Calidavir® (Kalidavir)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLopinavir + RitonavirLopinavir + Ritonavir
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    • Dosage form: & nbspfilm coated tablets
    Composition:

    Active substance:

    Lopinavir 100 mg 200 mg

    Ritonavir 25 mg 50 mg

    Excipients:

    Each film-coated tablet contains:

    Core: giprolose (hydroxypropyl cellulose) - 20.0 mg / 40.0 mg; carboxymethyl starch sodium (primogel) - 15.0 mg / 30.0 mg; Copovidone (Kollidone VA 64) 5.5 mg / 11.0 mg; silicon dioxide colloid (aerosil grade A-300) - 7.0 mg / 14.0 mg; croscarmellose sodium - 10.0 mg / 20.0 mg; lactose monohydrate - 70.0 mg / 140.0 mg; macrogol 6000 (polyethylene glycol 6000) 2.5 mg / 5.0 mg; sodium stearyl fumarate 2.5 mg / 5.0 mg; Polysorbate 80 (Tween 80) 2.5 mg / 5.0 mg.

    Film sheath: Finished water-soluble film shell - 7.0 mg / 14.0 mg (Sheath composition: hypromellose (hydroxypropylmethylcellulose) - 74.2%, macrogol 6000 (polyethylene glycol 6000) - 14.3%, titanium dioxide 3.5%, talc 2.3% , iron dye oxide red - 1.4%, iron oxide dye yellow - 4.3%).

    Description:

    For a dosage of 100 mg + 25 mg: the tablets covered with a film membrane, round, biconcave, from light brown to brown color.

    For the dosage of 200 mg + 50 mg: film-coated tablets, oval, biconvex, from light brown to brown.

    On the fracture, the core is white or white with a yellowish hue of color.
    Pharmacotherapeutic group:Antiviral [HIV] agent
    ATX: & nbsp

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

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

    Pharmacodynamics:

    The drug Kalidavir® is a combined preparation that contains lopinavir and ritonavir.

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

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

    Resistance

    Isolation of resistant strains in vitro

    The HIV-1 strain with reduced susceptibility to lopinavir was isolated in vitro. HIV-1 is passaged in vitro separately with lopinavir and a combination of lopinavir and ritonavir in concentrations equivalent to plasma concentrations observed during lopinavir / ritonavir treatment. Based on the genotypic and phenotypic study of virus subtypes isolated during the passage, it can be assumed that the presence of ritonavir at these concentrations does not significantly affect the isolation of the virus-resistant subtypes of lopinavir. In general, the study in vitro the characteristics of phenotypic cross-resistance between lopinavir and other protease inhibitors indicate that a decrease in susceptibility to lopinavir is closely related to a decrease in sensitivity to ritonavir and indinavir, but is not associated with a decrease in susceptibility to amprenavir, saquinavir, and nelfinavir.

    Resistance test in patients who did not have antiretroviral therapy in history

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

    Resistance test in patients treated with protease inhibitors

    The emergence of resistance to lopinavir in patients who failed unsuccessfully the main treatment with protease inhibitors was studied in long-term studies involving 19 patients receiving protease inhibitors in two Phase studies

    II and one phase III study. Patients had incomplete suppression of the virus or a viral response phenomenon resulting from a response to lopinavir / ritonavir and showed 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 underwent several mutations in the treatment of protease inhibitors, with no more than 40 times reduced initial sensitivity to lopinavir. Mutations V82A, I54V and M46I occurred most often. There were also mutations L33F, I50V and V32I in combination with I47V/A. In 19 strains there was a three- to four-fold increase in the concentration of 50 % inhibition (IC50) in comparison with the initial strains (from 6.2 to 43-fold, in comparison with wild types of the virus).

    There is a genotypic correlation between the decrease in phenotypic sensitivity to lopinavir in viruses isolated after treatment with other protease inhibitors. In vitro The 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 a decrease 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 in the above amino acid positions was 0.8, 2.7 and 13.5, respectively, which is 44 times higher than the EC50 wild type of HIV. All 16 types of virus with a 20-fold increase in sensitivity had mutations at positions 10, 54, 63 and 82 and / or 84. In addition, they contained the median 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90.

    In addition to the above mutations, mutations V32I and I47A were observed in relapsed strains with reduced susceptibility to lopinavir in patients treated with protease inhibitors and receiving lopinavir / ritonavir.In patients taking lopinavir / ritonavir, mutations I47A and L76V in recurrent strains with reduced susceptibility to lopinavir. Evaluation of the importance of individual mutations or sets of mutations may change with the receipt of additional data. It is always advisable to consult about the current system for evaluating the results of resistance studies.

    Antiviral activity of lopinavir in patients unsuccessfully treated with protease inhibitors

    Clinical significance of decreased sensitivity to lopinavir in vitro was evaluated by the method of virologic response to treatment lopinavir / ritonavir, taking into account the initial viral genotype and phenotype, in 56 patients who had not benefited from treatment with various protease inhibitors. The EC50 value of lopinavir on the basis of 56 initial strains of the virus exceeded the EC50 value of wild types of HIV in the range from 0.6 to 98 times. After 48 weeks of treatment with lopinavir / ritonavir, efavirenz and nucleoside reverse transcriptase inhibitors, the plasma HIV RNA level was <400 copies / ml in 93% (25/27), 73% (11/15), and 25% (2/8) patients with less than 10-fold.10-40-fold and more than 40-fold decrease in sensitivity to lopinavir, respectively, compared with the baseline. The virologic response was also observed in 91% (21/23), 71 % (15/21) and 33% (2/6) patients with 0-5, 6-7, and 8-10 mutations in the above mutations in the HIV protease associated with a decrease in susceptibility to lopinavir in vitro. Since these patients did not previously take lopinavir / ritonavir or efavirenz, in part 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 not taking lopinavir / ritonavir.

    Cross-resistance

    The effectiveness 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 recurring strains showing an increase in resistance to lopinavir during three Phase II and one Phase II studies lopinavir / ritonavir in patients receiving protease inhibitors. Median IC50 lopinavir for these 18 strains in the initial state and in the phenomenon of virological recoil was higher in the range from 6.9 to 63 times, respectively, compared with wild types of the virus. As a rule, strains with virological recoil are preserved (in the case of cross-resistance initially), and develop significant resistance to indinavir, saquinavir, atazanavir. A moderate decrease in amprenavir activity was observed with a median of a multiplicity IC50 from 3.7 to 8 for the initial and recurrent strains, respectively. Strains retained sensitivity to tipranavir with a median enhancement IC50 at the initial level and in the phenomenon of virological recoil with a multiplicity of 1.9 to 1.8, respectively, compared with wild types of the virus. For more information on tipranavir, including the genotypic response rates for the treatment of HIV-1-resistant lopinavir, see the instructions for the use of tipranavir.

    Pharmacokinetics:

    The pharmacokinetics of lopinavir in combination with ritonavir was studied in healthy volunteers and HIV-infected patients; there were no significant differences between the two groups.Lopinavir is almost completely metabolized by isoenzyme CYP3A. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma concentrations. When lopinavir / ritonavir was used at a dose of 400/100 mg twice a day, the average equilibrium concentrations of lopinavir in plasma in HIV-infected patients were 15-20 times higher than those of ritonavir, and the concentration of ritonavir in plasma was less than 7% of the concentration with ritonavir in a dose of 600 mg twice a day. EC50 of lopinavir in vitro 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), while taking 400/100 mg lopinavir / ritonavir twice daily with food for three weeks, the mean maximum concentration of lopinavir in plasma (Cmah) of 9.8 ± 3.7 μg / ml, which is noted about four hours after the administration of the drug. The mean equilibrium concentration before the morning dose was 7.1 ± 2.9 μg / ml and the minimum concentration within the dosing interval was 5.5 ± 2.7 μg / ml. Area under the curve "concentration-time" (AUC) lopinavir within 12 hours after taking the drug averaged 92.6 ± 36.7 μg-h / ml. Absolute bioavailability of lopinavir in combination with ritonavir in the human body is not established.

    Influence of food intake on intake

    The administration of a single dose of 400/100 mg of lopinavir / ritonavir in the tablet dosage form after ingestion (high fat content, 872 kcal, 56% fat) did not lead to significant changes in Cmah and AUCinf in comparison with reception on an empty stomach. Therefore, the drug Kalidavir * in the dosage form of the tablet can be taken as with food, and without it.

    Distribution

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

    Metabolism

    In studies in vitro It is shown,that lopinavir is mainly exposed to oxidative metabolism involving the cytochrome P450 system of hepatocytes, mainly under the influence of isoenzyme CYP3A. Ritonavir is a potent inhibitor of the isoenzyme CYP3A4, which inhibits the metabolism of lopinavir, which increases the concentration of lopinavir in the blood plasma. After a single 400/100 mg administration of lopinavir / ritonavir (with labeled 14C-lopinavir), 89% of the radioactivity is provided by the starting drug. In the human body, at least 13 oxidative metabolites of lopinavir were detected. Ritonavir is able to induce isoenzymes of cytochrome P450, which leads to the induction of its own metabolism. In the course of prolonged use, the concentrations of lopinavir before the administration of the next dose decreased with time, stabilizing after about 10-16 days.

    Excretion

    After taking 400/100 mg 14C-lopinavir / ritonavir after eight days approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the dose 14C-lopinavir is found in 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 dose of lopinavir is excreted unchanged through the kidneys. Clearance (CL/F) lopinavir for oral administration is 5.98 +/- 5.75 l / h.

    Reception once a day

    The pharmacokinetics of lopinavir / ritonavir with a once-daily dose rate was 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 daily. With long-term admission of 800/200 mg lopinavir / ritonavir once a day for 4 weeks at meal time the average the maximum concentration of lopinavir in plasma (Cmax) was 11.8 ± 3.7 μg / ml and was achieved approximately 6 hours after administration. The average equilibrium concentration of lopinavir before taking the morning dose was 3.2 ± 2.1 μg / ml, the minimum concentration within the dosage interval was 1.7 ± 1.6 μg / ml. AUC lopinavir at 24 hour interval of reception averaged 154.1 ± 61.4 μg-h / ml.

    Special patient groups

    Sex, race and age

    The pharmacokinetics of lopinavir has not been studied in elderly patients. No sex-dependent pharmacokinetic differences were observed in adult patients. No clinically significant pharmacokinetic differences depending on the race have been established.

    Children

    Pharmacokinetics of lopinavir / ritonavir at admission 300/75 mg / m2 twice daily and 230 / 57.5 mg / m2 Twice a day, a total of 53 patients under the age of 12 years were studied. Dosing scheme for 230 / 57.5 mg / m2 two times a day 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). The use of lopinavir / ritonavir once a day in children has not been studied.

    Average equilibrium AUC, FROMmah, and Cmin lopinavir after taking lopinavir / ritonavir 230 / 57.5 mg / m2 two times a day without nevirapine (n= 12) were 72.6 ± 31.1 μg-h / ml; 8.2 ± 2.9 and 3.4 ± 2.1 μg / ml, respectively; and 85.8 ± 36.9 μg-h / ml, 10.0 ± 3.3 and 3.6 ± 3.5 μg / 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 a day (in patients older than eight years).

    Renal insufficiency

    The pharmacokinetics of lopinavir has not been studied in patients with renal insufficiency; However, since renal clearance of lopinavir is negligible, a reduction in overall clearance in patients with renal insufficiency is not expected.

    Liver failure

    Lopinavir is mainly metabolized and excreted by the liver.The combined dosing of lopinavir / ritonavir 400/100 mg twice a day in patients simultaneously infected with HIV and hepatitis C virus, with a malfunction of the liver of moderate and mild severity, resulted in a 30% increase AUC lopinavir and a 20% increase in Cmah compared to HIV-infected patients with normal liver function. The binding of lopinavir to plasma proteins was lower for mild and moderate hepatic insufficiency compared to control groups (99.09% compared with 99.31%, respectively). Lopinavir / ritonavir has not been studied in patients with severe hepatic insufficiency (see "Contraindications")

    Pregnancy and the puerperium

    Pharmacokinetic data show that there is a slight decrease AUC and Cmah lopinavir in pregnant women in the third trimester of pregnancy compared with the second trimester of pregnancy. Pharmacokinetic data obtained from HIV-1-infected pregnant women receiving film-coated tablets, 400/100 mg lopinavir / ritonavir twice daily, are presented in the table below:

    Mean (variation coefficient,%) pharmacokinetic parameters of lopinavir in equilibrium in HIV-1-infected pregnant women

    Pharmacokinetic parameter

    2nd trimester

    n=171

    3rd trimester

    n=23

    Postpartum period

    n=172

    AUC0-12 (mcg *h /ml)

    68,7 (20,6)

    61,3 (22,7)

    94,3 (30,3)

    FROMmax

    7,9 (21,1)

    7,5 (18,7)

    9,8 (24,3)

    FROMpredose (μg / ml)

    4,7 (25,2)

    4,3 (39,0)

    6,5 (40,4)

    FROMpredose - the concentration of the drug in the blood before taking the next dose

    1- n= 18 for Cmax

    2- n= 16 for Cpredose
    Indications:

    Treatment of HIV infection in adults and children older than 3 years in combination therapy.

    Contraindications:

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

    - Severe hepatic insufficiency.

    - Simultaneous use of drugs whose clearance significantly depends on the metabolism by isoenzyme CYP3A. These drugs include: astemizole, blonanserin, terfenadine, midazolam (for oral administration), 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 methylergomethrin), inhibitors of HMG-CoA reductase (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine.

    - Simultaneous application with preparations of St. John's wort, boceprevir, simeprevir.

    - Simultaneous application of the standard dose of the preparation Kalidavir® with rifampicin.

    - Simultaneous use of the drug Kalidavir® and tipranavir with a low dose of ritonavir (see section "Interaction with other drugs").

    - Children under 3 years (for this dosage form).

    - Use of the preparation Kalidavir® once a day in combination with carbamazepine, phenobarbital or phenytoin.

    - Use of Calidavir® once a day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir.

    - The use of the drug Kalidavir® once a day in children (under 18 years of age).

    - Use of Calidavir® once a day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir.

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

    - Simultaneous application with dronedarone.

    - Simultaneous use with colchicine in patients with renal and / or liver failure.

    - Use of lopinavir / ritonavir once a day in pregnant women.

    - Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

    Carefully:

    - Viral hepatitis B and C.

    - Cirrhosis of the liver.

    - Mild and moderate severity of liver failure.

    - Increased activity of "liver" enzymes.

    - Pancreatitis.

    - Hemophilia A and B.

    - Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).

    - Elderly (over 65 years of age).

    - Patients with organic heart diseases and existing disorders of the conduction system of the heart or patients taking drugs that extend the interval PR (such as verapamil or atazanavir), or drugs that extend the interval QT (phenyramine, quinidine, erythromycin, clarithromycin).

    - Simultaneous use with drugs for the treatment of erectile dysfunction, namely with sildenafil (see "Interaction with other drugs"), tadalafil.

    - Simultaneous use with fentanyl, rosuvastatin, bupropion, inhaled or injected through the nose with glucocorticosteroids, for example, fluticasone, budesonide (see "Interaction with other drugs").

    - Simultaneous use with antiarrhythmic drugs, such as bepridil, lidocaine and quinidine.

    - Simultaneous use with digoxin.

    - Simultaneous use with lamotrigine and valproic acid.

    - Simultaneous use with Bedakvilinom.

    - Simultaneous use with trazodone.

    Pregnancy and lactation:

    Pregnancy

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

    Breastfeeding period

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

    Dosing and Administration:

    Inside, regardless of food intake. Tablets of the preparation Kalidavir® should be swallowed whole, not chewing, not breaking or crushing.

    Adults

    The recommended oral dose of Kalidavir® is:

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

    For 800/200 mg (eight tablets of the drug Calidavir® 100/25 mg or four tablets of the drug Kalidavir® 200/50 mg) once a day, regardless of food intake for patients who have less than 3 mutations associated with the development of resistance to lopinavir. There is insufficient data for the use of lopinavir / ritonavir once a day 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 hypersensitivity to lopinavir (shown clinically or laboratory), previously received antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir or nelfinavir, it is necessary to increase the dose of tablets Calidavir ® to 500/125 mg (5 tablets of 100/25 mg) twice a day. When combined with these medications, Calidavir® tablets should not be prescribed once a day.

    Children

    The use of the preparation Kalidavir® once a day by patients of childhood is contraindicated. An adult dose of Calidavir® tablets (400/100 mg twice daily) without simultaneous use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children weighing 35 kg or more or with a body surface area (PPT) of 1.4 m2 and more. To determine the dose for children with a body weight of less than 35 kg or with PPT from 0.6 to 1.4 m2 the following tables are recommended.

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

    Tables 1 and 2 contain guidelines for dosing Calidavir® 100/25 mg tablets based on PPT.

    Table 1.

    Principles for dosing tablets of the preparation Calidavir® 100/25 mg for children based on PPT, without simultaneous use of efavirenz, nevirapine, nelfinavir or amprenavir

    Body surface area * (m2)

    The recommended number of tablets is 100/25 mg when taken twice a day

    ≥ 0.6 to <0.9

    2 tablets (200/50 mg)

    ≥ 0.9 to <1.4

    3 tablets (300/75 mg)

    ≥1,4

    4 tablets (400/100 mg)

    * The surface area of ​​the body can be calculated by the following formula: PPT (m2) = V [Height (cm) x Body weight (kg)] / 3600.

    Table 2.

    Principles of dosing of tablets of the drug Kalidavir® 100/25 mg for children, based on PPT, with the simultaneous use of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Body surface area (m2)

    The recommended number of tablets is 100/25 mg when taken twice a day

    ≥ 0,6 to 0,8

    2 tablets (200/50 mg)

    ≥ 0.8 to 1.2

    3 tablets (300/75 mg)

    ≥1.2 to 1.7

    4 tablets (400/100 mg)

    ≥1,7

    5 tablets (500/125 mg)

    Tables 3 and 4 contain guidelines for dosing tablets of the preparation Calidavir® 100/25 mg by body weight.

    Table 3.

    The principles of dosing tablets of the drug Kalidavir® 100/25 mg for children by body weight, without the simultaneous use of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Body weight (kg)

    The number of tablets is 100/25 mg for taking twice

    day

    From 7 to <15 kg

    Taking tablets is not recommended. An oral solution should be used

    From 15 to 25 kg

    2

    > 25 to 35 kg

    3

    > 35 kg

    4* *

    ** Alternatively, two tablets of 200/50 mg can be used for patients who can swallow a large tablet.

    Table 4.

    The principles of dosing tablets of the preparation Kalidavir® 100/25 mg for children by body weight, with the simultaneous use of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Body weight (kg)

    Number of tablets 100/25 mg for reception twice a day

    From 7 to <15 kg

    Taking tablets is not recommended. An oral solution should be used

    From 15 to 20 kg

    2

    > 20 to 30 kg

    3

    > 30 to 45 kg

    4 * *

    > 45 kg

    5

    ** Alternatively, two tablets of 200/50 mg can be used for patients who can swallow a large tablet.

    Application during pregnancy and in the puerperium

    According to a number of clinical studies, a change in the dose of lopinavir / ritonavir during pregnancy and in the postpartum period is not required. The use of lopinavir / ritonavir once a day is contraindicated in pregnant women due to a lack of pharmacokinetic and clinical data.

    Side effects:

    Adults

    The most common side effects associated with taking lopinavir / ritonavir were diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. Diarrhea, nausea and vomiting can occur at the beginning of therapy, while hypertriglyceridemia and hypercholesterolemia may develop later. Moderate and severe side effects are listed below with frequency (often> 1/10, often> 1/100, but <1/10, infrequently> 1/1000, but <1/100).

    From the immune system

    Common: hypersensitivity reactions including urticaria and angioedema.

    Infrequently: a syndrome of restoration of immunity.

    From the side of the digestive system

    Very often: diarrhea, nausea.

    Often: vomiting, abdominal pain (upper and lower divisions), gastroenteritis, colitis, dyspepsia, pancreatitis, gastroesophageal reflux, hemorrhoids, flatulence, bloating, hepatitis, hepatomegaly, cholangitis, steatosis of the liver.

    Infrequent: constipation, stomatitis, ulcers of the oral mucosa, duodenitis, gastritis, gastrointestinal bleeding, including rectal bleeding, dry mouth, stomach and bowel ulcer, and stool incontinence.

    Frequency unknown: jaundice.

    From the nervous system

    Often: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety.

    Infrequently: agevzia, dysgeusia, convulsions, tremor, cerebrovascular disorders, sleep disturbance, decreased libido.

    From the side of the cardiovascular system

    Often: arterial hypertension.

    Infrequently: atherosclerosis, myocardial infarction, atrioventricular blockade, insufficiency of tricuspid valve, deep vein thrombosis.

    Frequency unknown: increase PR-Interval.

    From the skin and subcutaneous fat

    Often: rash, including maculopapular, dermatitis, eczema, seborrhea, increased sweating at night, itching.

    Infrequently: alopecia, capillaritis, vasculitis.

    The frequency is unknown: lipodystrophy and redistribution of subcutaneous fat.

    From the side of the musculoskeletal system

    Often: musculoskeletal pain, including arthralgia and back pain, myalgia, muscle weakness, muscle spasms.

    Infrequently: rhabdomyolysis, osteonecrosis.

    Metabolic disorders and disorders of the endocrine system

    Often: hypercholesterolemia, hypertriglyceridemia, weight loss, decrease appetite, diabetes mellitus.

    Infrequently: weight gain, lactic acidosis, increased appetite, male hypogonadism.

    The frequency is unknown: insulin resistance.

    From the side of the kidneys and urinary tract

    Often: kidney failure.

    Infrequently: hematuria, nephritis.

    From the side of the reproductive system

    Often: erectile dysfunction, amenorrhea, menorrhagia.

    From the system of blood and blood-forming organs

    Often: anemia, leukopenia, neutropenia, lymphadenopathy.

    From the sense organs

    Infrequent: vestibular dizziness, tinnitus, visual impairment.

    Infections

    Very often: infections of the upper respiratory tract.

    Often: infections of the lower respiratory tract, infections of the skin and subcutaneous fat, including cellulite, folliculitis and furunculosis.

    Are common

    Often: weakness, asthenia.

    Change in laboratory indicators: increase in the concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, increase activity of serum aspartate aminotransferase (ACT), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGTP), lipase, amylase, creatine phosphokinase, decrease in inorganic phosphorus concentration, hemoglobin, decrease in creatinine clearance.

    Children

    The profile of adverse events in children aged 6 months to 12 years was similar to that of adults. Most often there was a rash, dysgeusia, vomiting, diarrhea.

    From the side of laboratory parameters in children the following changes were registered: an increase in the content of total bilirubin, total cholesterol, increased activity of amylase, increased activity ACT, ALT, neutropenia, thrombocytopenia, increased or decreased sodium content.

    With the use of lopinavir / ritonavir, individual cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, multiform exudative erythema and bradyarrhythmia have also been reported.

    Description of individual side effects

    Cushing's syndrome was noted in patients receiving ritonavir and taking intranasal or inhalation-free fluticasone propionate. This effect can potentially occur in the case of the use of other corticosteroids metabolized by cytochrome P450, for example, budesonide.

    An increase in the activity of creatine phosphokinase, myalgia, myositis, and also in rare cases rhabdomyolysis have been documented in the treatment of protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors.

    In HIV-infected patients with severe immune deficiency, at the onset of combined antiretroviral therapy (CART), asymptomatic or residual opportunistic infections may occur. Also reported were autoimmune disorders (such as diffuse toxic goiter),the time of onset of which, however, is more variable - the disease can begin after a long time after the start of treatment.

    Osteonecrosis has been reported, especially in patients with a history of risk factors, progressive HIV infection, or after prolonged use of antiretroviral therapy. The frequency of their occurrence is unknown. Information on the redistribution of subcutaneous fat, see the section "Special instructions".

    Metabolic indicators

    Weight, as well as the concentration of lipids and glucose in the blood plasma may increase during antiretroviral therapy.

    Overdose:

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

    Treatment should include general supportive therapy, including monitoring of vital signs and monitoring the clinical status of the patient. If necessary, remove unabsorbed medicinal product by means of gastric lavage and prescribe Activated carbon. Since lopinavir / ritonavir binds to a high degree with plasma proteins, the use of dialysis is not advisable.

    Interaction:

    Lopinavir / ritonavir in vitro and in vivo is an inhibitor of the isoenzyme CYP3A. The simultaneous use of lopinavir / ritonavir and preparations mainly metabolized by isoenzyme CYP3A (E.g., dihydropyridine blockers "slow" calcium channels, HMG-CoA reductase inhibitors, immunosuppressants and inhibitors of phosphodiesterase 5 (PDE-5)), can lead to increased plasma concentrations of these drugs, the therapeutic or side effects which may increase or last. In drugs that are actively metabolized by the isoenzyme CYP3A and have a high pre-systemic metabolism, when taken concomitantly with lopinavir / ritonavir, there is a more frequent increase AUC (more than 3-fold).

    Lopinavir / ritonavir at clinically significant concentrations does not inhibit isoenzymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2.

    In vivo It was shown that lopinavir / ritonavir induce its own metabolism and increases the biotransformation of certain other drugs that undergo glucuronidation and metabolized by the cytochrome P450 isoenzymes (isozymes including CYP2C9 and CYP2C19).This can lead to a decrease in the concentration in the blood plasma and a decrease in the effectiveness of the drugs used together. Preparations that are contraindicated precisely because of unwanted interaction and the possibility of developing serious side effects are listed in the section "Contraindications." Lopinavir / ritonavir is metabolized by isoenzyme CYP3A. The simultaneous use of lopinavir / ritonavir and isozyme inducing drugs CYP3A, can reduce plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes were not noted with simultaneous application with ketoconazole.

    The simultaneous use of lopinavir / ritonavir and other drugs that inhibit the isoenzyme CYP3A, can increase plasma concentrations of lopinavir.

    Drugs for HIV treatment

    Nucleoside reverse transcriptase inhibitors (NRTIs)

    Stavudine and lamivudine

    There was no change in the pharmacokinetics of lopinavir with simultaneous use of lopinavir / ritonavir with stavudine and lamivudine compared with lopinavir / ritonavir alone.

    Didanosine

    Didanosine is recommended for fasting; therefore, in combination with didanosine, lopinavir / ritonavir tablets should be taken one hour before or two hours after ingestion.

    Zidovudine and abacavir

    Lopinavir / ritonavir induces glucuronidation, so the drug can reduce the concentrations of zidovudine and abacavir in plasma. 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, it should be observed for the occurrence of tenofovir-associated side effects, including renal dysfunction.

    Other NRTIs

    An increase in the activity of creatine phosphokinase (CK), myalgia, myositis and, rarely, rhabdomyolysis with the intake of HIV protease inhibitors, especially in combination with NRTIs, has been reported.

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    Nevirapine

    There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during simultaneous use of nevirapine and lopinavir / ritonavir.The results of a study involving HIV-positive children showed a decrease in the concentration of lopinavir during simultaneous 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.

    Patients who have previously had antiretroviral therapy or who have phenotypic or genotypic signs of a significant decrease in susceptibility to lopinavir, while using lopinavir / ritonavir with nevirapine may require an increase in the dose of lopinavir / ritonavir to 500/125 mg twice daily. Lopinavir / ritonavir in combination with nevirapine should not be used once a day.

    Efavirenz

    An increase in 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 compared to 400/100 mg of lopinavir / ritonavir twice a day without efavirenz.An increase in the dose of lopinavir / ritonavir tablets to 600/150 mg (three (3) 200/50 mg tablets) twice daily with simultaneous use with efavirenz increased the plasma concentration of lopinavir by approximately 36% and the concentration of ritonavir by approximately 56-92 % compared with the dose of lopinavir / ritonavir 400/100 mg tablets (two (2) 200/50 mg tablets) when taken twice a day without efavirenz (see "Dosage and Administration").

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

    The simultaneous use of lopinavir / ritonavir with both efavirenz and nevirapine once a day is contraindicated.

    Delavirdine

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

    Rilpivirine

    With the simultaneous use of rilpivirin with lopinavir / ritonavir, an increase in rilpivirin concentrations is possible, however, no change in the dose of lopinavir / ritonavir is required. The appointment and selection of a dose of rilpivirin should be made in accordance with its instructions for use.

    Etravirine

    With the simultaneous use of etravirine with lopinavir / ritonavir, an increase in the concentration of etravirine is possible, however, no change in the dose of lopinavir / ritonavir is required. The appointment and selection of a dose of etravirine should be made in accordance with its instructions for use.

    HIV protease inhibitors

    Amprenavir

    Lopinavir / ritonavir may increase plasma concentrations of amprenavir (taking amprenavir 750 mg twice daily plus lopinavir / ritonavir leads to an increase AUC, a similar Cmah, increase Cmin relative to amprenavir at a dose of 1200 mg twice daily). The simultaneous use of lopinavir / ritonavir and amprenavir helps to reduce the concentration of lopinavir (see section "Method of administration and dose"). The simultaneous use of lopinavir / ritonavir with amprenavir is contraindicated once a day.

    Fosamprenavir

    Research has shown that the simultaneous use of lopinavir / ritonavir, fosamprenavir with reduced concentrations of lopinavir and fosamprenavir. Adequate fosamprenavir and lopinavir / ritonavir doses in combination were not established in terms of safety and efficacy.

    The simultaneous administration 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 led to an increased incidence of side effects from the gastrointestinal tract (GI tract) and an increase in the concentration of triglycerides in the blood without enhancing the antiviral effect, compared with the standard dose of fosamprenavir / ritonavir.

    Indinavir

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

    Nelfinavir

    Lopinavir / ritonavir may increase the concentrations of nelfinavir and the metabolite of nelfinavir M8 (when taking nelfinavir 1000 mg twice daily and lopinavir / ritonavir compared to taking nelfinavir 1250 mg twice daily there is a similar AUC, a similar Cmah and increased Cmin). The simultaneous use of lopinavir / ritonavir and nelfinavir leads to a decrease in the concentrations of lopinavir (see section "Method of administration and dose").

    The simultaneous use of lopinavir / ritonavir with nelfinavir is contraindicated once a day.

    Ritonavir

    When co-administered with lopinavir / ritonavir with an additional 100 mg ritonavir twice daily AUC lopinavir increased by 33%, Cmin increased by 64% compared with the use of lopinavir / ritonavir in a dose of 400/100 mg twice a day.

    Saquinavir

    Lopinavir / ritonavir increases saquinavir concentrations (taking saquinavir 800 mg twice daily in conjunction with lopinavir / ritonavir leads to an increase AUC, FROMmah and Cmin compared with the administration of saquinavir 1200 mg three times a day). The dose of saquinavir, when used concomitantly with lopinavir / ritonavir 400/100 mg twice daily, may need to be reduced. The use of lopinavir / ritonavir in combination with saquinavir was not studied once a day.

    Tipranavir

    With the simultaneous administration of tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily) and lopinavir / ritonavir (400/100 mg twice daily), there is a decrease AUC and Cmin lopinavir by 55% and 70%, respectively.Simultaneous reception of lopinavir / ritonavir and tipranavir with a low dose of ritonavir is contraindicated.

    Hepatitis C Virus Protease Inhibitors

    Telaprevir

    The simultaneous use of lopinavir / ritonavir with telaprevir leads to decrease in the equilibrium concentration of bodyprevir without changing the equilibrium concentration of lopinavir. The simultaneous use of telaprevir and lopinavir / ritonavir is not recommended.

    Boceprevir

    The simultaneous use of lopinavir / ritonavir with bocetrevir leads to decrease in the equilibrium concentrations of bocepreviir and lopinavir. The simultaneous use of lopinavir / ritonavir with bocetreviros is contraindicated.

    Symeprevir

    With the simultaneous use of simeprevir with lopinavir / ritonavir, an increase in the concentration of simeprevir is possible. The simultaneous use of lopinavir / ritonavir and simeprevir is contraindicated.

    Antiviral drugs - chemokine receptor inhibitors CCR5

    Maraviroc

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

    Integrase inhibitors

    Raltegravir

    With the simultaneous use of lopinavir / ritonavir with raltegravir, there is no change AUC and Cmah raltegravir. There was a decrease in C12 raltegravir by 30%. The pharmacokinetic parameters of lopinavir did not change. With the simultaneous use of lopinavir / ritonavir with raltegravir, there is no need to change the dose of lopinavir / ritonavir.

    Other drugs

    Narcotic analgesics

    Fentanyl

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

    With the simultaneous use of lopinavir / ritonavir and fentanyl, therapeutic and side effects (including respiratory depression) must be carefully monitored.

    Antiarrhythmics

    Bepridil, lidocaine and quinidine

    When used concomitantly with lopinavir / ritonavir, concentrations of these drugs may increase. Care should be taken when using these drugs and monitoring therapeutic concentrations, if possible.

    Dronedaron

    When used concurrently with lopinavir / ritonavir, dronedarone concentrations may increase. Simultaneous use with lopinavir / ritonavir is contraindicated.

    Digoxin

    Analysis of the literature showed that simultaneous application of ritonavir (300 mg every 12 hours) and digoxin led to a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir / ritonavir concomitantly with digoxin with control of serum digoxin concentration. Special caution should be exercised 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 concentration.

    In those patients who started taking digoxin during lopinavir / ritonavir therapy, a smaller increase in digoxin concentration should be expected.

    Drugs that extend the interval QT

    Under the influence of lopinavir / ritonavir, the concentrations of phenyramine, quinidine, erythromycin, clarithromycin may increase with subsequent lengthening of the interval QT and the development of side effects from the heart. Special care should be taken when using lopinavir / ritonavir together with drugs that extend the interval QT. Antineoplastic agents (eg, dasatinib, nilotinib, vincristine, vinblastine)

    May increase serum concentrations of these drugs when applied simultaneously with lopinavir / ritonavir, which may lead to increased side effects normally associated with data reception anticancer drugs.

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

    Anticoagulants

    Possible effects on warfarin concentrations when used concomitantly with lopinavir / ritonavir. It is recommended to monitor INR (the international normalized ratio).

    Rivaroxaban

    The simultaneous use of rivaroxaban with lopinavir / ritonavir may cause an increase in rivaroxaban concentration, which may lead to an increased risk of bleeding. The simultaneous use of rivaroxaban with lopinavir / ritonavir is not recommended.

    Antidepressants

    Bupropion

    The simultaneous use of bupropion with lopinavir / ritonavir reduces the plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir / ritonavir with bupropion is necessary, it should be performed under close clinical control over the efficacy of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.

    Trazodone

    The simultaneous use of ritonavir and trazodone can lead to an increase in the concentration of trazodone in the blood plasma. There were side effects: nausea, dizziness, arterial hypotension and fainting. Use trazodone with an inhibitor of isoenzyme CYP3A4, such as lopinavir / ritonavir, should be administered with caution and by lowering the dose of trazodone.

    Antipsychotics

    Quetiapine, blonanserin and pimozide

    Since lopinavir / ritonavir is an inhibitor of the isoenzyme CYP3A, the concentration of quetiapine, blonanserin and pimozide in blood plasma may increase. The simultaneous use of lopinavir / ritonavir and drugs quetiapine, blonanserin and pimozide are contraindicated.

    Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

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

    In addition, the simultaneous use of phenytoin and lopinavir / ritonavir leads to a moderate decrease in equilibrium concentrations of phenytoin.

    Concentrations of phenobarbital, phenytoin, carbamazepine should be monitored while using lopinavir / ritonavir.

    Lamotrigine and valproic acid

    With the simultaneous use of these drugs with lopinavir / ritonavir, a decrease in the concentrations of lamotrigine and valproic acid was observed. Reduction of lamotrigine concentration reached 50%. These combinations of drugs should be used with caution. When these drugs are simultaneously used with lopinavir / ritonavir, especially during the dose selection period, an increase in the dose of lamotrigine or valproic acid may be required, as well as monitoring of their concentrations in the blood plasma.

    For patients who start or stop taking Calidavir® during lamotrigine therapy, monitor lamotrigine plasma concentrations prior to co-administration with the Calidavir® drug, during the first 2 weeks of joint intake, or within 2 weeks after discontinuation of the Calidavir® drug to determine whether a dose of lamotrigine should be changed.

    For patients who are already taking the drug Calidavir® and begin taking lamotrigine, there is no need to adjust the dose of lamotrigine.

    Sleeping Pills

    Midazolam for oral administration and triazolam

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

    Simultaneous use of midazolam inwards in combination with lopinavir / ritonavir is contraindicated. It is allowed with caution to apply midazolam parenterally in combination with lopinavir / ritonavir.In the latter case, hospitalization of the patient in the intensive care unit and careful clinical observation are necessary. In the event of oppression of respiratory activity and / or prolonged sedation, appropriate treatment should be prescribed. It is necessary timely correction of the dose of midazolam, especially with repeated administration.

    Alkaloids of ergot

    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. Joint use with lopinavir / ritonavir is contraindicated.

    Drugs that regulate the motor function of the digestive tract

    Cisapride

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

    Antihistamines

    Astemizole and terfenadine

    An increase in plasma concentrations of astemizole and terfenadine increases the risk of developing severe arrhythmia. Joint use with lopinavir / ritonavir is contraindicated.

    Beta-2-adrenomimetics

    Salmeterol

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of salmeterol in the blood plasma can increase. Simultaneous application lopinavir / ritonavir and salmeterol may increase the risk of cardiovascular side effects associated with the use of salmeterol, including lengthening the interval QT, palpitations and sinus tachycardia.

    The simultaneous use of lopinavir / ritonavir and salmeterol is contraindicated.

    Alfa-1-adrenoblockers

    Alfuzosin

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of alfuzosin in the blood plasma may increase, while increasing the risk of severe arterial hypotension. Simultaneous application Lopinavir / ritonavir and alfuzosin are contraindicated.

    Antiarrhythmics

    Amiodarone

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

    Antifungal means

    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) in conjunction with lopinavir / ritonavir is contraindicated.

    Voriconazole

    The study showed that simultaneous application of ritonavir at a dose of 100 mg every 12 hours reduces the equilibrium AUC voriconazole averaged 39%; the simultaneous use of lopinavir / ritonavir and voriconazole is contraindicated.

    Preparations for the treatment of gout

    The combined use of lopinavir / ritonavir with colchicine in patients with renal and / or hepatic insufficiency is contraindicated because of the possible increase in the risk of side effects, including life-threatening effects associated with colchicine, such as neuromuscular toxicity (including rhabdomyolysis). It is necessary to reduce colchicine dose or interrupt colchicine therapy in patients with normal renal or hepatic function if lopinavir / ritonavir therapy is required. For more information, see the colchicine.

    Antibacterial agents

    Lopinavir / ritonavir may cause moderate increase AUC clarithromycin. In patients with impaired hepatic function, the dose of clarithromycin should be reduced with simultaneous use with lopinavir / ritonavir. In patients with renal insufficiency (with a creatinine clearance <30 ml / min), the dose of clarithromycin should be reduced with simultaneous use with lopinavir / ritonavir. Therefore, caution should be exercised when using clarithromycin and lopinavir / ritonavir simultaneously in patients with impaired hepatic and renal function.

    Fusidic acid

    Simultaneous reception of lopinavir / ritonavir with fusidic acid leads to an increase in the concentration of fusidic acid in the blood plasma. The use of fusidic acid for the treatment of skin infections with simultaneous administration of lopinavir / ritonavir is contraindicated.

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

    Anti-TB drugs

    Rifabutin

    With the simultaneous use of rifabutin and lopinavir / ritonavir for ten days Cmah and AUC rifabutin (unchanged drug and active 25-O-deacetyl metabolite) increased by 3.5 and 5.7 times, respectively. Based on these data, it is recommended that the dose of rifabutin be reduced by 75% (i.e., taking 150 mg every other day or three times a week) when used with lopinavir / ritonavir. It may be necessary to further reduce the dose of rifabutin. In connection with the possible increase in the action of rifabutin, rifabutin-associated side effects (including neutropenia and uveitis) should be closely monitored. It may be necessary to further reduce the dose of rifabutin. Reduction of the dose of rifabutin to 150 mg twice 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 a dosing regimen of 150 mg 2 times a week may not provide the optimal therapeutic effect of rifabutin, which can lead to the development of resistance and inefficiency of treatment. A dose change for Calidavir® is not required.

    Rifampicin

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

    A dose adjustment of lopinavir / ritonavir 400 mg / 400 mg (i.e., Calidavir® at a dose of 400/100 mg + ritonavir in a dose of 300 mg) twice a day to compensate for the isozyme of the SURCA4-inducing effect of rifampicin. However, such a dose adjustment may be accompanied by an increase in ALT / AST activity and gastrointestinal disorders. Thus, without extreme necessity, it is recommended to avoid the use of this combination of drugs. If lopinavir / ritonavir is used at a corrected dose of 400 mg / 400 mg twice daily with rifampicin, careful monitoring of safety and efficacy is necessary. An increase in the dose of Kalidavir® should be given after rifampicin is started.

    Bedakvilin

    In a study on healthy volunteers, 400 mg of Beduklavine once and lopinavir / ritonavir 400/100 mg twice daily for 24 days were used, which resulted in an increase AUC Bedakvilina by 22%. Bedakvilin should be used with caution, together with lopinavir / ritonavir,and only if the benefit of joint application exceeds the potential risk of adverse reactions (see section "Special instructions" and "With caution").

    Delamanid

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

    Antiparasitic agents

    It is possible to reduce the therapeutic concentration of atovahona when used concurrently with lopinavir / ritonavir. An increase in the dose of atovahona may be required.

    Glucocorticosteroids (GCS)

    Dexamethasone may cause an increase in isoenzyme activity cyp3a4 and decrease concentrations of lopinavir.it is necessary to monitor antiviral activity during the use of dexamethasone and lopinavir / ritonavir.

    fluticasone

    simultaneous application of lopinavir / ritonavir and fluticasone can significantly increase the plasma concentration of fluticasone and lower serum concentrations of cortisol. it is recommended to consider alternatives to fluticasone, especially with prolonged use.

    on the systemic effects of glucocorticosteroids, including iscenko-cushing syndrome and suppression of the adrenal cortex, has been reported with simultaneous use of ritonavir with intranasal and inhaled forms of fluticasone and budesonide.

    the joint use of lopinavir / ritonavir and fluticasone, as well as other gx, which are metabolized by the isoenzyme cyp3a4, such as budesonide, is not recommended except when the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including cushing syndrome and suppression of adrenal cortex function.

    while simultaneous use of lopinavir / ritonavir and any of the glucocorticosteroids inhaled or injected through the nose should be particularly careful.should consider the possibility of reducing the dose of glucocorticoid with careful monitoring of local and general reactions, or the transition to a glucocorticosteroid that is not a substrate for isoenzyme cyp3a4 (e.g., beclomethasone). and also, in the event of cessation of glucocorticosteroid therapy, a gradual dose reduction should be performed over a long period.

    blockers of "slow" calcium channels (eg, 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 therapeutic effects and adverse reactions while using drugs of this group with lopinavir / ritonavir.

    inhibitors of fde-5

    special care should be taken when using sildenafil and tadalafil to treat erectile dysfunction in patients taking lopinavir / ritonavir, because with simultaneous administration of these drugs, one 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 low doses (25 mg every 48 hours) and more often monitor side effects. The use of sildenafil for the treatment of pulmonary arterial hypertension with concurrent administration of lopinavir / ritonavir is contraindicated.

    tadalafil

    use tadalafil for the treatment of erectile dysfunction should be cautious in reduced doses (not more than 10 mg every 72 hours) and more often to monitor side effects. The use of tadalafil for the treatment of pulmonary arterial hypertension with concurrent administration of lopinavir / ritonavir is contraindicated.

    vardenafil

    The simultaneous use of vardenafil with lopinavir / ritonavir is contraindicated.

    avanafil

    with the simultaneous use of avanafil and lopinavir / ritonavir, a significant increase in the concentrations of avanafil is possible. simultaneous application of avanafil and lopinavir / ritonavir is contraindicated.

    medicinal preparations based on medicinal plants

    patients receiving lopinavir / ritonavir treatment are contraindicated in the simultaneous administration of preparations containing St. John's wort, as this combination can help reduce plasma concentrations of lopinavir / ritonavir.this effect can occur due to induction of the isoenzyme cyp3a4 and may lead to loss of therapeutic effect and development of resistance.

    in case the patient is already taking St John's wort preparations and lopinavir / ritonavir is prescribed, it is necessary to cancel preparations of St. John's wort and to check the level of viral load. with the withdrawal of drugs containing St. John's wort, the concentration of lopinavir / ritonavir in the blood plasma may increase. a dose change of lopinavir / ritonavir may be required. The inducing effect may persist for at least 2 weeks after discontinuation of treatment with St. John's wort preparations. lopinavir / ritonavir is recommended to be administered 2 weeks after stopping the intake of St. John's wort.

    inhibitors of Gmg-CoA reductase

    lopinavir / ritonavir can cause a significant increase in plasma concentrations of the inhibitors of GMH-co-reductase metabolized by isoenzyme cyp3a4, such as lovastatin and simvastatin. an increase in the 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 isoenzyme cyp3a4, together with ritonavir / lopinavir should be used with caution in minimal doses. The combined use of atorvastatin with lopinavir / ritonavir is contraindicated. signs of clinically significant interaction of lopinavir / ritonavir with pravastatin was not revealed. the metabolism of pravastatin and fluvastatin does not depend on isoenzyme cyp3a4, so they should not interact with lopinavir / ritonavir. if the treatment is indicated HMG-CoA reductase in the application period of lopinavir / ritonavir, it is recommended to use pravastatin or fluvastatin.

    immunosuppressants

    concentrations of these drugs (e.g., cyclosporine, tacrolimus and sirolimus) can rise while the use of lopinavir / ritonavir. more frequent monitoring is recommended therapeutic concentrations as long as the concentrations of these drugs in the blood will not be stabilized.

    methadone

    it has been shown that lopinavir / ritonavir reduces plasma concentrations of methadone. it is recommended to monitor plasma concentrations of methadone.

    buprenorphine

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

    oral contraceptives or contraceptive in the form of a plaster

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

    vasodilator

    When bosentan was used concomitantly with lopinavir / ritonavir, there was an increase inmah and auc bosentan at 6 and 5 times, respectively. caution should be exercised when bosentan and lopinavir / ritonavir are used together. the appointment and selection of a dose of bosentan should be made in accordance with its instructions for use.

    it is also necessary to monitor the effectiveness of antiviral therapy and the side effects of bosentan, especially during the first week of sharing.

    clinically significant interaction is not expected

    conducted studies did not reveal a clinically significant interaction of lopinavir / ritonavir with desipramine, raltegravir, omeprazole and ranitidine.taking into account the information on metabolism, there is no expected clinically significant interaction of lopinavir / ritonavir with fluvastatin, dapsone, trimethoprim / sulfamethoxazole, azithromycin or fluconazole in patients with normal renal and hepatic function.

    Special instructions:

    Impaired liver function

    Lopinavir / ritonavir is mainly metabolized in the liver. In this regard, caution should be exercised in prescribing Kalidavir® to patients with mild to moderate hepatic impairment. The use of lopinavir / ritonavir is contraindicated in patients with severe impairment of liver function. Pharmacokinetic data indicate that in HIV-positive patients with hepatitis C and with a mild or moderate liver function disorder, an increase in plasma lopinavir concentration of about 30% is possible, as well as a decrease in its binding to plasma proteins. If the patient has hepatitis B or C or a significant increase in the activity of aminotransferases, the risk of further increase is higher before the start of treatment.

    In patients with already existing disorders of the liver, including chronic hepatitis,There is an increased incidence of liver function abnormalities during combined antiretroviral therapy. In this regard, careful monitoring is necessary in accordance with standard clinical practice. In case of worsening of patients, lopinavir / ritonavir therapy should be abolished.

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

    There have been reported cases of increased transaminase activity with a simultaneous increase in the concentration of bilirubin or without it within seven days after the commencement of lopinavir / ritonavir in combination with other antiviral agents. In some cases, violations of the liver were serious, but the cause-and-effect relationship of such cases with lopinavir / ritonavir therapy has not been established.

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

    Impaired renal function

    Since renal clearance of lopinavir and ritonavir is negligible, an increase in their plasma concentration is not expected in patients with renal insufficiency. Since lopinavir and ritonavir actively bind to blood plasma proteins, it is unlikely that they will be significantly removed during hemodialysis or peritoneal dialysis.

    Diabetes mellitus / hyperglycemia

    In the process of post-marketing research, cases of development and decompensation of diabetes mellitus and hyperglycemia were registered in HIV-infected patients receiving protease inhibitors. To treat these conditions, in some cases, you had to prescribe insulin or oral hypoglycemic drugs, or increase their doses. In some cases, diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after the withdrawal of the protease inhibitor. Reports of these cases have come in a voluntary manner, so it is not possible to assess their frequency and their 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

    Lopinavir / ritonavir-treated patients, including patients who had severe hypertriglyceridemia, developed pancreatitis. Cases with a lethal outcome are recorded. Although there is no association of this side effect with lopinavir / ritonavir, a significant increase in triglyceride concentration is a risk factor for pancreatitis. In patients with progressive HIV infection, the risk of developing hypertriglyceridemia and pancreatitis is increased, and in patients with pancreatitis a history of increased risk of recurrence during treatment with lopinavir / ritonavir is increased.

    Patients who have the following symptoms: nausea, vomiting, abdominal pain, or abnormalities in laboratory indicators (eg, increased lipase activity or amylase) should be examined, and if the diagnosis of pancreatitis is confirmed, treatment with the Kalidavir® drug should be discontinued.

    Resistance / Cross-resistance

    In the study of protease inhibitors, cross-resistance of varying degrees was observed.At present, the effect of lopinavir / ritonavir on the effectiveness of subsequent therapy with other protease inhibitors is being studied.

    Hemophilia

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

    Interval lengthening PR

    Against the background of lopinavir / ritonavir, some patients had mild asymptomatic lengthening of the interval PR. There have been reports of rare cases of atrioventricular blockade of grade II and III with lopinavir / ritonavir in patients with organic heart disease and previous disorders of the conduction system of the heart, or in patients taking drugs that extend the interval PR (such as verapamil or atazanavir). In such patients, lopinavir / ritonavir should be used with caution.

    Electrocardiogram

    Interval QTcF (with Fredericia correction) were evaluated in a randomized, placebo-controlled, cross-over-active study (moxifloxacin 400 mg once a day) involving 39 healthy adult volunteers. 10 measurements were made for 12 hours on day 3 of the study. Maximum standard deviation QTcF compared with placebo, was 3.6 (6.3) ms and 13.1 (15.8) ms for doses of lopinavir / ritonavir 400/100 mg twice daily and 800/200 mg twice daily, respectively. The changes observed with the use of the above two dosing regimens were approximately 1.5 and 3 times higher than those observed with the recommended doses of lopinavir / ritonavir once a day or twice a day in equilibrium. None of the patients reported an increase in the interval QTcF > 60 ms compared with the original value; interval QTcF did not exceed a potentially clinically significant threshold of 500 ms.

    In this study, on the third day, patients who took lopinavir / ritonavir also had a moderate increase in the interval PR. Max. Spacing PR was 286 ms; there was no development of atrial-ventricular blockade II or III degree.

    Redistribution of fat

    Against the backdrop of antiretroviral therapy, there was a redistribution / accumulation of fat with 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 the mammary glands and a Cushingoid. The mechanism and the long-term consequences of these undesirable phenomena are not known. Their association with lopinavir / ritonavir therapy has not been established.

    The high risk of lipodystrophy is associated with individual characteristics, such as advanced age, concomitant therapy (prolonged antiretroviral therapy and associated metabolic disorders). Clinical examination should include an assessment of both physical signs of fat redistribution and laboratory indicators (rapid measurement of lipids in blood serum and blood glucose concentration). Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice.

    Increase in lipid concentration

    Treatment with lopinavir / ritonavir resulted in an increase in the concentrations of total cholesterol and triglycerides. Before starting treatment with lopinavir / ritonavir and regularly during therapy,control the concentration of triglycerides and cholesterol. In the presence of lipid disorders, appropriate therapy is indicated. Particular care should be taken when administering lopinavir / ritonavir to patients with high initial lipid concentrations in the blood and lipid metabolism disorders in the anamnesis. Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice (see section "Interaction with other drugs: HMG-CoA reductase inhibitors").

    Immunodeficiency Syndrome

    Patients who received combined antiretroviral therapy, including lopinavir / ritonavir, observed the development of immune reconstitution syndrome. Against the backdrop of the restoration of the immune function at the onset of combined antiretroviral therapy, there may be an exacerbation of asymptomatic or residual opportunistic infections (such pathogens as Mycobacterium avium, cytomegalovirus, Pneumocystis jiroved (Pneumocystis carinii) or Mycobacterium tuberculosis), which may require additional examination and treatment.

    Against the backdrop of the development of the immune reconstitution syndrome, autoimmune diseases such as Graves' disease, polymyositis and Guillain-Barre syndrome,However, the period of occurrence of these events 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 GCS, alcohol abuse, high body mass index, pronounced immunosuppression, etc.). In particular, cases of osteonecrosis in patients with progressive HIV infection and / or prolonged use of combination antiretroviral therapy are reported. Therefore, such patients should be advised to consult a doctor when there is pain, joint stiffness and impaired motor function.

    Application in the elderly

    The number of patients 65 years of age or older was not sufficient to assess the possible differences in their response to lopinavir / ritonavir treatment compared to those in younger patients. When using lopinavir / ritonavir in elderly people, care should be taken in view of the increased incidence of impaired liver, kidney or heart function, concomitant diseases and concomitant therapy.

    Use in children

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

    Interaction

    Drugs, the simultaneous use of which with lopinavir / ritonavir is contraindicated: astemizole, blonanserin, terfenadine, midazolam (for oral administration), 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 methylergomethrin), inhibitors of HMG-CoA reductase (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine, preparations of St. John's wort, boceprevir, dronedaronApplying ketoconazole and itraconazole in high doses (over 200 mg / day), application of the standard dose Kalidavir® with rifampicin, drug application Kalidavir® tipranavir and ritonavir with a low dose, the preparation Kalidavir® once daily in combination with carbamazepine, phenytoin or phenobarbital, Kalidavir® application of the drug once a day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir, simeprevir.

    Joint application with colchicine Kalidavir® drug in patients with renal and / or hepatic insufficiency contraindicated due to possible increased risk of side effects, including life threatening associated with colchicine, such as neuromuscular toxicity (including rhabdomyolysis).

    Preparations, simultaneous use of which with lopinavir / ritonavir is not recommended: simultaneous application of lopinavir / ritonavir and fluticasone, as well as other GCS, which are metabolized by isoenzyme CYP3A4, such as budesonide, with the exception of cases,when the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and suppression of adrenal cortex function. The combined use of rivaroxaban and Kalidavir® may increase the risk of bleeding. The simultaneous use of the drug Kalidavir® with telaprevir is not recommended, since it can lead to a decrease in the equilibrium concentration of telprevir.

    Drugs with concomitant use with lopinavir / ritonavir should be used with caution: verapamil, atazanavir, phenyramine, quinidine, erythromycin, clarithromycin, simultaneous application with inhaled or nasal glucocorticosteroids, for example, fluticasone, budesonide, simultaneous use with drugs for the treatment of erectile dysfunction, namely with sildenafil, tadalafil, simultaneous use with fentanyl, rosuvastatin, bupropion, simultaneous use with antiarrhythmic agents such as beprideil, lidocaine and quinidine, simultaneous use with digoxin, lamotrigine, valproic acid, midazolam (administered parenterally), trazodone, Bedakville, bosentan.

    Effect on the ability to drive transp. cf. and fur:

    During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities, requiring increased concentration of attention and speed of psychomotor reactions. With the development of side effects that may affect these abilities, for example, dizziness, it is recommended to refrain from driving vehicles and controlling mechanisms. Studies of the ability to drive vehicles and control mechanisms have not been carried out.

    Form release / dosage:

    Tablets, film-coated, 100 mg + 25 mg, 200 mg + 50 mg.

    Packaging:

    Primary packaging of medicinal product.

    For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

    For 60, 80 or 160 tablets in a can of polymer with a lid pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing, or from polymer materials, self-adhesive.

    Secondary packaging of medicinal product.

    For 6 or 8 contour squares, together with the instructions for use, are placed in a pack of cardboard.

    On 1 bank together with the instruction on application place in a pack from a cardboard. The packets are placed in a group package.

    Storage conditions:

    In the original packaging of the manufacturer at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004303
    Date of registration:19.05.2017
    Expiration Date:19.05.2022
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp21.06.2017
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