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: & nbspfilm-coated tablets
    Composition:

    Each tablet contains:

    Active substances:

    Lopinavir - 100 mg, ritonavir - 25 mg;

    Excipients:

    Copovidone K 28 - 426.9 mg; sorbitan laurate - 41.95 mg; silicon dioxide colloid - 6.0 mg; the second layer: sodium stearyl fumarate - 6.15 mg; silicon dioxide colloid - 4.0 mg;

    film coating: Opadrai® II pink 85 F 14399 - 15.0 mg (polyvinyl alcohol 40.00%, titanium dioxide 24.85%, talcum 14.80%, macrogol 3350-20.20%, iron oxide dye red E172 - 0.15%).

    Description:Oval tablets covered with a film coat of pale pink color. On one side of the tablet is engraved the company logo Abbott "E" and "AS".

    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:

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

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

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

    Resistance

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

    In the phase study III During the antiretroviral (ARV) treatment of patients who had previously received therapy, viral isolates were analyzed from each patient with a plasma HIV RNA concentration of more than 400 copies / ml at 24, 32. 40 and / or 48 weeks. 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 clinical trials of the drug Kaletra® among 227 HIV-infected patients who received and did not receive antiretroviral therapy, in 4 of 23 patients with virological inefficiency of therapy (HIV RNA> 400 copies / ml) showed a decrease in susceptibility to lopinavir after 12-100 weeks of therapy with the drug 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 prior to initiating drug therapy 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

    To date, there is insufficient data on the development of cross-resistance against the background of therapy 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, L241, L33F, M361, 147V, 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 EC50 therapy (the concentration of the drug required to suppress the replication of 50% of the viruses), lopinavir for 56 strains of the virus was 0.5-96 times higher EC50 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.

    However, additional studies are needed to identify the mutations that cause the development of resistance to lopinavir.

    Pharmacokinetics:

    The pharmacokinetics of lopinavir in combination with ritonavir was studied in healthy volunteers and HIV-infected patients; there were no significant differences between the two groups. Lopinavir is almost completely metabolized by isoenzyme CYP3A. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma concentrations. When lopinavir / ritonavir was used at a dose of 400/100 mg twice a day, the average equilibrium concentrations of lopinavir in plasma in HIV-infected patients were 15-20 times higher than those of ritonavir, and the concentration of ritonavir in plasma was less than 7% of the concentration with ritonavir in a dose of 600 mg twice a day. EC50 of lopinavir in vitro approximately 10 times lower than that of ritonavir. In this way. The antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir. When eating, the concentration of lopinavir and ritonavir in the blood plasma after taking two 200/50 mg tablets is equivalent to three capsules of 133/33 mg with the minimum variability of pharmacokinetics.

    Suction

    In a pharmacokinetic study involving HIV-positive patients (n= 19), with taking 400/100 mg lopinavir / ritonavir twice daily with food for three weeks, the mean maximum concentration of lopinavir in plasma (Cmax) 9.8 ± 3.7 μg / ml, observed about four hours after taking the drug. The mean equilibrium concentration before the morning dose was 7.1 ± 2.9 μg / ml and the minimum concentration within the dosing interval was 5.5 ± 2.7 μg / ml. Area under the curve "concentration-time" (AUC) lopinavir for 12 hours after taking the drug averaged 92.6 ± 36.7 μg-h / ml. Absolute bioavailability of lopinavir in combination with ritonavir in the human body has been established.

    Distribution

    In an equilibrium state, approximately 98-99% of lopinavir is in association with plasma proteins. Lopinavir binds to alpha1-acid glycoprotein (ACG) and albumin, however, lopinavir has a higher affinity for ACS. In an equilibrium state, binding of lopinavir to plasma proteins remains constant in the range of registered concentrations, created after taking 400/100 mg lopinavir / ritonavir twice a day, and is comparable in healthy volunteers from HIV - positive patients.

    Metabolism

    In studies in vitro It was shown that lopinavir is mainly exposed to oxidative metabolism involving the cytochrome P450 system of hepatocytes. mainly under the influence of isoenzyme CYP3A. Ritonavir is a potent inhibitor of the isoenzyme 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 oxidative metabolites of lopinavir were detected. Ritonavir is able to induce isoenzymes of cytochrome P450, which leads to the induction of its own metabolism. In the course of prolonged use, the concentrations of lopinavir before the administration of the next dose decreased with time, stabilizing after about 10-16 days.

    Excretion

    After taking 400/100 mg 14C-lopinavir / ritonavir after eight days approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the dose 14C-lopinavir is found in urine and feces, respectively. And unchanged lopinavir is 2.2% and 19.8%, respectively. After prolonged use, less than 3% of the dose of lopinavir is excreted unchanged through the kidneys. Clearance (CL/F) lopinavir for oral administration is 5.98 +/- 5.75 l / h.

