Kaletra® (KALETRA)

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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  • Kaletra®
    pills inwards 
    EbbVi Ltd.     Russia
  • Kaletra®
    pills inwards 
    EbbVi Ltd.     Russia
  • Kaletra®
    solution inwards 
    EbbVi Ltd.     Russia
  • Calidavir®
    pills inwards 
    FARMASINTEZ, JSC (Irkutsk)     Russia
    • Dosage form: & nbspTfilm-covered abeys.
    Composition:

    Each tablet contains:

    First layer:

    active substances: lopinavir - 200 mg, ritonavir - 50 mg.

    Excipients: Copovidone To 28 - 853.8 mg; sorbitan laurate - 83.9 mg; silicon dioxide colloid - 12,00 mg;

    second layer: sodium stearyl fumarate - 12.3 mg; silicon dioxide colloidal - 8.0 mg; film coating: dye opedray red - 22.0 mg (hypromellose 6 tRa - 58.26% titanium dioxide - 10.32%, macrogol 400 -9.03%, giprolose - 5.78%, hypromellose 15 tRa - 5, 78%, talc - 4.11%, silicon colloidal dioxide - 0.15%, macrogol 3350 - 1.62%, iron stain oxide E172 - 4.80%, polysorbate 80 - 0.15%).

    Description:

    Red oval tablets covered with a film membrane. On one side the symbols "Ə"and"AL".

    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:

    Kaletra ® is a combination drug that contains lopinavir and ritonavir.

    Lopinavir is an inhibitor of HIV-1 and HIV-2 protease of the human immunodeficiency virus (HIV) and provides antiviral activity of the preparation Kaletra®.

    Kaletra® preparation, film coated tablets, is manufactured using MELTREX technology with the help of copovidone K28 (65 to 75% by weight). Inhibition of HIV proteases inhibits the synthesis of virus proteins, which leads to the formation of an immature and virus that is not able to infect.

    Ritonavir is an inhibitor of aspartyl-protease HIV-1 and HIV-2 for oral administration, an active peptidomimetic. Inhibition of HIV proteases inhibits the cleavage of the group-specific antigen-polymerase (gag-pol) bond of the polyprotein, which also leads to the formation of an immature and virus that is not able to infect. Ritonavir has a selective affinity for HIV protease and exhibits little activity with respect to aspartyl protease of a human.

    It inhibits isoenzyme mediated CYP3A metabolism of lopinavir in the liver, resulting in increased concentration of lopinavir in blood plasma.

    Resistance

    The development of resistance to lopinavir / ritonavir has been studied both in patients,previously untreated antiretroviral therapy, and in patients who received antiretroviral drugs earlier, including protease inhibitors HIV.

    In clinical studies of the antiviral activity of lopinavir / ritonavir in HIV-infected adults and children who have not received antiretroviral therapy before, no mutations associated with a decrease in sensitivity and development of resistance to lopinavir have been detected.

    In Phase II clinical trials of Kaletra®, among 227 HIV-infected patients who received and did not receive antiretroviral therapy before, 4 of 23 patients with virological inefficiency (HIV RNA> 400 copies / ml) showed a decrease in susceptibility to lopinavir through a 12- 100 weeks of therapy with Kaletra®; 3 out of 4 patients received a single protease inhibitor HIV (nelfinavir, saquinavir or indinavir), 1 out of 4 patients - multiple therapy with protease inhibitors HIV (indinavir, saquinavir and ritonavir). All 4 patients had at least 4 mutations associated with resistance to protease inhibitors HIV before starting therapy with Kaletra®.A further increase in viral load was associated with the appearance of additional mutations associated with the development of resistance to HIV protease inhibitors. However, these data are insufficient to identify the mutations responsible for the development of resistance to lopinavir.

    The determination of resistance to lopinavir in patients who did not respond to previous therapy with HIV protease inhibitors was performed by analyzing isolates isolated from 19 patients who underwent this type of therapy in two Phase II and one Phase III studies. These patients had incomplete virologic suppression or a sharp increase in viral load due to a primary response to Kaletra® therapy, and additional resistance was noted in vitro in the period from the initial level to a sharp increase in the viral load (defined as the emergence of new mutations or a change in the phenotypic sensitivity to lopinavir by a factor of 2). Additional resistance was most often observed in patients whose isolates at baseline showed several mutations associated with the use of HIV protease inhibitors, while sensitivity to lopinavir at the baseline was reduced by less than 40-fold.The most frequently observed mutations V82A, I54V and M46I. Also, mutations L33F, I50V and V32I in combination with I47V/A. In isolated 19 isolates, an increase IC50 (Half Maximal Inhibitory Concentration - the concentration of the drug necessary to suppress the replication of 50% of the viruses) is 4.3 times higher than that of the isolates at the baseline level (from 6.2 to 43 times in comparison with the wild type virus).

    Genotypic correlates associated with a decrease in the phenotypic sensitivity of viruses to lopinavir are taken into account when selecting other protease inhibitors. A study was made of the antiviral activity of lopinavir in vitro against 112 clinical isolates isolated from patients who did not respond to therapy with one or more HIV protease inhibitors. With reduced sensitivity to lopinavir in vitro the following mutations of HIV proteases were associated: L10F/I/R/V, K20M/R, L24I. M46I / L, F53L, I54L / T / V, L63P, A71I / L / T / V, V82A / F / T, I84V and L90M. Average EC50 (Effective concentration for inhibition of 50% of isolates - concentration that causes 50% lupinavir against isolates containing 0-3, 4-5, 6-7 and 8-10 mutations in the above amino acid positions was 0.8, 2.7, 13.5 and 44.0 times higher than the EU50 against HIV of the "wild" type, respectively.All 16 viruses, the sensitivity of which changed more than 20 times, contained mutations at positions 10, 54, 63 plus 82 and / or 84. In addition, they contained, on average, 3 mutations in amino acid positions 20, 24, 46, 53 , 71 and 90. In addition to the above mutations, in mutations with a reduced susceptibility to lopinavir isolated after a sharp increase in viral load in patients previously treated with HIV protease inhibitors and currently undergoing treatment with Kaletra®, mutations V32I and I47A, and in isolates with reduced sensitivity to lopinavir, isolated after a sharp increase in viral load in patients undergoing treatment with Kaletra®, mutations I47A and L76V.

    Conclusions made regarding the relevance of specific mutations and mutation maps may change when additional data are received, therefore, when evaluating the results of the sensitivity analysis, it is recommended that the current data interpretation systems be used.

    The antiviral activity of the Kaletra® drug in patients who did not respond to HIV protease inhibitor therapy: a clinical relevance study was conducted in vitro susceptibility to lopinavir by evaluating the virologic response to Kaletra® therapy for the genotype and phenotype of the virus at baseline in 56 patients without responding to previous therapy with a combination of HIV protease inhibitors. The EC50 of lopinavir versus 56 viral isolates isolated at the baseline level was 0.6-96 times higher than the EC50 against HIV of the "wild" type. After therapy with Kaletra®, Efavirenz and nucleoside reverse transcriptase inhibitors lasting 48 weeks, a plasma concentration of HIV RNA <400 copies / ml was observed in 93% (25/27), 73% (11/15) and 25% (2/8) of patients, while a decrease in susceptibility to lopinavir at the baseline was less than 10 times. 10-40 times and more than 40 times, respectively. In addition, a virologic response was noted in 91% (21/23), 71% (15/21) and 33% (2/6) of patients whose isolates contained 0-5, 6-7 and 8-10 mutations from the above mutations of HIV protease with reduced sensitivity to lopinavir in vitro. In view of the fact that these patients were not previously treated with Kaletra® and Efavirenz, the response may be partly due to the antiviral activity of the drug Efavirenz, especially in patients infected with a virus with high resistance to lopinavir.The design of the study did not imply the presence of a control group of patients who had not been treated with Kaletra®.

    Cross-resistance

    There is insufficient information on the development of cross-resistance during lopinavir / ritonavir therapy.

    The virologic response to lopinavir / ritonavir therapy has changed in the presence of three or more of the listed amino acid substitutions in the HIV protease gene. (L10F / I / R / V, K20M / N / R, L24I, M36I, I54L / T / V, I84V, G48V, L33F.147V, 82A / C / F / S / T).

    Clinical significance of decreased susceptibility to lopinavir in vitro was studied on the basis of a virologic response to lopinavir / ritonavir therapy depending on the initial genotype and phenotype of the virus in 56 patients with HIV RNA above 1000 copies / ml previously treated with nelfinavir, indinavir, saquinavir or ritonavir (study M98-957). In this randomized trial patients lopinavir / ritonavir was administered in one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Prior to the start of EC50 therapy (the concentration of the drug required to suppress the replication of 50% of the viruses), lopinavir in 56 strains of the virus was 0.5-96 times higher than EC50 for the wild type virus.In 55% (31/56) strains of the virus, the sensitivity to lopinavir was decreased by more than 4 times, while the average decrease in sensitivity to lopinavir among 31 strains was 27.9 times.

    Forty-eight weeks after initiation of lopinavir / ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, the HIV RNA concentration ≤400 copies / ml was determined in 93% (25/27), 73% (11/15), and 25% (2/8) patients, whose initial sensitivity to lopinavir was reduced <10 times, 10-40 times and> 40 times, respectively. In these groups, the concentration of HIV RNA was <50 copies / ml in 81% (22/27), 60% (9/15), and 25% (2/8) patients respectively.

    However, additional studies are needed to identify the mutations associated with resistance to lopinavir.

    Children

    Study M98-940 is an open study of the liquid dosage form of the preparation Kaletra® in 100 children who had previously undergone (56%) and did not undergo (44%) antiretroviral therapy. None of the patients were treated with nucleoside reverse transcriptase inhibitors. Patients were randomized to 2 treatment groups: 230 mg lopinavir / 57.5 mg ritonavir / m2 or 300 mg of lopinavir / 75 mg of ritonavir / m2. Previously untreated patients additionally received nucleoside reverse transcriptase inhibitors. Previously treated patients received nevirapine in combination with one or two nucleoside reverse transcriptase inhibitors. After 3 weeks, for each patient, the safety, efficacy and pharmacokinetic profile of both treatment regimens were assessed. Then, all patients continued treatment according to the scheme 300/75 / m ". The average age of the patients was 5 years (6 months to 12 years), the age of 14 patients was less than 2 years, the age of 6 patients was 1 year or less. Average concentration Cd4+ T cells at baseline were 838 cells / mm3, and the average plasma concentration of HIV-1 RNA at baseline was 4.7 (decimal logarithm) copies / ml.

    Table 1

    Outcomes in Week 48: Study M98-940


    Patients who did not previously antiretroviral therapy (N = 44)

    Patients who had previously undergone antiretroviral therapy (N=56)

    HIV RNA <400 copies / ml

    84%

    75%

    Average increase in content Cd4+ T cells in comparison with baseline (kl / mm3)

    404

    284

    KONCERT/PENTA 18 is a prospective, multicenter, randomized, open-label study of the pharmacokinetic profile,efficacy and safety of lopinavir / ritonavir regimens in the form of 100 mg / 25 mg tablets (body weight) 2 times a day and 1 time per day as part of combination antiretroviral therapy (CART) in HIV-1 infected children with virologic suppression (n=173). To participate in the study, children under the age of 18, with a body weight> 15 kg, undergoing a cART (including lopinavir / ritonavir), with an HIV-1 RNA content <50 copies / ml for at least 24 weeks, are able to take the pill. At the 24th week, the efficacy and safety of the lopinavir / ritonavir-administered regimen in the form of 100 mg / 25 mg 2 pills / day tablets (n= 87) in the pediatric population were comparable to the safety and efficacy results obtained in previous studies of 2 r / day in adults and children with lopinavir / ritonavir. The percentage of patients with HIV-1 RNA <50 copies / ml at week 24 was lower in the pediatric population who received the combination lopinavir / ritonavir (tablets) 1 p / day (88.2%) than in the population of patients receiving medication 2 r / day (96.6%, p = 0.040), mainly due to a decrease in compliance in the group with a regimen of 1 p / day.The results show the efficacy of the drug regimen of 2 p / day, as evidenced by the analysis of pharmacokinetic parameters.

    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 action isoenzyme CYP3A. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its concentrations in the plasma. When using lopinavir / ritonavir 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 when taking ritonavir 600 mg twice daily. 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 HIV-positive patients who received lopinavir / ritonavir 400/100 mg twice daily for three weeks, the mean maximum concentration of lopinavir in plasma (CmOh) was 9.8 ± 3.7 μg / ml and was achieved approximately 4 hours after administration. Average equilibrium concentration (in the morning before taking the next dose) was 7.1 ± 2.9 μg / ml, and the minimum concentration was 5.5 ± 2.7 μg / ml. AUC (area under the pharmacokinetic curve "concentration-time") lopinavir for 12 hours averaged 92.6 ± 36.7 μg * h / ml. Absolute bioavailability of lopinavir in combination with ritonavir is not established.

    Effect of food on drug absorption

    With a single admission of lopinavir / ritonavir tablets at a dose of 400/100 mg with food AUC and Cmax significantly did not change in comparison with those when taking the drug on an empty stomach. AUC increases with the intake of tablets together with food with a moderate fat content (500-682 kcal, 23-25% of calories due to fat) and a high fat content (872 kcal, 56% of calories from fat) by 26.9% and 18.9% respectively, compared with reception on an empty stomach. FROMmOh increases by 17.6% when taking tablets with moderately fatty foods, a high fat content in food does not significantly change CmOh. Therefore, lopinavir / ritonavir tablets can be used regardless of food intake.

    Distribution

    In the equilibrium state, lopinavir is approximately 98-99% bound to plasma proteins.Lopinavir binds both to the alpha-1-acid glycoprotein and albumins, however, it has a great affinity for the alpha-1-acid glycoprotein. In an equilibrium state, binding of lopinavir to proteins remains constant in the range of registered concentrations produced after taking lopinavir / ritonavir at a dose of 400/100 mg twice a day, and is comparable in healthy volunteers and Of HIV-positive patients.

    Metabolism

    Lopinavir is primarily subjected to intense oxidative metabolism involving the cytochrome P450 system of hepatocytes almost exclusively under the influence of isoenzyme CYP3A. Ritonavir is a potent inhibitor isoenzyme CYP3A and interferes with the metabolism of lopinavir, which provides an increase concentrations lopinavir in blood plasma. There were 13 oxidative metabolites of lopinavir in human blood plasma, 4-oxo and 4-hydroxymetabolite isomeric pairs are the main metabolites with antiviral activity. After a single 400/100 mg administration of lopinavir / ritonavir, labeled with 14C-lopinavir, 89% of the radioactivity in the plasma was associated with the unchanged drug.Concentrations of lopinavir before taking the next dose decrease with time and stabilize after about 10-16 days.

    Excretion

    After a single administration of lopinavir / ritonavir in a dose of 400/100 mg after 8 days, about 10.4 ± 2.3% of the dose of lopinavir taken is detected in the urine and 82.6 ± 2.5% of lopinavir is found in the stool, and unchanged lopinavir is respectively 2.2% and 19.8%. After repeated administration of less than 3% of the dose, lopinavir is excreted unchanged through the kidneys. The clearance of lopinavir for oral administration is 5.98 ± 5.75 l / h.

    Application once a day

    The pharmacokinetics of lopinavir / ritonavir with a multiple of once daily was studied in HIV-infected patients who had not previously received antiretroviral therapy. Lopinavir / ritonavir in a dose of 800/200 mg was prescribed in combination with emtricitabine at a dose of 200 mg and tenofovir at a dose of 300 mg. All drugs were used once a day. When lopinavir / ritonavir was used at a dose of 800/200 mg once a day with food for 4 weeks, the maximum concentration of lopinavir was reached approximately 6 hours after administration and averaged 11.8 ± 3.7 μg / ml. Average equilibrium concentration (before taking the morning dose) averaged 3.2 ± 2.1 μg / ml, and the minimum concentration within the dosing interval was 1.7 ± 1.6 μg / ml. AUC lopinavir during the day was equal to an average of 154.1 ± 61.4 μg-h / ml.

    Special Groups

    Sex, race and age

    The pharmacokinetics of lopinavir in elderly people has not been studied. In adults, the pharmacokinetics of lopinavir did not depend on sex. The clinically significant dependence of pharmacokinetics on race is also not established.

    Renal insufficiency

    The pharmacokinetics of lopinavir has not been studied in patients with renal insufficiency. However, the kidney clearance of lopinavir is insignificant, so there is no reason to expect a decrease in the overall clearance of the drug in the presence of kidney failure.

    Impaired liver function

    Lopinavir is metabolized and excreted mainly by the liver. With the repeated use of lopinavir / ritonavir at a dose of 400/100 mg twice daily for patients, infected with HIV and hepatitis C virus with impaired liver function of moderate or mild severity increased AUC and CmOh lopinavir at 30% and 20%, respectively, compared with those in HIV-infected patients with normal liver function.

    The binding of lopinavir to plasma proteins in patients with impaired liver function of moderate or mild severity was slightly lower than in the control group (99.09% and 99.31%, respectively).

    The pharmacokinetics of lopinavir / ritonavir have not been studied in patients with severe impairment of liver function.

    Pregnancy and the puerperium

    Pharmacokinetic data show that there is a slight decrease AUC and FROMmax 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 lopinavir / ritonavir coated tablets, 400/100 mg twice daily, are presented in the table below:

    The average 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 (μg - 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)

    FROMpredose3 (μg / ml)

    4,7 (25,2)

    4,3 (39,0)

    6,5 (40,4)

    1- n = 18 FOR FROMmax

    2 - n = 16 FOR Cpredose *

    3 - the concentration of the drug (in the serum) immediately before the next dose.
    Indications:Treatment of HIV infection in adults and children from 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 via the CYP3A isoenzyme. These drugs include: astemizole, blonanserin, terfenadine, midazolam (for oral administration), triazolam, cisapride, pimozide, salmeterol, sildenafil (only in case of treatment of pulmonary hypertension, see "Interaction with other drugs"), tadalafil (only in case of 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 a standard dose of Kaletra® with rifampicin.

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

    - Children up to 3 years of age (children aged 6 months to 3 years are prescribed a drug in the form of a drug "oral solution").

    - Use of Kaletra * once a day in children under 18 years.

    - The use of the preparation Kaletra® once a day in combination with carbamazepine, phenobarbital or phenytoin.

    - The use of the preparation Kaletra® 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).

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

    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, Patients with disorders of the conduction system of the heart in the anamnesis or Patients, taking drugs, lengthening the interval PR (such as verapamil or atazanavir).

    - 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), antiarrhythmic drugs (for example, bepridilom, lidocaine, quinidine), digoxin, lamotrigine, valproic acid (see "Interaction with other drugs ").

    - Simultaneous application with drugs that extend the interval QT.

    - Simultaneous application with bedakvilinom, trazodone.

    Pregnancy and lactation:

    During pregnancy, one should analyze the potential benefits of taking the drug with respect to the possible risk to the mother and child.

    Women should stop breastfeeding.

    Dosing and Administration:

    Inside, regardless of food intake. Tablets Kaletra ® should be swallowed whole, not chewing, not breaking and not crushing.

    Adults

    - The recommended dose of the preparation Kaletra® (film-coated tablets, 200/50 mg) is 400/100 mg (2 tablets) twice a day or

    - 800/200 mg (4 tablets) once a day in patients with less than 3 mutations associated with the development of resistance to lopinavir. There is insufficient data for the use of Kaletra® once a day in patients with 3 and more mutations associated with the development of resistance to lopinavir.

    Concomitant therapy

    Taking Kaletra® once a day with simultaneous medication carbamazepine, phenobarbital or phenytoin is contraindicated.

    The use of the preparation Kaletra ® in combination with omeprazole and ranitidine does not require dose adjustment.

    With simultaneous reception with drugs efavirenz, nevirapine, amprenavir or nelfinavir in patients taking antiviral drugs for a long time in case of suspected decrease in susceptibility to lopinavir (based on medical history or laboratory studies), an increase in the dose of Kaletra® to 500/125 mg is necessary (two tablets of Kaletra® 200/50 mg + one tablet of Kaletra® 100 / 25 mg) 2 times a day.

    Taking Kaletra® once a day with simultaneous medication efavirenz, nevirapine, amprenavir or nelfinavir is contraindicated.

    Children

    Use Kaletra® once a day in pediatric patients it is contraindicated. The dose of drug Kaletra® adult patients (400/100 mg twice daily) without the simultaneous application of efavirenz, nevirapine, amprenavir or nelfinavir can be used in children from 35 kg body weight and more or body surface area (BSA) of 1.4 m2 and more.

    In children with a body weight of less than 35 kg and with a body surface area of ​​0.6 m2 up to 1.4 m2 it is recommended to use Kaletra ® tablets 100 mg + 25 mg; for children with PPT less than 0.6 m2 3 years or younger there Kaletra® drug in solution form for oral administration of 80 mg + 20 mg / ml.

    Guidelines for dispensing tablets Kaletra® 100 mg + 25 mg and Kaletra® drug in solution form for oral administration are given in the instructions for use of these drugs.

    The surface area of ​​the body can be calculated by the following formula:

    PPT (m2) = √ (Poct (cm) x Body weight (kg) / 3600)

    Application during pregnancy and in the puerperium

    - According to several clinical studies, the change in the dose of the drug Kaletra during pregnancy and in the postpartum period is not required.

    - The use of lopinavir / ritonavir once daily is contraindicated in pregnant women due to the 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 (very 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.

    Disturbances from the liver and bile ducts

    Unknown: jaundice.

    From the nervous system

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

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

    From the side of the cardiovascular system

    Often: arterial hypertension.

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

    Unknown: elongation PR interval.

    From the skin and subcutaneous fat

    Often: rash, including maculopapular, dermatitis, eczema, seborrhea, increased sweating at night, itching, lipodystrophy and redistribution of subcutaneous fat.

    Infrequently: alopecia, capillaritis, vasculitis.

    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, decreased appetite, diabetes mellitus.

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

    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, increased serum aspartate aminotransferase activity (ACT), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGTP), lipase,amylase, creatine phosphokinase, decrease concentration of inorganic phosphorus, hemoglobin, decrease in creatinine clearance.

    Description of individual adverse reactions

    Cushing's syndrome was reported in patients who received ritonavir on the background of inhalation or intranasal application of fluticasone propionate; this phenomenon can develop in the treatment of other glucocorticosteroids metabolized with the participation of cytochrome P450 3A (for example, budesonide).

    In the treatment of HIV protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors, there have been reports of increased activity of creatine phosphokinase, myalgia. Myositis and, in rare cases, rhabdomyolysis.

    With combined antiretroviral therapy, redistribution of adipose tissue (lipodystrophy) was noted in HIV-positive patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat content, mammary hypertrophy, and dorso-cervical obesity (buffalo buffalo).

    With combined antiretroviral therapy, metabolic disturbances have also been observed,such as hypertriglyceridemia, hypercholesterolemia, insulin resistance. hyperglycemia and hyperlactatemia.

    In HIV-positive patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may develop at the onset of the CART. Also reported were autoimmune disorders (such as Graves' disease); However, the period of development of such violations varies and can be several months.

    Osteonecrosis has been reported, especially in patients with related risk factors, progressive HIV infection, or long-term MAP. Information on the frequency of development of this phenomenon is absent.

    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, elevation or lowering of sodium content.

    In applying lopinavir / ritonavir were also reported some cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, Multimoulds hydrochloric exudative erythema and bradyarrhythmias.

    Overdose:

    At present, the clinical experience of acute overdose with lopinavir / ritonavir in humans is limited. There is no specific antidote. Treatment consists of activities aimed at maintaining the life support of the body, including monitoring vital systems and monitoring the clinical condition patient. If necessary, the unabsorbed drug is removed by gastric lavage, for which purpose the use of activated charcoal may be beneficial. 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. Simultaneous use of lopinavir / ritonavir and drugs, mainly metabolized by isoenzyme CYP3A (for example, dihydropyridine blockers of "slow" calcium channels,inhibitors of HMG-CoA reductase, immunosuppressants and phosphodiesterase 5 (PDE5) inhibitors) may lead to an increase in plasma concentrations of these drugs, the therapeutic or side effects of which may be increased or prolonged. 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 in clinically significant concentrations does not inhibit isozymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2.

    In vivo it has been shown that lopinavir / ritonavir induces its own metabolism and enhances the biotransformation of some other drugs that undergo glucuronidation and are metabolized with the participation of cytochrome P450 isoenzymes (including isozymes 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

    It is recommended that didanosine on an empty stomach; 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 side effects associated with tenofovir.

    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 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 be applied once a day it is contraindicated.

    Efavirenz

    An increase in the dose of lopinavir / ritonavir tablets to 500/125 mg (two tablets of Kaletra® 200/50 mg + one tablet of Kaletra® 100/25 mg) twice a day does not affect the concentration of lopinavir in blood plasma compared with 400 lopinavir / ritonavir / 100 mg twice daily 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 to dose of lopinavir / ritonavir 400/100 mg tablets (two (2) 200/50 mg tablets) twice daily 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 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 concentrations of amprenavir (taking amprenavir 750 mg twice daily plus lopinavir / ritonavir leads to an increase AUC, a similar CmOh, an increase in 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 use of fosamprenavir and lopinavir / ritonavir is not recommended.

    Indinavir

    Lopinavir / ritonavir may increase concentrations of indinavir (when indinavir is combined at a dose of 600 mg twice daily with concomitant use of lopinavir / ritonavir, a decrease in CmOh, an increase in 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 can increase the concentration of nelfinavir and nelfinavir metabolite M8 (at reception Nelfinavir 1000 mg twice a day, and lopinavir / ritonavir compared to nelfinavir 1,250 mg twice daily observed similar AUC, a similar CmOh, 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 plus lopinavir / ritonavir compared with taking saquinavir 1200 mg three times a day leads to an increase AUC, FROMmOh and Cmin). 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

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

    Boceprevir

    Simultaneous use of lopinavir / ritonavir with bocetrevir leads to a decrease equilibrium concentrations of boceprevir 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 an increase in the concentration of maraviroc. When used concomitantly with lopinavir / ritonavir at 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.

    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 (beprideil, 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.

    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 digoxin concentrations in serum.

    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 development 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)

    It is possible to increase their serum concentrations when used concomitantly with lopinavir / ritonavir, which can lead to the occurrence of side effects, usually associated with these antitumor 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 and 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 trazodone concentration. 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 phenytoin should be monitored when the drug is used concomitantly with 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 concentration in the blood plasma.

    For patients who start or stop taking Kaletra® during lamotrigine therapy, monitor the plasma lamotrigine concentration before starting co-administration with Kaletra®, during the first 2 weeks of co-administration, or 2 weeks after the discontinuation of Kaletra® to determine whether a dose of lamotrigine should be changed.

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

    Sleeping Pills

    Midazolam and triazolam

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

    It is forbidden to use midazolam inward in combination with the drug Kaletra®, but it is allowed with caution to apply midazolam parenterally in combination with the Kaletra® drug. 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, methylergonovine

    An increase in the plasma concentration of ergot derivatives leads to an increase in its toxicity, including vasospasm and ischemia.

    Medicinal products, regulating motor function of the digestive tract

    Cisapride

    An increase in the plasma concentration of cisapride increases the risk of developing severe arrhythmia.

    Antihistamines

    Astemizole, terfenadine

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

    Beta-2-adrenomimetics

    Salmeterol

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of salmeterol in the blood plasma can increase. The simultaneous use of 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.

    Alpha-1-adrenoblockers

    Alfuzosin

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of alfuzosin in the blood plasma can increase, while increasing the risk of severe arterial hypotension. The simultaneous use of lopinavir / ritonavir and alfuzosin is 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. Use ketoconazole and itraconazole in high doses (more than 200 mg / day) together with lopinavir / ritonavir it is contraindicated.

    Voriconazole

    The study showed that simultaneous application of ritonavir in 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

    With the simultaneous use of colchicine with lopinavir / ritonavir, an increase in colchicine concentration is possible. The appointment and selection of colchicine dose should be made in accordance with its instruction for use.

    The simultaneous use of colchicine with lopinavir / ritonavir is not recommended because of the side effects of colchicine associated with neuromuscular toxicity.

    Antibacterial agents

    Lopinavir / ritonavir may cause moderate increase AUC clarithromycin. Have patients with a violation of liver function should reduce the dose of clarithromycin when used simultaneously with lopinavir / ritonavir. In patients with renal insufficiency (creatinine clearance <30 ml / min), the dose of clarithromycin should be reduced while simultaneous application with lopinavir / ritonavir.

    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 preparation Kaletra® is inevitable, it is recommended to monitor side effects from the side musculoskeletal and connective tissue.

    Anti-TB drugs

    Rifabutin

    With the simultaneous use of rifabutin and lopinavir / ritonavir for ten days CmOh 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.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 the Kaletra® preparation is not required.

    Rifampicin

    Co-administration of the drug Kaletra® with riffs with picin is not recommended, as a decrease in the concentration of lopinavir can lead to a significant reduction in its therapeutic effect. It is allowed to adjust the dose of Kaletra® 400 mg / 400 mg (i.e., Caletra® 400/100 mg + ritonavir 300 mg) twice a day to compensate for the isoenzyme CYP 3A4-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 a combination of Kaletra® is used at the adjusted dose of 400 mg / 400 mg twice daily and rifampicin, careful monitoring of safety and efficacy is necessary. An increase in the dose of Kaletra® is necessary Perform only after starting rifampicin.

    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").

    Antiparasitic agents

    It is possible to reduce the therapeutic concentration of atovahona when used concurrently with lopinavir / ritonavir. It may be necessary to increase the doses of atovahona.

    Glucocorticosteroids (GCS)

    Dexamethasone may cause an increase in isoenzyme activity CYP3A4 and decreased concentrations of lopinavir. It is necessary to monitor antiviral activity during the use of dexamethasone and the preparation Kaletra®.

    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 systemic effects of corticosteroids, including Cushing's syndrome and depression of adrenocortical reported while the use of ritonavir with intranasal and inhaled forms of fluticasone and budesonide.

    The combined use of lopinavir / ritonavir and fluticasone and other corticosteroids that are metabolized isoenzyme CYP3A4, 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 suppression of adrenal cortex function.

    With the simultaneous use of lopinavir / ritonavir and any of the glucocorticosteroids inhaled or injected through the nose, care should be taken.Consider the possibility of reducing the dose of a glucocorticosteroid with careful monitoring of local and general reactions or switching to a glucocorticosteroid that is not a substrate for isoenzyme CYP3A4 (e.g., beclomethasone). And also, in In the event of cessation of glucocorticosteroid therapy, a gradual dose reduction should be performed over a long period.

    Blocks of "slow" calcium channels (eg, felodipine, nifedipine, nicardipine)

    An increase in the serum concentrations of these drugs may be observed with simultaneous use with lopinavir / ritonavir. It is recommended to monitor therapeutic effects and adverse reactions while using Kaletra® with the drugs of this group.

    PDE-5 Inhibitors

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

    Sildenafil

    Use sildenafil for the treatment of erectile dysfunction should be cautiously 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 simultaneous administration of lopinavir / ritonavir is contraindicated.

    Tadalafil

    Use tadalafil for treatment of erectile dysfunction should be cautiously in reduced doses (not more than 10 mg every 72 hours) and more often monitor side effects.

    Use of tadalafil for the treatment of pulmonary arterial hypertension simultaneous administration of lopinavir / ritonavir is contraindicated.

    Vardenafil

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

    Avanafil

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

    Herbal medicines

    Patients receiving lopinavir / ritonavir treatment are contraindicated in the simultaneous administration of preparations containing St. John's wort, as this combination may help reduce plasma concentrations of lopinavir / ritonavir.This effect can occur due to induction of the isoenzyme CYP3A4 and can lead to loss of therapeutic effect and development of resistance.

    In the event that the patient is already taking the preparations of St. John's wort, he is prescribed Kaletra®, it is necessary to cancel preparations of St. John's wort and to check the level of viral load. If you cancel preparations containing St. John's Wort, the concentration of lopinavir / ritonavir in the blood plasma may increase. It may be necessary to change the dose of Kaletra®. The inducing effect may persist for at least 2 weeks after discontinuation of treatment with St. John's wort preparations. The drug Kaletra® is recommended to be administered 2 weeks after stopping the intake of St. John's wort preparations.

    Inhibitors of HMG-CoA reductase

    Lopinavir / ritonavir can cause a significant increase in plasma concentrations of HMG-CoA reductase inhibitors metabolized by isoenzyme CYP3A4, such as lovastatin and simvastatin. An increase in the concentrations of these statins can lead to the development of myopathy, including rhabdomyolysis, so their combination with lopinavir / ritonavir is contraindicated. Rosuvastatin, the metabolism of which is less dependent on isoenzyme CYP3A4, together with ritonavir / lopinavir should be used with caution in minimal doses. The use of atorvastatin with the preparation Kaletra® is contraindicated.

    Signs of clinically significant interaction of lopinavir / ritonavir with pravastatin have not been revealed. The metabolism of pravastatin and fluvastatin does not depend on isoenzyme CYP3A4, so they should not interact with lopinavir / ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated during the period of lopinavir / ritonavir use, pravastatin or fluvastatin.

    Immunosuppressive drugs

    Concentrations of these drugs (eg, cyclosporine, tacrolimus and sirolimus) may increase with simultaneous use with lopinavir / ritonavir. It is recommended more frequent monitoring of therapeutic concentrations until the concentrations of these drugs in the blood are stabilized.

    Methadone

    It has been shown that lopinavir / ritonavir reduces plasma concentrations of methadone. Control of plasma concentrations of methadone is recommended.

    Buprenorphine

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

    Oral contraceptives or contraceptives in the form of a plaster

    Since ethinyl estradiol concentrations 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 funds

    With the simultaneous use of bosentan in combination with lopinavir / ritonavir, there was an increase in CmOh and AUC bosentan in 6 and 5 times, respectively. The drug Kaletra® with bosentan should be administered with caution. The appointment and selection of a dosage of bosentan should be made in accordance with its instruction 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 joint use.

    Clinically significant interaction is not expected

    The conducted studies did not reveal clinically significant interaction of lopinavir / ritonavir with desipramine, raltegravir, omeprazole and ranitidine.

    Given the information on metabolism, no clinically significant interaction of lopinavir / ritonavir with fluvastatin, dapsone, trimethoprim / sulfamethoxazole, azithromycin, or fluconazole is expected patients with normal kidney and liver function.

    Special instructions:

    Impaired liver function

    Lopinavir / ritonavir is mainly metabolized in the liver. In this regard, care should be taken when prescribing this drug patients with mild to moderate severity of the liver.

    The use of the drug Kaletra® is contraindicated in severe hepatic insufficiency. The use of lopinavir / ritonavir has not been studied in patients with severe impairment of liver function, so this use is contraindicated. Patients with chronic hepatitis B and C receiving CART are at high risk of developing severe and potentially lethal adverse reactions from the liver. In case of concomitant antiviral therapy of hepatitis B and C, it is necessary to get acquainted with the information on the medical use of medicines used in combination therapy.

    In patients with previously diagnosed liver dysfunction, including chronic hepatitis, there is a higher incidence of liver function abnormalities in the context of MTCT, so in this case monitoring in accordance with existing standards of medical care is needed. In case of worsening of the course of liver disease in such patients, it is necessary to consider the issue of temporary discontinuation or withdrawal of drugs.

    Pharmacokinetic data suggest that HIV-positive patients from hepatitis C and mild or moderate severity of liver function impairment may increase the concentration of lopinavir in plasma by about 30%, as well as reduce its binding to plasma proteins. In the presence of hepatitis B or C or a significant increase in the activity of aminotransferases before the start of treatment, the risk of their further increase is increased. HIV-infected patients with chronic hepatitis B or C. receiving 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 of the liver receiving excessive drug therapy. The association 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 the renal clearance of lopinavir and ritonavir is negligible, an increase in the plasma concentration of these substances in patients with kidney disease is not expected. Given the high degree of binding of lopinavir and ritonavir to proteins, the removal of these substances in a significant amount in hemodialysis or peritoneal dialysis seems unlikely.

    Diabetes mellitus / hyperglycemia

    In the process of post-registration observation, cases of development and decompensation of diabetes mellitus and hyperglycemia were registered in HIV-infected patients receiving protease inhibitors. In some cases, it was necessary to prescribe insulin or oral hypoglycemic agents or increase their doses. Sometimes diabetic ketoacidosis developed. Some patients Hyperglycemia persisted after the withdrawal of the protease inhibitor. Reports of these cases have been received voluntarily, so assess their frequency and their association with protease inhibitor therapy HIV was not possible. When using lopinavir / ritonavir in patients with diabetes mellitus, it is necessary to monitor the concentration of glucose in the blood.

    Pancreatitis

    Have patients, who received lopinavir / ritonavir, observed the development of pancreatitis, including the appearance of severe hypertriglyceridemia. Cases with a lethal outcome are recorded. Although the association of this side effect with lopinavir / ritonavir has not been established, nevertheless, a significant increase in triglyceride concentration is a risk factor for pancreatitis. Have patients with progressive HIV infection, the risk of developing hypertriglyceridemia and pancreatitis is increased, and patients with pancreatitis in the anamnesis increased the risk of its aggravation during treatment with lopinavir / ritonavir.

    If there are clinical symptoms (nausea, vomiting, abdominal pain) or abnormal laboratory parameters (increased serum lipase or amylase concentration), the probability of developing pancreatitis should be considered. In the case of diagnosing pancreatitis, therapy with Kaletra® should be discontinued.

    Redistribution of adipose tissue and metabolic disorders

    With CART, HIV patients may have a redistribution of adipose tissue (lipodystrophy). The long-term consequences of this phenomenon are not currently it is known. The mechanism of development of this phenomenon is not completely clear. There is a hypothesis about a link between visceral lipomatosis and the use of HIV protease inhibitors, as well as between lipoatrophy and the use of nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy is associated with individual factors, such as belonging to the older age group, as well as with the factors of therapy,such as the long duration of antiretroviral therapy and associated metabolic disorders. The clinical examination should include an assessment of the physical signs of fat tissue redistribution. It is necessary to determine serum lipid and fasting blood glucose. Therapy of lipid metabolism disorders should be carried out in accordance with clinical practice.

    Resistance / Cross-resistance

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

    Hemophilia

    Have patients with haemophilia type A and B, when treated with protease inhibitors, cases of bleeding are described, including spontaneous subcutaneous hematoma formation and hemarthrosis development. 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. No causative link or mechanism for the development of such adverse events in the treatment of protease inhibitors has been established.

    Interval lengthening PR

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

    Electrocardiogram

    Interval QTcF (adjusted for Fridericia) were evaluated in a randomized, placebo-controlled, cross-over study with active control (moxifloxacin 400 mg once a day) involving 39 healthy adult volunteers. 10 measurements were made for 12 hours on day 3 of the study. Average maximum difference QTcF compared with placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for doses of 400/100 mg twice daily and 800/200 mg twice daily for lopinavir / ritonavir, respectively. The changes observed with the use of the above two dosing 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 in an equilibrium state. 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 the same study on Day 3, patients who took lopinavir / ritonavir also had an increase in the interval PR in an average degree. Max. Spacing PR was 286 ms, there was no development of atrioventricular block of II or III degree.

    Increase in lipid concentration

    Treatment with lopinavir / ritonavir resulted in an increase in the concentrations of total cholesterol and triglycerides. Before beginning treatment with lopinavir / ritonavir and regularly during therapy should monitor the concentration of triglycerides and cholesterol. Special care must be taken in the treatment of patients with an elevated lipid content at the baseline and with lipid alterations in the anamnesis. Therapy of lipid metabolism disorders should be carried out in accordance with clinical practice (see section "Interaction with other drugs").In the presence of lipid disorders, appropriate therapy is indicated.

    Immunodeficiency Syndrome

    Have patients, who received combined antiretroviral therapy, including lopinavir / ritonavir, observed the development of immune reconstitution syndrome. Against the background of restoration of the immune function at the onset of combined antiretroviral therapy, asymptomatic or residual opportunistic infections (such as Mycobacterium avium, cytomegalovirus, Pneumocystis jiroveci (Pneumocystis carinii) or Mycobacterium tuberculosis), which may require additional examination and treatment.

    Against the backdrop of the development of immune reconstitution syndrome, autoimmune diseases such as Graves' disease, polymyositis and Guillain-Barre syndrome have been observed, but the timing of these events may 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 have been reported in patients with progressive HIV infection and / or prolonged use of combination antiretroviral therapy. Therefore, these patients should be advised to consult a doctor when there is pain, joint stiffness and impaired motor function.

    Application in the elderly

    amount patients at the age of 65 years and older was insufficient to assess the possible differences in their response to lopinavir / ritonavir treatment compared with those in younger patients. When using lopinavir / ritonavir in elderly people, care should be taken in view of the increased incidence of decreased hepatic, renal or cardiac function, concomitant diseases and concomitant therapy.

    Use in children

    The safety and pharmacokinetics of lopinavir / ritonavir in children less than 6 months old have not been established. In HIV-infected children aged 6 months to 18 years side effect profile in clinical trials was similar to that of adults. Use lopinavir / ritonavir once a day in children it is contraindicated.

    Interaction

    The preparation Kaletra® contains lopinavir and ritonavir, which are inhibitors of the isoenzyme CYP3A - cytochrome P450. With the use of the preparation Kaletra®, the probability of an increase in the plasma concentration of drugs metabolized predominantly by isoenzyme CYP3A, as a result, it is possible to increase or prolong the therapeutic effect and undesirable reactions associated with the use of these agents (see the sections "Contraindications" and "Interaction with other drugs").

    Strong inhibitors of isoenzyme CYP3A4, such as HIV protease inhibitors, can enhance the action of Bedakwin and increase the risk of developing relevant adverse reactions. Therefore, it is recommended that joint use of poorakwin and lopinavir / ritonavir be avoided. However, if the benefit is greater than the risk, co-administration of Bedakville and lopinavir / ritonavir is permitted with caution. It is recommended to carry out ECG more often and to control the content of transaminases (see the section "Interaction with other drugs" and instructions on the medical use of Bedakville).

    Joint use with colchicine, especially in patients with liver or kidney disease, is prohibited (see section "Interaction with other drugs").

    It is not recommended to use the drug Kaletra® in combination with the following agents (see the sections "With caution", "Contraindications" and "Interaction with other medicinal products"):

    - tadalafil for the treatment of pulmonary arterial hypertension is contraindicated;

    - Fusidic acid for the treatment of skin infections is contraindicated;

    - salmeterol is contraindicated;

    - Rivaroxaban is not recommended.

    The use of the preparation Kaletra® in combination with atorvastatin is contraindicated.

    When using the preparation Kaletra ® in combination with rosuvastatin should be cautious and use drugs in low doses.

    If it is necessary to administer therapy with HMG-CoA reductase inhibitors, the drugs of choice are pravastatin and fluvastatin (see section "Interaction with other drugs").

    Inhibitors of PDE-5: caution should be exercised when administering Kaletra® together with drugs sildenafil or tadalafil for the treatment of erectile dysfunction due to a significant increase in their concentration and the development of relevant undesirable phenomena such as hypotension, fainting,impairment of vision, prolongation of erection (see section "Interactions with other drugs").

    The use of avanafil or vardenafil in combination with lopinavir / ritonavir is contraindicated (see section "Interactions with other drugs").

    Joint use of sildenafil for the treatment of pulmonary arterial hypertension and the drug Kaletra® is contraindicated (see section "Interactions with other drugs").

    Special care should be taken when administering Kaletra® together with drugs that increase the interval QT, such as chlorpheniramine, quinidine, erythromycin, clarithromycin. The use of the preparation Kaletra ® can increase the concentration of co-administered agents and cause corresponding undesirable reactions from the heart. In preclinical studies of the Kaletra® drug, heart events were reported, therefore, the possible impact of Kaletra® on the heart can not be ruled out.

    Co-administration of the drug Kaletra® with rifampicin is not recommended, as a decrease in the concentration of lopinavir may in turn lead to a significant reduction in its therapeutic effect.This phenomenon can be avoided by increasing the dose of Kaletra ®, which is associated with an increased risk of toxic effects on the liver and gastrointestinal tract. Thus, without the utmost necessity of using this combination of drugs should be avoided (see section "Interactions with drugs").

    Co-administration of the preparation Kaletra® and fluticasone or other glucocorticosteroids metabolized by isoenzyme CYP3A4, such as budesonide should be performed with caution because of the risk of developing a systemic corticosteroid effect, including Cushing's syndrome and adrenal suppression, unless the benefits of therapy outweigh the risks (see "Drug Interactions" section).

    Interaction with Bedakvilinom

    Combined use with Bedaklavin with strong inhibitors of isoenzyme CYP3A4 may increase the systemic effect of Bedakville, which may lead to the development of adverse reactions characteristic of Bedaklavina (see section "Interaction with other drugs").

    Bedakvinin should be used with caution with lopinavir / ritonavir, and only if the benefits of joint application exceed the potential risk of adverse reactions.

    Other instructions

    The drug Kaletra® is not a medicine directly against HIV or AIDS. Although it has been proven that effective viral suppression in antiretroviral therapy significantly reduces the risk of sexual transmission, it can not be ruled out residual risk. It is necessary to take preventive measures in accordance with the guidelines of national competent authorities in order to avoid transmission of infection. People who take Kaletra® can develop infections associated with HIV and AIDS.

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

    During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased 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, 200 mg + 50 mg.

    Packaging:

    120 tablets in a vial of high-density polyethylene with a screw cap.

    1 bottle with instructions for use in a cardboard pack.

    Storage conditions:

    At a temperature of 15 ° C to 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    4 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-000539/08
    Date of registration:11.02.2008 / 24.10.2013
    Expiration Date:Unlimited
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp17.07.2016
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