated in patients with severe hepatic impairment. Pharmacokinetic data indicate that in HIV-positive patients with hepatitis C and mild or moderate hepatic impairment, lopinavir may increase the concentration in blood plasma by about 30%, as well as a decrease in its binding to plasma proteins. If a patient has hepatitis B or C or a significant increase in aminotransferase activity before starting treatment, the risk of further increase is increased.

Patients with pre-existing liver disorders, including chronic hepatitis, have an increased incidence of liver function disorders during combination antiretroviral therapy. In this regard, it is necessary to conduct careful monitoring in accordance with standard clinical practice. If the patient’s condition worsens, lopinavir/ritonavir therapy should be discontinued.

HIV-infected patients with chronic hepatitis B or C who receive combination antiretroviral therapy are at an increased risk of developing serious and potentially fatal side effects. They were usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis of the liver, who received excessive drug therapy. The causal relationship of these cases with lopinavir/ritonavir therapy has not been established.

Cases of increased transaminase activity have been reported with or without a concomitant increase in bilirubin concentrations within seven days of starting lopinavir / ritonavir in combination with other antiviral agents. In some cases, liver function disorders were severe, but a causal relationship between these cases and lopinavir/ritonavir therapy has not been established.

In such situations, it is advisable to monitor the activity of AST/ALT more often, especially in the first months after the appointment of lopinavir/ritonavir.

Impaired renal function

Since the renal clearance of lopinavir and ritonavir is insignificant, no increase in their plasma concentrations is expected in patients with renal insufficiency. Since lopinavir and ritonavir actively bind to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis.

Diabetes mellitus/hyperglycemia

In the course of post-marketing studies, cases of development and decompensation of diabetes mellitus and hyperglycemia were reported in HIV-infected patients treated with protease inhibitors. To treat these conditions, in some cases, it was necessary to prescribe insulin or oral hypoglycemic drugs, or increase their doses. In some cases, diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after discontinuation of the protease inhibitor. These cases were reported on a voluntary basis, so it is not possible to assess their frequency and association with protease inhibitor therapy. When using lopinavir / ritonavir in patients with diabetes mellitus, it is necessary to monitor the concentration of glucose in the blood.

Pancreatitis

Pancreatitis has been reported in patients treated with lopinavir/ritonavir, including patients with severe hypertriglyceridemia. Fatal cases have been reported. Although the association of this side effect with lopinavir/ritonavir has not been established, a significant increase in triglyceride concentrations is a risk factor for pancreatitis. Patients with advanced HIV infection have an increased risk of developing hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis have an increased risk of recurrence during treatment with lopinavir/ritonavir.

Patients who experience the following symptoms: nausea, vomiting, abdominal pain, or laboratory abnormalities (for example, increased lipase or amylase activity) should be evaluated, and if the diagnosis of pancreatitis is confirmed, treatment with Kalidavir® should be discontinued.

Resistance/cross-resistance

When studying protease inhibitors, cross-resistance of varying severity was observed. The effect of lopinavir/ritonavir on the effectiveness of subsequent therapy with other protease inhibitors is currently being studied.

Hemophilia

Cases of bleeding, including spontaneous formation of subcutaneous hematomas and development of hemarthrosis, have been reported in patients with type A and B hemophilia treated with protease inhibitors. Some patients were given additional doses of factor VIII. In more than half of the cases described, treatment with protease inhibitors was continued or resumed. The causal relationship or mechanism of development of such adverse events during treatment with protease inhibitors has not been established.

Lengthening the PR interval

When taking lopinavir/ritonavir, some patients showed a moderate asymptomatic prolongation of the PR interval. Rare cases of grade II and III atrioventricular block have been reported when taking lopinavir/ritonavir in patients with organic heart disease and pre-existing disorders of the cardiac conduction system, or in patients taking drugs that extend the PR interval (such as verapamil or atazanavir). Lopinavir / ritonavir should be used with caution in these patients.

Electrocardiogram

The QTcF interval (with Friederiatric adjustment) was evaluated in a randomized, placebo-controlled cross – sectional study with active control (moxifloxacin 400 mg once daily) in 39 healthy adult volunteers. 10 measurements were performed for 12 hours on day 3 of the study. The maximum standard deviation of QTcF compared to placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for lopinavir / ritonavir doses of 400/100 mg twice daily and 800/200 mg twice daily, respectively. The changes observed when using the above two dosage regimens were approximately 1.5 and 3 times higher than those observed when taking the recommended doses of lopinavir/ritonavir once a day or twice a day at steady state. None of the patients showed an increase in the QTcF interval > 60 ms compared to the baseline value; the QTcF interval did not exceed the potentially clinically significant threshold of 500 ms. >

In this study, a moderate increase in the PR interval was also observed on day 3 in patients taking lopinavir/ritonavir. The maximum PR interval was 286 ms; there was no development of grade II or III atrioventricular block.

Fat redistribution

On the background of antiretroviral therapy, there was a redistribution/accumulation of fat with its deposition in the central parts of the body, in the back, neck, the appearance of a “buffalo hump”, a decrease in fat deposits on the face and limbs, an increase in mammary glands and kushingoid. The mechanism and long-term consequences of these adverse events are not known. Their association with lopinavir/ritonavir therapy has not been established.

A high risk of developing lipodystrophy is associated with individual characteristics, such as old age, concomitant therapy (long-term antiretroviral therapy and associated metabolic disorders). Clinical examination should include assessment of both physical signs of fat redistribution and laboratory parameters (measurement of fasting serum lipids and blood glucose concentration). Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice.