    Reception once a day

    The pharmacokinetics of lopinavir / ritonavir with a once-daily dose rate was evaluated in HIV-infected patients who had not previously received antiretroviral therapy. Lopinavir / ritonavir 800/200 mg was used in combination with emtricitabine 200 mg and tenofovir 300 mg once daily daily. With the long-term admission of 800/200 mg lopinavir / ritonavir once a day for 4 weeks during the intake, write the average maximum concentration of lopinavir in plasma (Cmax) was 11.8 = 3.7 μg / ml, and was achieved approximately 6 hours after administration. The mean equilibrium concentration of lopinavir before taking the morning dose was 3.2 ± 2.1 μg / ml, the minimum concentration within the dosing interval was 1.7 ± 1.6 μg / ml. AUC lopinavir at 24 hour interval of reception averaged 154.1 ± 61.4 μg-h / ml.

    Special patient groups

    Sex, race and age

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

    Children

    Pharmacokinetics of lopinavir / ritonavir at admission 300/75 mg / m2 twice a day and 230/57.5 mg / m twice a day was studied in a total of 53 patients aged less than 12 years. Dosing scheme for 230 / 57.5 mg / m2 two times a day without nevirapine and 300/75 mg / m2 Twice daily with nevirapine provided plasma concentrations of lopinavir, similar to those obtained in adult patients taking 400/100 mg twice daily (without nevirapine). The use of lopinavir / ritonavir once a day in children has not been studied.

    Average equilibrium AUC, Cmin, and Cmax lopinavir after taking lopinavir / ritonavir 230 / 57.5 mg / m2 two times a day without nevirapine (n= 12) were 72.6 ± 31.1 μg-h / ml; 8.2 ± 2.9 and 3.4 ± 2.1 μg / ml, respectively; and 85.8 ± 36.9 μg-h / ml, 10.0 ± 3.3 and 3.6 ± 3.5 μg / ml, respectively, after taking 300/75 mg / m2 Twice daily with nevirapine (n= 12). The nevirapine regimen was 7 mg / kg twice daily (in patients from six months to eight years) or 4 mg / kg twice a day (in patients older than 8 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. The combined dosing of lopinavir / ritonavir but 400/100 mg twice daily in patients simultaneously infected with HIV and hepatitis C virus, with moderate hepatic insufficiency resulted in a 30% increase AUC lopinavir and a 20% increase in Cmax compared with HIV-infected patients with normal liver function. The binding of lopinavir to plasma proteins was lower for mild and moderate hepatic insufficiency compared with control groups (99.09% compared with 99.31%, respectively).Lopinavir / ritonavir has not been studied in patients with severe hepatic insufficiency (see section "Contraindications").

    Pregnancy and the puerperium

    Pharmacokinetic data show that slight decrease AUC and CmOh lopinavir in pregnant women in the third trimester of pregnancy compared with the second trimester of pregnancy.

    Pharmacokinetic data obtained in HIV-infected pregnant women receiving tablets coated with film shell, 400/100 mg lopinavir / ritonavir twice a day are presented in the table below:

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

    Pharmacokinetic

    2nd

    3rd

    Postpartum

    Parameter

    trimester

    trimester

    period


    n=171

    n=23

    n=172

    AUC0-12 (mcg - h / ml)

    68,7

    61,3

    94,3 (30,3)


    (20,6)

    (22,7)


    FROMmOh

    7,9(21,1)

    7,5(18,7)

    9,8 (24,3)

    FROMpredose (μg/ ml)

    4,7 (25,2)

    4,3 (39,0)

    6,5 (40,4)

    Cpredose concentration of the drug in the blood before admission

    the next dose.




    1 n=18 for FROMmOh




    2 n=16 for Cpredose




    Drug Interactions

    See also the sections "Contraindications", "With caution", "Special instructions", "Interactions with other drugs").

    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 concentrations of this drug in the plasma, which may enhance or prolong its therapeutic or side effect (see the section "Contraindications").

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

    Lopinavir / ritonavir in vivo induces its own metabolism and enhances the biotransformation of some drugs metabolized by cytochrome P450 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 plasma concentrations of lopinavir. The simultaneous use of lopinavir / ritonavir and other drugs that inhibit the isoenzyme CYP3A, can increase plasma concentrations lopinavir.

    Clinical recommendations are listed in the section "Interactions with other drugs ".

    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 by isoenzyme CYP3A. These drugs include: astemizole, blonanserin, terfenadine, midazolam (duration of oral administration), triazolam. cisapride, pimozide, salmeterol, sildenafil (only if used for the treatment of pulmonary hypertension, see "Interaction with other drugs"), tadalafil (only if used for the treatment of pulmonary hypertension, see "Interaction with other drugs"), vardenafil, avanafil, voriconazole, ergot alkaloids (for example, ergotamine and dihydroergotamine, ergometrine and methylergomethrin), inhibitors of HMG-CoA reductase (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine.

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

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

    - Simultaneous use of a standard dose of the drug 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").

    - Application of the drug Kaletra® once a day in combination with carbamazepine, phenobarbital or phenytoin.

    - Application of the drug Kaletra® once a day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir.

    - Application of the drug Kaletra® once a day in children (under 18 years of age).

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

    Carefully:

    - Viral hepatitis B and C.

    - Cirrhosis of the liver.

    - mild and moderate hepatic insufficiency.

    - Increased activity of "liver" enzymes.

    - Pancreatitis.

    - Hemophilia A and B.

    - Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).

    - The elderly (over 65 years).

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

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

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

    Pregnancy and lactation:

    The effect of lopinavir / ritonavir was evaluated in 3366 women during pregnancy.

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

    Dosing and Administration:

    Inside, regardless of food intake. Pills Kaletra® should be swallowed whole, not chewing, not crushing or grinding.

    Adult patients

    The recommended oral dose of the drug Kaletra® is:

    - Four tablets Kaletra® 100/25 mg (400/100 mg) twice daily, regardless of food intake.

    - Eight tablets Kaletra® 100/25 mg (800/200 mg) once a day, regardless of the intake of food for patients who have less than 3 mutations associated with the development of resistance to lopinavir. There is insufficient data for the use of lopinavir / ritonavir once a day in adult patients with 3 or more mutations associated with the development of resistance to lopinavir.

    Concomitant therapy

    - Use of tablets Kaletra® in combination with omeprazole and ranitidine does not require dose adjustment.

    - In patients with suspected hypersensitivity to lopinavir (shown clinically or laboratory), previously treated with antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir, or nelfinavir, it is necessary to increase the dose of tablets Kaletra® up to 500/125 mg (5 tablets of 100/25 mg) 2 times a day. When used simultaneously with these drugs, tablets Kaletra® Do not administer once a day.

    Children

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

    For children with PPT less than 0.6 m2 or for children under 3 years of age there is a drug solution Kaletra® for oral administration.

    Tables 1 and 2 contain guidance on the dosage of tablets Kaletra® 100/25 mg based on PPT.

    Table No. 1

    Principles of dosing for children based on PPT, without the simultaneous use of efavirenz, nevirapine, nelfinavir or amprenavir

    Surface area

    Recommended amount of tablets by

    body * (m2)

    100/25 mg twice a day

    > 0.6 to <0.9

    2 tablets (200/50 mg)

    > 0.9 to <1.4

    3 tablets (300/75 mg)

    > 1,4

    4 tablets (400/100 mg)

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

    PPT, m2 = C (height, cm × body weight, kg) / 3600.

    Table No. 2

    Principles of dosing for children, based on PPT, with the simultaneous use of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Surface area body (m2)

    Recommended amount of tablets by

    100/25 mg twice a day

    ≥ 0,6 to 0,8

    2 tablets (200-50 mg)

    ≥ 0.8 to 1.2

    3 tablets (300/75 mg)

    ≥ 1.2 to 1.7

    4 tablets (400/100 mg)

    ≥ 1,7

    5 tablets (500/125 mg)

    Tables 3 and 4 contain guidance on the dosage of tablets Kaletra® 100/25 mg by weight of body.

    Table No. 3

    Principles of dosing for children by body weight, without simultaneous application of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Body weight (kg)

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

    From 7 to <15 kg

    Taking tablets is not recommended. Use a solution for oral administration.

    From 15 to 25 kg

    2

    > 25 to 30 kg

    3

    > 35 kg

    4s

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

    Table 4.

    Principles of dosing for children by body weight, with the simultaneous use of drugs efavirenz, nevirapine, nelfinavir or amprenavir

    Body weight (kg)

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

    From 7 to <15 kg

    Receiving tablets is recommended.Use a solution for oral administration.

    From 15 to 20 kg

    2

    > 20 to 30 kg

    3

    > 30 to 45 kg

    4*

    > 45 kg

    5

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

    Application during pregnancy and in the puerperium

    According to a number of clinical studies, dose adjustments are not required Kaletra® during pregnancy and in the postpartum period.

    Side effects:

    Adult patients

    The most frequent, side effect associated with taking lopinavir / ritonavir was diarrhea from mild to moderate severity. Side effects possibly caused by the use of the drug, both clinical and laboratory, are given below with frequency (very often ≥1 / 10, often ≥1 / 100, but <1/10, infrequently ≥1 / 1000, but < 1/100, rarely ≥1 / 10000, but <1/1000).

    From the immune system

    Infrequent: hypersensitivity reactions.

    Rare: immune reconstitution syndrome.

    From the side of the digestive system

    Very often: diarrhea.

    Often: abdominal pain, flatulence, nausea, vomiting, irregular stools.

    Infrequent: dyspepsia, abdominal discomfort, dry mouth, hemorrhagic enterocolitis, fecal incontinence, gastritis, gastroesophageal reflux, pancreatitis, hepatitis.

    Rarely: dysphagia, abdominal pain, constipation, duodenitis, enterocolitis, enteritis, eructation, esophagitis, stomach ulcer, hemorrhoids, mouth ulcers, periodontitis, rectal bleeding, stomatitis, hepatomegaly, cholecystitis, jaundice, steatosis of the liver and pains in the region of the liver .

    Less than 2% had cholangitis.

    From the nervous system

    Often: headache.

    Infrequently: insomnia, paresthesia, decreased libido, depression, sleep disturbance, anxiety, nervousness, dizziness, peripheral neuropathy, drowsiness, perversion of taste.

    Rarely: stimulation, confusion, emotional lability, disorientation, disorders of thinking, amnesia, ataxia, dyskinesia, encephalopathy, extrapyramidal syndrome, paresis of the facial nerve, muscle tone, migraine, neuropathy, loss of taste and tremor.

    Less than 2% observed: apathy, cerebral infarction and convulsions.

    From the side of the cardiovascular system

    Infrequently: vascular disorders.

    Rarely: increased blood pressure, angina pectoris, atrioventricular blockade, myocardial infarction, palpitations, tricuspid valve insufficiency, deep vein thrombosis, thrombophlebitis,varicose veins and vasculitis.

    Less than 2% observed: fibrillation, atrial, orthostatic hypotension.

    From the skin and subcutaneous fat

    Often: lipodystrophy.

    Infrequent: rash, acne, alopecia, allergic dermatitis, maculopapular rash, itching and hyperhidrosis.

    Rare: dry skin, eczema, idiopathic pulmonary capillaries, exfoliative dermatitis, swelling of the face, nail disorders structures, seborrhea, skin discoloration, stretch marks, sores on the skin.

    Less than 2% had hypertrophy of the skin.

    From the side of the musculoskeletal system

    Infrequently: myalgia, arthralgia.

    Rarely: osteoarthritis, back pain and necrosis of bone, joint disease.

    Less than 2% had muscle weakness.

    Metabolic disorders and disorders of the endocrine system

    Infrequently: dehydration, diabetes mellitus, Itenko-Cushing syndrome, obesity, anorexia, a decrease or increase in body weight.

    Rare: male hypogonadism, decreased or increased appetite, hyperamylasemia, giperlipazemiya, giperurekemiya, hypophosphatemia, hypocholesterolemia, vitamin deficiencies, and hypothyroidism, lactic acidosis, lipomatosis.

    From the side of the kidneys and urinary tract

    Rarely: hematuria, nephrolithiasis, nephritis and abnormalities in laboratory urine, changes in the smell of urine.

    From the side of the reproductive system

    Infrequent: erectile dysfunction.

    Rarely: amenorrhea, ejaculatory disorder, breast enlargement, gynecomastia, menorrhagia.

    From the respiratory system

    Infrequent: bronchitis.

    Rarely: cough, shortness of breath, pulmonary edema.

    Less than 2% had bronchospasm.

    From the system of blood and blood-forming organs

    Rarely: anemia, leukopenia and lymphadenopathy.

    From the sense organs

    Infrequent: noise in the ears.

    Rarely: visual disturbances, hyperacusis, and dizziness, imbalance.

    Infections

    Rarely: bacterial infection, bronchopneumonia, inflammation of subcutaneous fat, foliculitis, furunculosis, gastroenteritis, otitis media, perineal abscess, pharyngitis, rhinitis, sialadenitis, sinusitis and viral infection (including influenza).

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Rarely: neoplasms (including benign neoplasms of the skin), cysts.

    Are common

    Often: asthenia.

    Infrequent: pain, pain in the retrosternal area, fever, swelling, malaise.

    Rarely: chills, peripheral edema, chest pain, splenomegaly.

    Changes in laboratory indicators

    Very often: an increase in the concentration of total cholesterol, triglycerides; increased activity of gamma-glutamyltranspeptidase (GTTP).

    Often: Increased glucose concentration, abnormalities in "liver" tests, increased serum aspartate aminotransferase activity (ACT), alanine aminotransferase (ALT), amylase.

    Infrequent: increasing the concentration of total bilirubin, deviating from the norm of tests to determine hormone concentrations and other laboratory tests, increasing lipase activity, lowering the creatinine clearance, and reducing glucose tolerance.

    Rarely: neutropenia, increased activity of alkaline phosphatase.

    Less than 2% observed: an increase in the concentration of uric acid, an increase in the activity of creatine phosphokinase, a decrease in the concentrations of inorganic phosphorus, hemoglobin.

    Children

    The profile of adverse events in children was similar to that of adults. Most often observed perversion of taste, vomiting, diarrhea and rash.

    Often also observed: viral infections, constipation, pancreatitis, hepatomegaly, dryness of the skin, fever, increased activated partial thromboplastin time, decreased hemoglobin, reduced platelet count, increased sodium, increased potassium, increased calcium, increased bilirubin, increased CGRT / ALT, increased COTT / AST, increased total cholesterol, increased amylase, increased uric acid , decreased sodium, decreased potassium, decreased calcium, decreased neutrophils.

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

    Overdose:

    At present, the clinical experience of acute overdose with lopinavir / ritonavir in humans is limited. There is no special antidote. Treatment should include general supportive therapy, including monitoring of vital signs and monitoring the clinical status of the patient. If necessary, remove unabsorbed medicinal product by means of gastric lavage and prescribe Activated carbon. Since lopinavir / ritonavir binds to a high degree with plasma proteins,then the use of dialysis is inexpedient.

    Interaction:

    A drug Kaletra® contains lopinavir and ritonavir, both of which are inhibitors of isoenzymes CYP3A cytochrome P450 in vitro. Joint use of the drug Kaletra® and drugs that are predominantly metabolized CYP3A can lead to an increase in the concentration in the blood plasma of another drug that could enhance its therapeutic and adverse reactions. Kaletra does not inhibit isoenzymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP1A2 or CYP2B6 in clinically significant concentrations.

    Kaletra® in vivo induces its own metabolism and increases the biotransformation of some drugs metabolized with the participation of cytochrome P450 (including isoenzymes CYP2C9 and CYP2C19) and glucuronization. This can lead to a decrease in the concentration in the blood plasma and a decrease in the effectiveness of the drugs used together.

    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 blockers of "slow" calcium channels, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of these drugs, the therapeutic or side effects of which may increase or last. 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, may increase plasma concentrations of lopinavir, although these changes were not noted when used concomitantly 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 and lamivudine compared with lopinavir / ritonavir alone.

    Didanosine

    Didanosin is recommended for use on an empty stomach.

    Since lopinavir / ritonavir tablets are taken regardless of food intake, their combined use with didanosine is possible one hour before or two hours after eating.

    Zidovudine / abacavir

    Lopinavir / ritonavir induces glucuronidation, so the drug Kaletra® can reduce the concentration of zidovudine and abacavir in 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, the possibility of occurrence of tenofovir-associated side effects should be monitored.

    Other NRTIs

    There were reported cases of increased activity of creatine phosphokinase (CK), myalgia, myositis, and rhabdomyolysis (rarely) with HIV protease inhibitors, especially in combination with NRTIs.

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    Nevirapine

    There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during 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 of nevirapine. Presumably, the drug interaction of nevirapine and lopinavir / ritonavir in HIV-positive adult patients may be similar to that in children (there may be a decrease in lopinavir concentration). 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 simultaneous use of lopinavir / ritonavir with nevirapine may require an increase in the dose of lopinavir / ritonavir to 500/125 mg twice daily.

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

    Efavirenz

    With an increase in the dose of lopinavir / ritonavir to 500/125 mg (two 200/50 mg tablets + one 100/25 mg tablet) twice a day in patients taking HIV protease inhibitors, the concentration of lopinavir in plasma was similar to that of lopinavir / ritonavir 400/100 mg twice daily without efavirenz.

    Increased dose of lopinavir / ritonavir to 600/150 mg (three (3) tablets 200/50 mg) twice daily with simultaneous use with efavirenz significantly increased the plasma concentration of lopinavir by approximately 36% and the concentration of ritonavir approximately 56-92% in comparison with the dose lopinavir / ritonavir 400/100 mg (two (2) tablets 200/50 mg) when taken twice daily 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 efavirenz is contraindicated.

    Delavirdine

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

    Etravirine

    The use of lopinavir / ritonavir in a dose of 400/100 mg (two (2) tablets of 200/50 mg) twice daily with etravirine leads to a decrease AUC, Cmin and CmOh Etravirine by 35%? 45%, 30%, respectively. Wherein Cmin lopinavir is reduced by 20%, a AUC and Cmax remain unchanged.

    Correction of the dose of lopinavir / ritonavir is not required.

    Rilpivirine

    The use of lopinavir / ritonavir at a dose of 400/100 mg twice daily with rilpivirin leads to an increase AUC, FROMmin and CmOh rilpivirin by 52%, 74%, 29%, respectively. Moreover, Cmin lopinavir decreased by 11%, a AUC and Cmax remain unchanged. Simultaneous use of lopinavir / ritonavir and rilpivirin leads to an increase in the concentration of rilpivirin in the blood plasma, however, correction of the dose of lopinavir / ritonavir is not required.

    HIV protease inhibitors

    Amprenavir

    Lopinavir / ritonavir may increase the concentration of amprenavir in blood plasma (taking amprenavir 750 mg twice daily plus lopinavir / ritonavir leads to an increase AUC, similar CmOh, increase in Cmin with respect to amprenavir in a dose of 1200 mg twice in a day). The simultaneous use of lopinavir / ritonavir and amprenavir 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 amprenavir is contraindicated.

    Fosamprenavir

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

    Simultaneous use is not recommended.

    Indinavir

    Lopinavir / ritonavir may increase concentrations of indinavir (the use of indinavir at a dose of 600 mg twice daily with the simultaneous use of lopinavir / ritonavir leads to a decrease in Cmax, 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. Taking lopinavir / ritonavir once a day in combination with indinavir has not been studied.

    Nelfinavir

    Lopinavir / ritonavir may increase the concentrations of nelfinavir and the metabolite of nelfinavir M8 (the use of nelfinavir 1000 mg twice daily with the simultaneous use of lopinavir / ritonavir leads to a similar AUC, a similar FROMmax 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 by compared with taking 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

    The simultaneous use of lopinavir / ritonavir with telaprevir leads to a decrease in the equilibrium concentration of bodyprevir without changing the equilibrium concentration of lopinavir.

    Simultaneous use is not recommended.

    Boceprevir

    The simultaneous use of lopinavir / ritonavir with boceprevirov leads to a decrease in the equilibrium concentrations of bocepreviir and lopinavir in blood plasma. The simultaneous use of lopinavir / ritonavir with bocetrevir it is contraindicated.

    Symeprevir

    The simultaneous use of simeprevir with lopinavir / ritonavir may cause an increase in the concentration of simeprevir in the blood plasma. The simultaneous use of lopinavir / ritonavir and simeprevir is contraindicated.

    Antiviral drugs - chemokine receptor inhibitors CCR5

    Maraviroc

    Simultaneous application of maraviroc with lopinavir / ritonavir leads to an increase in the concentration of maraviroc in the blood plasma. 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.

    If lopinavir / ritonavir and fentanyl are used concomitantly, careful monitoring therapeutic and side effects (including respiratory depression).

    Antiarrhythmic drugs (beprideal, 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 the 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 side effects from the heart. Care must 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 the application simultaneously with lopinavir / ritonavir. which can lead to increased side effects, is 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 that INE (International normalized ratio).

    Rivaroxaban

    Simultaneous application of rivaroxaban from lopinavir / ritonavir can cause an increase the concentration of rivaroxaban in the blood plasma, which can lead to an increased risk of bleeding. Simultaneous use is not recommended.

    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

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

    Patients who start or stop taking the drug Kaletra® and simultaneously take maintaining a dose of lamotrigine: it may be necessary to increase the dose of lamotrigine in case the drug Kaletra® was appointed in addition. In case the drug Kaletra® was canceled, the dose of lamotrigine it is necessary to reduce. The concentration of lamotrigine in blood plasma should be monitored prior to the commencement of a joint application with the drug Kaletra®, during the first 2 weeks of co-administration or within 2 weeks after discontinuation of the drug Kaletra®, to determine the need to change the dose of lamotrigine.

    Patients who take the Kaletra drug and are additionally assigned lamotrigine: there is no need to adjust the dose of lamotrigine.

    Antidepressants

    Bupropion

    The simultaneous use of bupropion with lopinavir / ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir / ritonavir with bupropion is necessary, 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, lowering blood pressure and fainting. Use trazodone with an inhibitor of isoenzyme CYP3A4, such as lopinavir / ritonavir, should be taken with caution and it is necessary to consider a reduction in the dose of trazodone.

    Antipsychotics

    Quetiapine, blonanserin and pimozide

    Like how lopinavir / ritonavir is an inhibitor of 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 for oral administration 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 significant sedation and respiratory failure. The simultaneous use of lopinavir / ritonavir and drugs midazolam and triazolam is contraindicated.

    Midazolam for parenteral use

    FROM caution should be applied to the preparation Kaletra® and midazolam for parenteral administration. Midazolam therapy should be performed in an intensive therapy or similar conditions that can provide clinical control and appropriate medical equipment in the event of respiratory depression and / or prolonged sedation. Correction of the dose of midazolam is necessary if more than one injection is used.

    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 may 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, heart 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.

    Alkaloids of ergot

    Ergotamine, dihydroergotamine, ergometrine and methylergomethrin

    Since lopinavir / ritonavir inhibits isoenzyme CYP3A, the concentration of ergotamine, dihydroergotamine, ergometrine and methylergometrine in the 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 than 200 mg / day) in conjunction with lopinavir / ritonavir is contraindicated.

    Voriconazole

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

    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. Simultaneous use is not recommended due to side effects of colchicine associated with neuromuscular toxicity (including rhabdomyolysis), especially in patients with renal and hepatic insufficiency.

    Antibacterial agents

    Lopinavir / ritonavir may cause moderate increase AUC clarithromycin. In patients with impaired renal function (with clearance of creatinine <30 ml / min) or liver should be 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, a reduction in the dose of rifabutin by 75% is recommended (i.e., taking 150 mg through day or three times a week) when used with lopinavir / ritonavir. It may be necessary to further reduce the dose of rifabutin. In connection with the possible increase in the action of rifabutin, it is necessary to closely monitor the side effects associated with rifabutin (including neutropenia and uveitis). It may be necessary further reduction in 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 change in the dose of Kaletra® is not required.

    Rifampicin

    The simultaneous use of rifampicin with lopinavir / ritonavir in a standard dose is accompanied by a dose-dependent decrease in plasma lopinavir concentration as 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 can lead to loss of the virologic response and the possible formation of resistance to lopinavir / ritonavir or to a class of inhibitors HIV protease or other antiretroviral drugs used simultaneously. 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 the simultaneous use 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 a 400/100 mg dose of 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 activity and ACT; 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 about 10 days before the onset reception of rifampicin. while the dose of lopinavir / ritonavir should gradually increase only after the initiation of therapy rifampicin. Careful monitoring of liver function is necessary.

    Correction of the dose of Kaletra® 400 mg / 400 mg (ie Kaletra® 400/100 mg + ritonavir 300 mg) twice a day made it possible to compensate for the inductor effect CYP3A4 rifampicin. However, with this dosing regimen, ALT / ACT and increased gastrointestinal disorders. Therefore, the combined use of lopinavir / ritonavir and rifampicin is not recommended.It is necessary to conduct clinical monitoring. Selection of a dose of Kaletra® should be performed after the initiation of rifampicin.

    Antiparasitic agents

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

    Glucocorticosteroids (GCS)

    Dexamethasone may cause an increase in isoenzyme activity CYP3A4 and a decrease in the concentrations of lopinavir. It is necessary to monitor antiviral activity.

    Fluticasone

    The simultaneous use of lopinavir / ritonavir and fluticasone can significantly increase plasma concentrations fluticasone and lower 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 adrenal cortex suppression, 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 substrate for isoenzyme CYP3A4 (eg, beclomethasone). 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 when combined with lopinavir / ritonavir.Clinical monitoring should be carried out 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 done with caution in low doses (ns more than 10 mg every 72 hours) and more often 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 can help reduce concentrations lopinavir / ritonavir in the blood plasma. 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 St John's wort preparations and lopinavir / ritonavir is prescribed, it is necessary to cancel the preparations of St. John's wort and check the level of the viral load. If you cancel preparations containing St. John's Wort, the concentration of lopinavir / ritonavir in the blood plasma may increase. A dose change of lopinavir / ritonavir may be required. The inducing effect may persist for at least 2 weeks after discontinuation of treatment with St. John's wort preparations.Lopinavir / ritonavir is recommended to be administered 2 weeks after stopping the intake of St. John's wort.

    Inhibitors of 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 it is contraindicated. Metabolism of rosuvastatin, 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 Cmax and AUC atorvastatin in 4.7 and 5.9 times, respectively, which increases the risk of serious adverse reactions of myopathy and rhabdomyolysis.

    The combined use of atorvastatin with lopinavir / ritonavir is not recommended.

    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. Caution should be exercised when bosentan is used together and lopinavir / ritonavir. With simultaneous use, it is necessary to monitor the effectiveness of antiviral therapy and the side effects characteristic of bosentan, especially during the first week of joint use.

    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, or 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, care should be taken when prescribing the drug Kaletra® patients with mild and moderate severity of impaired liver function. The use of lopinavir / ritonavir contraindicated in patients with severe impairment of liver function. Pharmacokinetic data indicate that in HIV-positive patients with hepatitis C and mild or moderate severity of liver function, an increase in the concentration of lopinavir in the blood plasma by about 30% is possible, as well as a reduction in its binding to blood 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.

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

    HIV-infected patients with chronic hepatitis B or FROM, patients 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 liver, 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 is not established.

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

    Impaired renal function

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

    Diabetes mellitus / hyperglycemia

    In the process of post-marketing research, cases of development and decompensation of diabetes mellitus and hyperglycemia were registered in HIV-infected patients 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 possible to assess their frequency and 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 there is no association of this side effect with lopinavir / ritonavir, a significant increase in triglyceride concentration is a risk factor for pancreatitis. In patients with progressive HIV infection, the risk of developing hypertriglyceridemia and pancreatitis is increased, and in patients with pancreatitis in the anamnesis, the risk of its recurrence during the treatment with lopinavir / ritonavir is increased. Patients, the who experience the following symptoms: nausea, vomiting, abdominal pain, or abnormal laboratory indicators (for example, increased lipase or amylase activity) should be examined, and if the diagnosis is confirmed pancreatitis, treatment with Kaletra® must be terminated.

    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 the factor VIII. In more than half of the cases described, treatment with protease inhibitors has been continued or resumed. A causal relationship or mechanism for the development of such adverse events in the treatment of protease inhibitors has not been established.

    Interval lengthening PR

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

    Electrocardiogram

    The QTcF interval (with Freederization adjustment) was 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. The maximum standard deviation of 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 QTcF interval> 60 ms compared to the baseline value; the QTcF interval did not exceed a potentially clinically relevant threshold of 500 ms. In this study, on day 3, lopinavir / ritonavir, there was also a moderate increase in the interval PR. Max. Spacing PR was 286 msec: not Atrial-ventricular 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.

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

    Increase in lipid concentration

    Treatment with lopinavir / ritonavir resulted in an increase 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. Particular care should be taken when administering lopinavir / ritonavir to patients with high initial lipid concentrations in the blood and lipid metabolism disorders in the anamnesis. Treatment of lipid metabolism disorders should be carried out in accordance with standard clinical practice (see section "Interaction with other drugs: HMG-CoA reductase inhibitors").

    Immunodeficiency Syndrome

    Have patients who received combined antiretroviral therapy, including with the use of lopinavir / ritonavir, observed the development of immune reconstitution syndrome. Against the background of the restoration of the immune function at the onset of combined antiretroviral therapy, the 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 immune reconstitution syndrome, autoimmune diseases such as Graves' disease, polymyositis and Guillain-Barre syndrome have been observed, but the time of occurrence of this phenomenon 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 aged 65 years and over was Inadequate to assess the possible difference in their response to lopinavir / ritonavir treatment compared to that in younger patients.When using lopinavir / ritonavir in elderly people, follow the caution, given the increased incidence of decreased liver, kidney or heart function, concomitant disease and concomitant therapy.

    Use in children

    Security and pharmacokinetic profile lopinavir / ritonavir in children less than 6 months of age have not been established. In HIV-infected children aged 6 months to 18 years, the side effect profile in the clinical trial was similar to that of adults.

    The use of lopinavir / ritonavir once a day in children is contraindicated.

    Interaction

    Preparations, simultaneous use of which with lopinavir / ritonavir is contraindicated: astemizole, blonanserin, terfenadine, midazolam (duration of oral administration), triazolam, cisapride, pimozide, salmeterol, sildenafil (only if used for the treatment of pulmonary hypertension, see "Interaction with other drugs"), tadalafil (only if used for the treatment of pulmonary hypertension, see "Interaction with other drugs"), vardenafil, avanafil, voriconazole, ergot alkaloids (for example, ergotamine and dihydroergotamine, ergometrine and methylergomethrin), inhibitors of HMG-CoA reductase (lovastatin, simvastatin), 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-administered 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, simeprevir.

    Preparations, simultaneous use of which with lopinavir / ritonavir is not recommended: simultaneous the use of lopinavir / ritonavir and fluticasone, as well as other glucocorticosteroids, 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. Joint application rivaroxaban and Kaletra® may increase the risk bleeding.


    The combined use of the preparation Kaletra® and colchicine is not recommended because of the potential increase in neuromuscular toxicity of colchicine (including rhabdomyolysis),     especially in patients with renal or hepatic insufficiency.

    Drugs with simultaneous use of which with lopinavir / ritonavir should be used with caution: verapamil, atazanavir, phenyramine, quinidine, erythromycin, clarithromycin, simultaneous use with drugs for the treatment of erectile dysfunction, namely with 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.

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

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

    Form release / dosage:

    Film-coated tablets, 100 mg + 25 mg.

    Packaging:

    60 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 to 30 ° C. Keep out of the reach of children.

    Shelf life:

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-000116
    Date of registration:28.12.2010 / 30.06.2014
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp18.01.2016
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