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: & nbspRAstvor for oral administration.
    Composition:

    1 ml of the preparation Kaletra® contains:

    Active substance: lopinavir - 80.0 mg; ritonavir - 20.0 mg.

    Excipients: macrogol glyceryl hydroxy stearate-10.2 mg; water purified - 69.2 mg; sodium chloride - 3.6 mg; sodium citrate - 2.0 mg; sodium saccharinate - 4.1 mg; potassium acesulfame - 4.1 mg; citric acid anhydrous 1.1 mg; ethanol 356.3 mg; propylene glycol 152.7 mg; levomenthol - 0.5 mg; Povidone K-30 - 30.5 mg; glycerol - 59.6 mg; corn syrup with a high content of fructose - 168.6 mg; flavoring magnaswith-110 (2X) - 29.5 mg; menthol oil 3.1 mg; flavoring vanilla - 12.7 mg; flavored synthesized additive - 10.2 mg.

    Description:

    Transparent, light yellow or yellow solution.

    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:

    Mechanism of action

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

    Lopinavir is an inhibitor of the HIV-1 and HIV-2 protease of the human immunodeficiency virus (HIV) and thus provides antiviral activity of the drug. Inhibition of HIV protease 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

    Isolates of HIV-1 with reduced sensitivity to lopinavir were isolated in vitro. The presence of ritonavir did not affect the isolation of lopinavir-resistant viruses in vitro.

    In a clinical trial, viral isolates from each patient with plasma HIV RNA levels> 400 copies / ml at 24, 32, 40 and / or 48 weeks were analyzed during antiretroviral (ARV) treatment in previously untreated patients. All 37 evaluable patients treated with lopinavir / ritonavir had no evidence of genotypic or phenotypic resistance to lopinavir / ritonavir. In children who have not previously received ARV therapy, resistance to lopinavir / ritonavir has also not been identified.

    In phase II of clinical studies of Kaletra® Among 227 HIV-infected patients who received and did not receive antiretroviral therapy previously, in 4 of 23 patients with virological inefficiency of therapy (HIV RNA> 400 copies / ml) a decrease in susceptibility to lopinavir was found 12-100 weeks of therapy with Kaletra® 3 of 4 patients received previously one of the HIV protease inhibitorsnelfinavir, saquinavir or indinavir), 1 out of 4 patients - combination therapy with HIV protease inhibitors (indinavir, saquinavir and ritonavir). All 4 patients had at least 4 mutations associated with resistance to HIV protease inhibitors immediately prior to the initiation of 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.

    Cross-resistance

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

    The virologic response to lopinavir / ritonavir therapy has been altered in the presence of three or more of the following amino acid substitutions in the HIV protease gene: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, I84V. 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 study, patients were assigned lopinavir / ritonavir in one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Before the start of EU therapy50 (the concentration of the drug necessary to suppress the replication of 50% of the viruses) of lopinavir against 56 strains of the virus was 0.5-96 times higher than the EU50 for the virus of the "wild" type. 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.

    After 48 weeks of initiating lopinavir / ritonavir therapy,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) of patients who had a baseline sensitivity to lopinavir in ≤10 times, 10-40 times and ≥ 40 times, respectively. In these groups, the HIV RNA concentration was ≤ 50 copies / ml in 81% (22/27), 60% (9/15) and 25% (2/8) patients, respectively.

    There is insufficient data to identify mutations that cause the development of resistance to lopinavir.
    Pharmacokinetics:

    Suction

    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 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 blood plasma in HIV-infected patients were 15-20 times higher than the average equilibrium concentrations of ritonavir, and the plasma ritonavir concentration was less than 7% of the concentration when taking ritonavir in a dose of 600 mg twice a day. EU50 lopinavir in vitro about 10 times lower than the EU50 ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

    Effect of food on drug absorption

    When using lopinavir / ritonavir (in the form of a solution for oral administration) with fatty foods (872 kcal, 56% of calories due to fat) AUC and CmOh lopinavir increased by 130% and 56%, respectively, compared with those when taking the drug on an empty stomach. To increase bioavailability and minimize the variability of pharmacokinetics, lopinavir / ritonavir solution should be taken with meals.

    Distribution

    In the equilibrium state, approximately 98-99% lopinavir are in association with plasma proteins. Lopinavir binds to alpha-1-acid glycoprotein (ACE) and albumin, however, lopinavir has a higher affinity for ACE. In the 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 was shown that lopinavir undergoes oxidative metabolism mainly with the participation of the cytochrome P450 system of hepatocytes, mainly under the influence of isoenzyme CYP3A. Ritonavir - a potent inhibitor of isoenzyme CYP3A, 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 metabolites of lopinavir were detected. Ritonavir is able to induce isoenzymes of cytochrome P450, which leads to the induction of its own metabolism. During long-term use, concentrations of lopinovir decreased with time, before application, the next dose, stabilizing after about 10-16 days.

    Excretion

    Eight days after the application of a dose of 400/100 mg 14C-lopinavir / ritonavir approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the dose 14C-lopinavir is found in urine and feces, respectively. Moreover, lopinavir in the unchanged state 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) of lopinavir for oral administration is 5.98 ± 5.75 l / h.

    Special Groups

    Sex, race and age

    The pharmacokinetics of lopinavir has not been studied in elderly patients. There are no sex-dependent pharmacokinetic differences in adult patients. No clinically significant pharmacokinetic differences depending on the race are also established.

    Children

    Pharmacokinetics of lopinavir / ritonavir when used 300/75 mg / m2 twice daily and 230 / 57.5 mg / m2 Twice a day, a total of 53 patients 6 months to 12 years. The use of lopinavir / ritonavir in a dose of 230 / 57.5 mg / m2 two times a day without nevirapine and at a dose of 300/75 mg / m2 Twice daily with nevirapine had similar concentrations of lopinavir in plasma, similar to those obtained in adult patients taking a dose of 400/100 mg twice daily (without nevirapine) for lopinavir / ritonavir. The use of lopinavir / ritonavir once a day in children has not been studied.

    Average equilibrium AUC, FROMmOh, and Cmin lopinavir after application of lopinavir / ritonavir in a dose of 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 application of 300/75 mg / m2 Twice daily with nevirapine (n=12). Nevirapine were used according to the following regimens: 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 insignificant, a decrease in overall clearance in patients with renal insufficiency is not expected.

    Liver failure

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

    Drug Interactions

    Lopinavir / ritonavir in vitro inhibits isoenzyme CYP3A. The simultaneous use of lopinavir / ritonavir and drugs metabolized by isoenzyme CYP3A, can lead to an increase in the concentration of this drug in the blood plasma, which may enhance or prolong its therapeutic or side effect (see the section "Contraindications").

    In therapeutic concentrations, lopinavir / ritonavir does not inhibit isoenzymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2.

    Lopinavir / ritonavir in vivo induces its own metabolism and enhances the biotransformation of some drugs metabolized by enzymes of the cytochrome P450 system and by glucuronation.

    Lopinavir / ritonavir is metabolized with the participation of isoenzyme CYP3A. It is expected that drugs that induce isoenzyme activity CYP3A, can increase the clearance of lopinavir, which can lead to a decrease in the concentration of lopinavir in the blood plasma. The simultaneous use of lopinavir / ritonavir and other drugs that inhibit the isoenzyme CYP3A, can increase plasma concentrations of lopinavir.
    Indications:

    The syndrome of acquired human immunodeficiency virus (HIV infection) in adults and children from 6 months in combination antiretroviral 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, 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), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine.

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

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

    - Simultaneous application of a standard dose of Kaletra® with rifampicin.

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

    - Children age up to 6 months.

    - 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.

    - The use of Kaletra® once a day in patients with more than two mutations associated with the development of resistance to lopinavir.

    - Intolerance to fructose.
    Carefully:

    - Viral hepatitis B and C.

    - Cirrhosis of the liver.

    - Hepatic insufficiency of mild and moderate severity.

    - Increased activity of "liver" enzymes.

    - Renal failure.

    - Pancreatitis.

    - Hemophilia A and B.

    - Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).

    - Pregnancy.

    - Alcoholism.

    - Epilepsy.

    - Craniocerebral injury.

    - Diseases of the brain.

    - Children's age (up to 18 years).

    - Elderly (over 65 years of age).

    - Patients with organic heart diseases, patients with a history of conduction of the heart system, or taking drugs, extending the interval PR (such as verapamil or atazanavir).

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

    - Simultaneous use with fentanyl, rosuvastatin, atorvastatin, bupropion, inhaled or injected through the nose with glucocorticosteroids (eg, fluticasone, budesonide), antiarrhythmic drugs (eg, bepridil, lidocaine, quinidine), digoxin, rifampicin, lamotrigine, valproic acid (see "Interaction with other drugs ").

    - Simultaneous application with drugs that extend the interval QT.

    - Simultaneous administration of drugs disulfiram or metronidazole (cm. "Interaction with other drugs").

    Pregnancy and lactation:

    Pregnancy

    When pregnancy is used only if the intended benefit for the mother exceeds the potential risk to the fetus.

    Breastfeeding period

    If you need to use the drug Kaletra ® breastfeeding should be discontinued.

    Dosing and Administration:

    Inside. The solution for oral administration of Kaletra® should be taken with food.

    The dose is measured with a calibrated syringe (dispenser).

    Adults:

    The preparation Kaletra® is used in a dose

    - 400/100 mg (5 ml solution) twice daily or

    - 800/200 mg (10 ml solution) once a day in patients with no more than two mutations associated with the development of resistance to lopinavir.

    The use of Kaletra® once a day in patients with more than two mutations associated with the development of resistance to lopinavir has not been adequately studied and therefore contraindicated.

    Concomitant therapy

    Joint use of the preparation Kaletra® once a day with drugs carbamazepine, phenobarbital or phenytoin it is contraindicated.

    Omeprazole and ranitidine

    The use of the preparation Kaletra ® in a dosage form solution for ingestion in combination with omeprazole and ranitidine does not require dose adjustment.

    Efavirenz, nevirapine, amprenavir or nelfinavir

    If a decrease in susceptibility to lopinavir is suggested (based on anamnesis or laboratory data), an increase in the dose of Kaletra ® to 533/133 mg (6.5 ml solution) is recommended twice a day when combined with efavirenz, nevirapine, amprenavir or nelfinavir. Simultaneous use of the preparation Kaletra® Once a day with efavirenz, nevirapine, amprenavir or nelfinavir is contraindicated.

    Children:

    To avoid the toxic effects of ethanol and propylene glycol when using the preparation Kaletra® (oral solution) in children, the total amount of these substances entering the body with the use of medicinal products containing them, including the preparation Kaletra®.

    Children aged from 6 months to 12 years with a body weight of 7 kg to 15 kg, the recommended dose of the preparation Kaletra ® (solution for ingestion) is 12/3 mg / kg, and with a body weight of 15 kg to 40 kg - 10 / 2.5 mg / kg (equivalent to 230 / 57.5 mg / m2); the preparation Kaletra® is prescribed twice a day during meals; the maximum dose in children weighing more than 40 kg should not exceed 400/100 mg (5 ml solution) twice a day. Application of the preparation Kaletra® once a day children have not been studied.

    The doctor should calculate an adequate dose in mg for each child under 12 years of age and determine the appropriate volume of the solution. Table 1 contains recommendations for the selection of a dose of the preparation Kaletra® (oral solution) depending on the body weight in children.

    Table 1. Recommendations for the selection of a dose of the preparation Kaletra® depending on the body weight in children.

    Body weight (kg)

    Dose (mg / kg) *

    Volume of oral solution (80 mg of lopinavir/20 mg ritonavir in 1 ml)

    Without efavirenz, nevirapine, amprenavir or nelfinavir

    7-15 kg

    12 mg / kg twice daily

    7-10 kg

    1.25 ml twice daily

    10-15 kg

    1.75 ml twice daily

    15-40 kg

    10 mg / kg twice daily

    15-20 kg

    2.25 ml twice daily

    20-25 kg

    2.75 ml twice daily

    25-30 kg

    3.50 ml twice daily

    30-35 kg

    4,00 ml two times a day

    35-40 kg

    4.75 ml twice daily

    More than 40 kg

    Dose for an adult

    5 ml twice daily

    * Dose is selected taking into account the content of lopinavir in a solution of lopinavir / ritonavir (80/20 mg / ml). Note: in children over the age of 12, the recommendations for dose selection are appropriate for adults.

    Concomitant therapy

    Efavirenz, nevirapine, amprenavir or nelfinavir

    If children 6 months to 12 years, a decrease in susceptibility to lopinavir (based on anamnesis or laboratory data), then when combined with efavirenz, nevirapine,amprenavir or nelfinavir, an increase in the dose of Kaletra® to 13 / 3.25 mg / kg twice daily in children weighing between 7 kg and 15 kg and up to 11 / 2.75 mg / kg twice daily is recommended, in children with a body weight of 15 kg to 45 kg (approximately 300/75 mg / m2).

    The maximum dose in children weighing more than 45 kg should not exceed 533/133 mg twice a day.

    Table 2 contains recommendations for the selection of doses of the preparation Kaletra® (oral solution) depending on the body weight when the drug is used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in children.

    Table 2. Recommendations for the selection of a dose of Kaletra® in combination with efavirenz, nevirapine, amprenavir or nelfinavir, depending on body weight in children

    Body weight (kg)

    Dose (mg / kg) *

    Volume of oral solution (80 mg of lopinavir/20 mg ritonavir) in 1 ml

    With efavirenz, nevirapine, amprenavir, or nelfinavir

    7-15 kg

    13 mg / kg twice daily

    7-10 kg

    1.5 ml twice daily

    10-15 kg

    2 ml twice daily

    15-45 kg

    11 mg / kg twice daily

    15-20 kg

    2.5 ml twice daily

    20-25 kg

    3.25 ml twice daily

    25-30 kg

    4 ml twice daily

    30-35 kg

    4.5 ml twice daily

    35-40 kg

    5 ml twice daily

    40-45 kg

    5.75 ml twice daily

    More than 45 kg

    Adult dose

    6.5 ml twice daily

    * Dose is selected taking into account the content of lopinavir in a solution of lopinavir / ritonavir (80/20 mg / ml). Note: in children over the age of 12, the dosage recommendations correspond to those of adults.

    Recommendations for dosing based on body surface area (m2)

    Children from the age of 6 months: recommended dose of Kaletra® is 230 / 57.5 mg / m2 twice a day with meals, the maximum dose is 400/100 mg twice a day.

    For some children who are simultaneously receiving efavirenz, nevirapine, amprenavir or nelfinavir, this dose may not be sufficient. In such cases, it is possible to increase it to 300/75 mg / m2.

    Table 3. Recommendations for the use of a solution for oral administration of Kaletra® in children.

    Body surface area (m2)*

    230 / 57.5 mg / m2 twice a day

    0,25

    0.7 ml (57.5 / 14.4 mg) twice daily

    0,4

    1.2 ml (92/23 mg) twice daily

    0,5

    1.4 ml (115 / 28.8 mg) twice daily

    0,75

    2.2 ml (172.5 / 43.1 mg) twice daily

    0,8

    2.3 ml (184/46 mg) twice daily

    1

    2.9 ml (230 / 57.5 mg) twice daily

    1,25

    3.6 ml (287.5 / 71.9 mg) twice daily

    1,3

    3.7 ml (299 / 74.8 mg) twice daily

    1,4

    4 ml (322 / 80.5 mg) twice daily

    1,5

    4.3 ml (345 / 86.3 mg) twice daily

    1,75

    5 ml (402.5 / 100.6 mg) twice daily

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

    BSA (m2) = √(Growth (cm)x Body mass (kg) / 3600)

    Special patient groups

    Application in the elderly

    The number of patients 65 years of age or older was insufficient 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 decreased hepatic, renal or cardiac function, concomitant diseases and concomitant therapy.

    Liver failure

    Lopinavir / ritonavir is mainly metabolized and excreted by the liver, so caution should be exercised when using lopinavir / ritonavir in patients with hepatic insufficiency. The use of lopinavir / ritonavir in patients with severe hepatic insufficiency has not been studied (see the section "Contraindications").

    Side effects:

    Adults:

    The most common adverse reactions 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 can developlater.

    Moderate and serious adverse reactions are given below, indicating the 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.

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

    Uncommon: constipation, stomatitis, ulcer of the oral mucosa, duodenitis, gastritis, gastrointestinal bleeding, including rectal bleeding, dry mouth, stomach and bowel disease, faecal incontinence.

    From the liver and biliary tract

    Often: hepatitis, including increased serum aspartate aminotransferase (ACT), Alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), hepatomegaly, cholangitis, hepatic steatosis.

    From the nervous system

    Common: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness.

    Infrequently: agesia, convulsions, tremor, cerebrovascular disorders.

    Disorders of the psyche

    Often: anxiety.

    Uncommon: unusual dreams, decreased libido.

    From the side of the cardiovascular system

    Often: arterial hypertension.

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

    From the skin and subcutaneous fat

    Often: rash, including maculopapular, lipodystrophy, including depletion of subcutaneous fat in the face, dermatitis, eczema, seborrhea, increased sweating at night, itching.

    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.

    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, lipase, amylase, creatine phosphokinase, decrease in inorganic phosphorus concentration, hemoglobin, decrease in creatinine clearance.

    Post-registration application experience

    Children:

    Profile of adverse effects in children aged from 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, increase or decrease in sodium content.

    With the use of lopinavir / ritonavir, individual cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, multiforme exudative erythema, bradyarrhythmia and hypersensitivity reactions (characterized by fever, rash and jaundice) have also been reported.

    Overdose:

    There are reports of cases of an overdose of Kaletra® in the form of a drug for oral administration. The following effects have been reported on the background of a random overdose in premature infants: complete atrioventricular blockade, cardiomyopathy, lactate acidosis, acute renal failure. The preparation Kaletra® in oral dosage form is highly concentrated and contains 42.4% (v / v) ethanol and 15.3% (w / v) propylene glycol, therefore care should be taken when calculating the dose of lopinavir / ritonavir for prevention of overdose, especially when used in infants and young children.

    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 of vital functions of the body and monitoring the clinical condition of the patient. If necessary, remove unabsorbed medicinal product by washing the stomach. The removal of a non-absorbed drug can be beneficial using activated carbon. Since lopinavir / ritonavir binds to a high degree with plasma proteins, the use of dialysis is not advisable. However, in case of an overdose of Kaletra® (oral solution), dialysis can be used to remove ethanol and propylene glycol.

    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 (eg, dihydropyridine slow calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE5) inhibitors) may increase the plasma concentrations of these drugs, the therapeutic or side effects of which may be prolonged or prolonged.When taken concomitantly with lopinavir / ritonavir, there is a more frequent increase AUC (more than 3-fold) drugs that are actively metabolized by isoenzyme CYP3A and have a high pre-systemic metabolism. 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.

    The simultaneous use of lopinavir / ritonavir and other drugs that inhibit the isoenzyme CYP3A, can increase plasma concentrations of lopinavir, although these changes were not noted with simultaneous application with ketoconazole. 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 andlamivudine compared with lopinavir / ritonavir alone.

    Didanosine

    It is recommended that didanosine on an empty stomach; so didanosine should be applied an hour before or two hours after taking Kaletra® solution during meals.

    Zidovudine and abacavir

    Lopinavir / ritonavir induces glucuronidation, so the drug can reduce zidovudine and abacavir concentrations in the blood 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. In patients taking lopinavir / ritonavir and tenofovir, side effects associated with the use of tenofovir should be monitored.

    Other NRTIs

    There have been reported cases of increased activity of creatine phosphokinase (CK), myalgia, myositis and rhabdomyolysis (rarely) with the intake of HIV protease inhibitors, especially in combination with NRTI.

    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 childhood patients showed a decrease in the concentrations of lopinavir during simultaneous use with nevirapine. Presumably, the drug interaction of nevirapine and lopinavir / ritonavir in HIV-positive adult patients may be similar to that of children (a decrease in the concentration of lopinavir may be possible). 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 533/133 mg twice daily.

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

    Efavirenz

    In patients who received previously different protease inhibitors, with an increase in the dose of lopinavir / ritonavir by 33.3% from 400/100 mg twice daily to 533/133 mg twice daily with the therapy of efavirenz and two nucleoside reverse inhibitorstranscriptase, the concentration of lopinavir in plasma was comparable to that of lopinavir / ritonavir in a dose of 400/100 mg twice without efavirenz.

    In patients who received various protease inhibitors or who have phenotypic or genotypic signs of decreased susceptibility to lopinavir, simultaneous treatment with efavirenz may require an increase in the dose of lopinavir / ritonavir to 533/133 mg twice daily.

    An increase in the dose of lopinavir / ritonavir to 600/150 mg twice daily with simultaneous use with efavirenz increased plasma concentrations of lopinavir by approximately 36% and ritonavir concentrations by approximately 56-92% compared with the dose of lopinavir / ritonavir 400/100 mg when taken twice in day without efavirenz (see section "Method of administration and dose").

    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 once a day with both efavirenz and nevirapine is contraindicated.

    Delavirdine

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

    Rilpivirine

    With the simultaneous use of rilpivirin with lopinavir / ritonavir, an increase in rilpivirin concentration in the blood plasma 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, a decrease in the concentration of etravirine in the blood plasma is possible, however, a dose change of lopinavir / ritonavir is not 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 in combination with lopinavir / ritonavir leads to an increase AUC, similar CmOh, 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 once a day with amprenavir is contraindicated.

    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.

    Indinavir

    Lopinavir / ritonavir can increase the concentration of indinavir (IDV application in a dose of 600 mg twice a day with simultaneous application of lopinavir / ritonavir results in a decrease FROMmOh, increase Cmin and similar AUC compared with taking indinavir three times a day at a dose of 800 mg). It may be necessary to reduce the dose of indinavir with simultaneous use of lopinavir / ritonavir in a dose of 400/100 mg twice a day. The use of lopinavir / ritonavir once a day in combination with indinavir has not been studied.

    Nelfinavir

    Lopinavir / ritonavir can increase the concentrations of nelfinavir and the metabolite of nelfinavir M8 (Using nelfinavir 1000 mg twice a day with simultaneous application of lopinavir / ritonavir leads to similar AUC, similar CmOh and increase Cmin compared with taking nelfinavir 1250 mg twice daily). The simultaneous use of lopinavir / ritonavir and nelfinavir leads to a decrease in the concentration of lopinavir (see the section "Dosing and Administration").

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

    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 the concentration of saquinavir (application of saquinavir 800 mg twice daily in combination with lopinavir / ritonavir leads to an increase AUC, FROMmOh and Cmin compared with the administration of saquinavir 1200 mg three times a day). It may be necessary to reduce the dose of saquinavir when used concurrently with lopinavir / ritonavir at a dose of 400/100 mg twice daily. The use of lopinavir / ritonavir once a day in combination with saquinavir has not been studied.

    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.

    Boceprevir

    The simultaneous use of lopinavir / ritonavir with boceprevir leads to a decrease in the equilibrium concentrations of bocepreviir and lopinavir. The simultaneous use of lopinavir / ritonavir with bocetreviros 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 it is possible to increase the concentration of fentanyl in blood plasma.

    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, plasma concentrations of these drugs may increase. Care should be taken when using these drugs and monitoring therapeutic concentrations, if possible.

    Digoxin

    In the literature, there is evidence that simultaneous use of ritonavir (300 mg every 12 hours) and digoxin led to a significant increase in the concentration of digoxin in the blood plasma. Caution should be exercised when using lopinavir / ritonavir concurrently with digoxin and controlling 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 the development of adverse reactions 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 with simultaneous use with lopinavir / ritonavir, which may lead to an increase in the side effects usually associated with the use of 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 the concentration of warfarin in blood plasma 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 in the blood plasma, which may lead to an increased risk of bleeding.

    Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

    It is known that these drugs induce isoenzyme CYP3A4 and, thus, can reduce the concentration of lopinavir in the blood plasma. 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. With the simultaneous use of phenytoin and lopinavir / ritonavir, the concentration of phenytoin in the blood plasma should be monitored.

    Lamotrigine and valproic acid

    A decrease in the concentrations of lamotrigine and valproic acid was observed when they were combined with lopinavir / ritonavir; the decrease in 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.

    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, lower blood pressure and fainting. Use trazodone with an inhibitor of the CYP3A4 isoenzyme, such as lopinavir / ritonavir, should be treated with caution and a dose reduction of trazodone should be considered.

    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.

    Sleeping Pills

    Midazolam and triazolam

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

    Stimulators of gastrointestinal motility, including emetics

    Cisapride

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of cisapride in the blood plasma can increase, while increasing the risk of severe forms of arrhythmias. The simultaneous use of lopinavir / ritonavir and cisapride is contraindicated.

    Beta2-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 may 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.

    Alkaloids of ergot

    Ergotamil, dihydroergotamine, ergometrine and methylergometrine

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of ergotamine, dihydroergotamine, ergometrine and methylergometrine in blood plasma may increase, while increasing the risk of toxic effect of ergot alkaloids including vasospasm and ischemia. The simultaneous use of lopinavir / ritonavir and ergot alkaloids 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 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

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

    Antibacterial agents

    Lopinavir / ritonavir may cause moderate increase AUC clarithromycin. Patients with impaired renal or hepatic function should consider the possibility of reducing the dose of clarithromycin when taken concomitantly with lopinavir / ritonavir.

    Fusidic acid

    Since lopinavir / ritonavir is an inhibitor of the isoenzyme CYP3A, the concentration of fusidic acid in the blood plasma can increase.

    The simultaneous use of lopinavir / ritonavir with fusidic acid is contraindicated due to an increased risk of side effects associated with the use of fusidic acid, in particular acute necrosis of skeletal muscles. When using fusidic acid for the treatment of osteoarticular infections, where its joint use with lopinavir / ritonavir is inevitable, it is necessary to carefully monitor the side effects arising from the 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 substance 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. A further reduction in the dose of rifabutin may be required.

    Rifampicin

    The simultaneous use of rifampicin with lopinavir / ritonavir is accompanied by a dose-dependent decrease in plasma lopinavir concentration compared with lopinavir / ritonavir in a standard dose of 400/100 mg without rifampicin. The use of rifampicin with a standard dose of lopinavir / ritonavir may result in the loss of a virologic response and the possible formation of resistance to lopinavir / ritonavir or a class of HIV protease inhibitors or other antiretroviral drugs simultaneously used. The combined use of rifampicin with a standard dose of lopinavir / ritonavir is contraindicated.

    With the simultaneous use of rifampicin with lopinavir / ritonavir (800/200 mg twice daily), the decrease in plasma concentrations of lopinavir reached 57% compared with 400/100 mg lopinavir / ritonavir twice daily without simultaneous administration of rifampicin. With simultaneous application of rifampicin with lopinavir / ritonavir at a dose of 400/400 mg twice a day, a corresponding decrease in plasma lopinavir concentrations reached 7% compared with 400/100 mg lopinavir / ritonavir twice daily without simultaneous reception of rifampicin.

    In studies with higher doses of lopinavir / ritonavir with simultaneous use with rifampicin, there was an increase in ALT and ACT activity; this phenomenon may depend on the sequence of dose administration.

    If simultaneous use of lopinavir / ritonavir and rifampicin is required, lopinavir / ritonavir should be started at a standard dose of 400/100 mg twice daily for approximately 10 days before the start of rifampicin, with the dose of lopinavir / ritonavir gradually increasing only after the initiation of rifampicin therapy. Careful monitoring of liver function is necessary.

    Antiparasitic agents

    It is possible to decrease 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 decreased concentrations of lopinavir.

    Fluticasone

    The simultaneous use of lopinavir / ritonavir and fluticasone can significantly increase plasma concentrations of fluticasone and decrease serum cortisol concentrations. Use with caution.It is recommended to consider alternatives to fluticasone, especially when long-term use is required.

    With simultaneous application of ritonavir with intranasal and inhalation forms of fluticasone and budesonide, systemic effects of glucocorticosteroids, including Itenko-Cushing syndrome and suppression of adrenal cortex function, have been reported.

    Joint use of lopinavir / ritonavir and fluticasone, as well as other glucocorticosteroids, which are metabolized by 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 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).In the event of cessation of glucocorticosteroid therapy, a gradual dose reduction should be performed over a long period.

    Disulfiram / Metronidazole

    The solution of lopinavir / ritonavir for oral administration contains ethanol, which can cause an antagonistic reaction while using disulfiram and other drugs that cause such a reaction, such as metronidazole.

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

    An increase in the serum concentrations of these drugs may be observed when combined with lopinavir / ritonavir.

    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 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.

    Avanafil

    The simultaneous use of lopinavir / ritonavir with avanafil is expected to lead to a significant increase in the concentration of avanafil in serum.

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

    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

    The use of tadalafil for the treatment of pulmonary arterial hypertension with concurrent administration of lopinavir / ritonavir is contraindicated.

    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.

    Vardenafil

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

    Medicinal preparations based on medicinal plants

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

    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 drugs may lead to the development of myopathy, including rhabdomyolysis, so their combination with lopinavir / ritonavir is contraindicated.

    Rosuvastatin and atorvastatin, whose metabolism is less dependent on isoenzyme CYP3A4, together with ritonavir / lopinavir should be used with caution in minimal doses. When taken in combination with lopinavir / ritonavir, there was an increase in CmOh and AUC atorvastatin in 4.7 and 5.9 times, respectively, which increases the risk of serious adverse reactions of myopathy and rhabdomyolysis.

    Signs of clinically significant interaction of lopinavir / ritonavir with pravastatin have not been revealed. 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 in the blood plasma (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.

    Antihistamines

    Astemizole and terfenadine

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of astemizole and terfenadine in the blood plasma can increase, while increasing the risk of severe forms of arrhythmias. The simultaneous use of lopinavir / ritonavir and drugs astemizole and terfenadine is contraindicated.

    Methadone

    It is known 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 the concentration of ethinylestradiol in blood plasma can be reduced with 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 appointment and selection of a dosage of bosentan should be made in accordance with its instruction for 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, and fluconazole is expected 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 when administering Kaletra® to patients with mild to moderate liver function disorder. The use of lopinavir / ritonavir has not been studied in patients with severe liver function impairment. Pharmacokinetic data indicate that in HIV-positive patients with hepatitis C and mild or moderate severity of liver function disorder, an increase in the concentration of lopinavir in blood plasma by about 30% is possible, as well as a reduction in its binding to plasma proteins.

    If the patient has 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.

    In post-registration studies, cases of liver dysfunction, including fatal outcome, have been reported. 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 activity of transaminases with 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.

    Ethanol and propylene glycol

    Solution for oral administration of lopinavir / ritonavir as excipients contains ethanol (42.4% v / v) and propylene glycol (15.3% w / v). In 1 ml of the drug contains 356.3 mg of ethanol and 152.7 mg of propylene glycol. Ethanol competitively inhibits the metabolism of propylene glycol when combined, which can lead to an increase in the concentration of propylene glycol.

    Ethanol can be potentially dangerous for patients with liver disease, alcoholism, epilepsy, traumatic brain injury, brain diseases, pregnant women and children.

    To avoid the toxic effects of ethanol and propylene glycol in children, the total amount of these substances entering the body when using medicines containing them should be taken into account. Children taking lopinavir / ritonavir as a solution for oral administration need careful monitoring of such reactions as increased osmolality (with or without lactate acidosis) and creatinine concentration in the blood plasma, renal damage, CNS depression (including obscuration of consciousness, to whom and apnea), convulsions, hypotension, cardiac arrhythmias, changes in the ECG and hemolysis.

    The standard dose of Kaletra® (oral solution) contains 0.8 g of fructose, which should be taken into account when prescribing the drug to patients with hereditary intolerance to fructose.

    Contained in the solution for oral administration of Kaletra® glycerol (up to 0.3 g in a single dose) may cause headache and gastrointestinal upset if the drug is overdosed.

    In the case of an overdose of the drug contained in the solution for ingestion of Kaletra® potassium, acesulfame can cause gastrointestinal upset.

    The presence of potassium acesulfame in the composition of the drug should also be taken into account for patients who are prescribed a diet low in potassium.

    Preterm infants

    A safe and effective dose of Kaletra® (oral solution) in preterm infants is not defined. Taking into account the potential toxic effects of ethanol and propylene glycol, the preparation Kaletra® (oral solution) is contraindicated in premature infants in the early postpartum period.

    Premature infants are at risk for the occurrence of adverse reactions caused by propylene glycol, due to a reduced ability to metabolize it, leading to the accumulation of propylene glycol in the body.

    In post-marketing studies, mainly in preterm infants who received the preparation Kaletra® (solution for oral administration),life-threatening cases of cardiotoxicity (including complete atrioventricular block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and fatal breathing difficulties have been described.

    Diabetes mellitus / hyperglycemia

    In the process of post-registration studies, cases of development and decompensation of diabetes mellitus and hyperglycemia were registered in HIV-infected patients who received 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.

    Pancreatitis

    In patients receiving lopinavir / ritonavir, including patients who had severe hypertriglyceridemia, pancreatitis was observed. Cases with a lethal outcome are recorded.Although the association of this adverse reaction with lopinavir / ritonavir has not been established, 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 in the anamnesis, the risk of its recurrence during treatment with the preparation of the preparation Kaletra® is increased.

    Consideration should be given to the possibility of developing pancreatitis with the appearance of appropriate clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory indicators (eg, increased serum lipase or amylase activity). Patients who develop these signs or symptoms should be examined; If there is a clinical indication, the therapy with Kaletra® and / or other antiretroviral drugs should be temporarily 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 coagulation 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 reactions 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 with existing disorders of the conduction system of the heart or in patients taking medications extending the PR interval (such as verapamil or atazanavir). In such patients, the preparation of Kaletra® should be used with caution.

    Electrocardiogram

    Interval QTcF (with Freederization adjustment) was evaluated in a randomized,a 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. 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 atrioventricular blockade II or III degree.

    Redistribution of fat

    Against the backdrop of antiretroviral therapy, redistribution / accumulation of fat was observed with deposition in the central parts of the body, in the back, neck, the appearance of the buffalo, the reduction of fat deposits on the face and limbs, the enlargement of the mammary glands and the Cushinggoid. The mechanism and the long-term consequences of these undesirable phenomena are not known. Their connection with therapy with Kaletra® is not established.

    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. In the presence of lipid disorders, appropriate therapy is indicated.

    Immunodeficiency Syndrome

    In patients who received combined antiretroviral therapy, including with the use of lopinavir / ritonavir, the development of the immune reconstitution syndrome was observed. 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 jiroveci (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 have been observed, but the timing 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, these 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 insufficient 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, given the increased incidence of decreased liver, kidney and 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 12 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 has not been studied.

    Interaction

    Drugs, the simultaneous use of which with lopinavir / ritonavir is contraindicated: astemizole, blonanserin, terfenadine, midazolam, 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), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine, preparations of St. John's wort, boceprevir; use with ketoconazole and itraconazole at high doses (more than 200 mg / day), the use of a standard dose of Kaletra® with rifampicin, the use of Kaletra® and low-dose ritonavir-tipranavir, the use of 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.

    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, except when the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and suppression of adrenal cortex function.

    Preparations,When using lopinavir / ritonavir simultaneously, care should be taken: verapamil, atazanavir, phenyramine, quinidine, erythromycin, clarithromycin, drugs for the treatment of erectile dysfunction, namely sildenafil, tadalafil, simultaneous use with fentanyl, rosuvastatin, atorvastatin, bupropion, simultaneous use with antiarrhythmics such as bepridil, lidocaine and quinidine, simultaneous use with digoxin, lamotrigine, valproic acid.

    Kaletra® is not a tool for the complete cure of HIV-1 infection, and patients may have HIV-1-related illnesses, including opportunistic infections. When using the drug Kaletra® patients should be under medical supervision.

    In order to avoid the spread of HIV-1 infection, patients should be recommended the following:

    - Do not transfer to other people disposable needles and other injection tools;

    - not to transfer to other people personal things on which there may be blood or biological fluids, such as toothbrushes and razors;

    - not have any sex without protection.Always practice safe sex using latex or polyurethane condoms to reduce the risk of exposure to sperm, vaginal discharge, or blood;

    - refrain from breastfeeding. It is not known whether a child can receive Kaletra® through breast milk, and whether it can harm a child. In addition, mothers infected with HIV-1 should not breast-feed, because a child can be infected with HIV-1 through mother's milk.

    Recommendations on storage conditions

    It is recommended to store in the refrigerator at a temperature of +2 ° C to +8 ° C. Outside the refrigerator can be stored at a temperature of no higher than + 25 ° C for 42 days (6 weeks) after which the residue must be destroyed. On the vial, it is recommended that the storage start date outside the refrigerator be noted.

    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 effects of lopinavir / ritonavir on the ability to drive vehicles and control mechanisms have not been conducted.

    Solution for oral administration of lopinavir / ritonavir contains ethanol (42.4% v / v).

    Form release / dosage:

    Solution for oral administration, 80 mg + 20 mg / ml.

    Packaging:

    60 ml of solution in a polyethylene terephthalate plastic bottle with a screwed polypropylene cap having a device preventing children from opening the bottle.

    For 5 bottles and 5 dispensers together with instructions for use in a cardboard pack.

    Storage conditions:

    At temperatures from +2 ° С to + 8 ° С.

    Keep out of the reach of children.

    Shelf life:

    2 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:П N013751 / 02
    Date of registration:21.01.2008 / 11.08.2014
    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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