Increased lipid concentrations

Lopinavir/ritonavir treatment resulted in increased total cholesterol and triglyceride concentrations. Before starting treatment with lopinavir/ritonavir and regularly during therapy, triglyceride and cholesterol concentrations should be monitored. In the presence of lipid disorders, appropriate therapy is indicated. Special care should be taken when prescribing lopinavir/ritonavir to patients with high baseline blood lipid concentrations and a history of lipid metabolism disorders. Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice (see the section “Interaction with other drugs. HMG-CoA reductase inhibitors”).

Immune recovery syndrome

Patients who received combination antiretroviral therapy, including lopinavir/ritonavir, have been observed to develop immune recovery syndrome. Against the background of restoration of immune function at the beginning of combined antiretroviral therapy, an exacerbation of asymptomatic or residual opportunistic infections (pathogens such as Mycobacterium avium, cytomegalovirus, Pneumocystis jiroved (Pneumocystis carinii) or Mycobacterium tuberculosis), which may require additional testing and treatment.

Autoimmune diseases, such as Graves ‘ disease, polymyositis, and Guillain-Barre syndrome, have been observed with the development of immune recovery syndrome, but the duration of occurrence of these phenomena can vary significantly and be several months from the start of therapy.

Osteonecrosis

It is known that many factors play a role in the etiology of osteonecrosis (taking corticosteroids, alcohol abuse, high body mass index, severe immunosuppression, etc. ). In particular, cases of osteonecrosis have been reported in patients with advanced HIV infection and / or long-term use of combined antiretroviral therapy. Therefore, such patients should be advised to consult a doctor if they experience pain, stiffness in the joints and impaired motor function.

Use in the elderly

The number of patients aged 65 years and older was insufficient to assess the possible differences in their response to lopinavir/ritonavir treatment compared to those in younger patients. Caution should be exercised when using lopinavir/ritonavir in the elderly, given the increased frequency of impaired liver, kidney or heart function, concomitant diseases and concomitant therapy.

Use in children

The safety and pharmacokinetic profile of lopinavir/ritonavir in children less than 6 months of age have not been established. In HIV-infected children aged 6 months to 18 years, the side effect profile in the clinical study was similar to that in adults. The use of lopinavir / ritonavir once daily in children is contraindicated.

Interaction

Concomitant use of drugs with lopinavir / ritonavir is contraindicated: astemizole, blonanserin, terfenadine, midazolam (for oral use), triazolam, cisapride, pimozide, salmeterol, sildenafil (only if used for the treatment of pulmonary hypertension, see “Interaction with other drugs”), tadalafil (only if used for the treatment of pulmonary hypertension, see “Interaction with other drugs”), vardenafil, avanafil, voriconazole, ergot alkaloids (for example, ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine, St. John’s wort preparations, boceprevir, dronedarone, use with ketoconazole and itraconazole in high doses (more than 200 mg/day), the use of a standard dose of Kalidavir® with rifampicin, the use of Kalidavir® and tipranavir with a low dose of ritonavir, the use of Kalidavir® once a day in combination with carbamazepine, phenobarbital or phenytoin, the use of Kalidavir® once a day in combination with efavirenz, nevirapine, amprenavir or nelfinavir, simeprevir.

Concomitant use of Calidavir with colchicine in patients with renal and/or hepatic insufficiency is contraindicated due to the possible increased risk of side effects, including life-threatening colchicine-related side effects, such as neuromuscular toxicity (including rhabdomyolysis).

Medications that are not recommended for concomitant use with lopinavir/ritonavir: concomitant use of lopinavir/ritonavir and fluticasone, as well as other CORTICOSTEROIDS that are metabolized by the CYP3A4 isoenzyme, such as budesonide, unless the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression. Concomitant use of rivaroxaban and Calidavir may increase the risk of bleeding. Concomitant use of Kalidavir with telaprevir is not recommended, as it may lead to a decrease in the steady-state concentration of telaprevir. Medications that should be taken with caution when used concomitantly with lopinavir/ritonavir: verapamil, atazanavir, phenyramine, quinidine, erythromycin, clarithromycin, concomitant use with inhaled or nasal glucocorticosteroids, for example, fluticasone, budesonide, concomitant use with drugs for the treatment of erectile dysfunction, namely sildenafil, tadalafil, concomitant use with fentanyl, rosuvastatin, bupropion, concomitant use with antiarrhythmic agents, such as bepridil, lidocaine and quinidine, simultaneous use with digoxin, lamotrigine, valproic acid, midazolam (administered parenterally), trazodone, bedaquiline, bosentan. Influence on the ability to drive vehicles and fur. :

During the treatment period, care should be taken when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions. If you develop side effects that may affect these abilities, such as dizziness, it is recommended to refrain from driving vehicles and operating mechanisms. Studies of the ability to drive motor vehicles and manage mechanisms have not been conducted.

Form of production

Primary packaging of the medicinal product.

10 tablets in a contour cell package made of polyvinyl chloride film and aluminum foil printed varnished.

60,80 or 160 tablets in a polymer jar with a tensioned lid with the control of the first opening. Free space is filled with medical cotton wool.Labels made of label or writing paper, or self-adhesive polymer materials are pasted on cans.

Secondary packaging of a medicinal product.

6 or 8 contour cell packages together with the instructions for use are placed in a pack of cardboard.

1 jar together with the instructions for use is placed in a pack of cardboard. Packs are placed in a group package.

Storage conditions

Store in the original manufacturer’s packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf

life is 2 years. Do not use after the expiration date indicated on the package.

Active ingredient

Lopinavir, Ritonavir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets