Composition, form of production and packaging
The tablets covered with a film membrane of pale pink color, oval, on one side the engraving of a logotype of the company Abbott and "AC" is put.
1 tab.
lopinavir 100 mg
ritonavir 25 mg
Excipients: copovidone K28 - 426.9 mg, sorbitan laurate - 41.95 mg, silicon dioxide colloid - 6 mg; second layer: sodium stearyl fumarate - 6.15 mg, silicon dioxide colloid - 4 mg.
The composition of the film shell: Opadrai В® II pink 85F14399 - 15 mg (polyvinyl alcohol - 40%, titanium dioxide - 24.85%, talcum - 14.8%, macrogol 3350 - 20.2%, ferric oxide red oxide (E172) - 0.15%).
60 pcs. - bottles of high-density polyethylene (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
A combined antiviral drug that contains lopinavir and ritonavir.
Lopinavir is an inhibitor of the HIV-1 and HIV-2 protease of human immunodeficiency virus (HIV) and provides antiviral activity of the preparation Kaletra В® .Inhibition of HIV proteases inhibits the synthesis of virus proteins and prevents the splitting of the polypeptide gag-pol, which leads to the formation of an immature and virus that is not able to infect.
Ritonavir inhibits the metabolism of lopinavir mediated by the isoenzyme CYP3A4 in the liver, which leads to an increase in the concentration of lopinavir in the blood plasma. Ritonavir is also an inhibitor of HIV protease.
Resistance
Isolation of resistant strains in vitro
The HIV-1 strain with reduced sensitivity to lopinavir was isolated in vitro . HIV-1 is passaged in vitro separately with lopinavir and a combination of lopinavir and ritonavir in concentrations equivalent to plasma concentrations observed during treatment with Kaletra В® . Based on the genotypic and phenotypic study of virus subtypes isolated during the passage, it can be assumed that the presence of ritonavir at these concentrations does not significantly affect the isolation of the virus-resistant subtypes of lopinavir. In general, an in vitro study of the characteristics of phenotypic cross-resistance between lopinavir and other protease inhibitors suggests that a decrease in susceptibility to lopinavir is closely related to a decrease in sensitivity to ritonavir and indinavir, but not to a decrease in susceptibility to amprenavir, saquinavir and nelfinavir.
Resistance test in patients who did not have antiretroviral therapy in history
In clinical trials with a limited number of strains studied, there was no selective resistance to lopinavir in patients without significant resistance to protease inhibitors at baseline.
Resistance test in patients treated with protease inhibitors
The emergence of resistance to lopinavir in patients who failed the main treatment with protease inhibitors was studied in a long-term study involving 19 patients receiving protease inhibitors in two phase II studies and one phase III study. Patients had incomplete suppression of the virus or a viral return phenomenon resulting from a response to Kaletra В® and showed increasing in vitro resistance between baseline and recruitment (defined as the emergence of new mutations or a twofold change in phenotypic sensitivity to lopinavir). Increasing resistance was characteristic of patients characterized by the presence of initial strains that underwent several mutations in the treatment of protease inhibitors, with no more than 40 times reduced initial sensitivity to lopinavir. Mutations of V82A, I54V and M46I appeared most often. Also mutations L33F, I50V and V32I in combination with I47V / A were observed. In 19 strains there was a 3- to 4-fold increase in the concentration of 50% inhibition (IC 50 ) compared to the original strains (from 6.2 to 43-fold, compared to wild types of the virus).
There is a genotypic correlation between the decrease in phenotypic sensitivity to lopinavir in viruses isolated after treatment with other protease inhibitors. In vitro , the antiviral activity of lopinavir was evaluated against 112 strains isolated from patients who were unsuccessfully treated with one or more protease inhibitors. Within this group, the following mutations in the HIV protease were associated with a decrease in in vitro susceptibility to lopinavir: L10F / I / R / V, K20M / R, L24I, M46I / L, F53L, I54L / T / V, L63P, A71I / L / T / V, V82A / F / T, I84V and L90M. The median EC 50 of lopinavir against isolates with mutations of 0-3, 4-5, 6-7 and 8-10 in the above amino acid positions was 0.8, 2.7 and 13.5, respectively, 44 times higher than wild type EC 50 HIV. All 16 types of virus with a 20-fold increase in sensitivity had mutations at positions 10, 54, 63 and 82 and / or 84. In addition, they contained the median 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the above mutations, mutations of V32I and I47A have been observed in relapsed strains with reduced susceptibility to lopinavir in patients treated with protease inhibitors and treated with KaletraВ®. Patients taking Kaletra В® received mutations I47A and L76V in recurrent strains with reduced susceptibility to lopinavir. Evaluation of the importance of individual mutations or sets of mutations may change with the receipt of additional data. It is always advisable to consult about the current system for evaluating the results of resistance studies.
Antiviral activity of lopinavir in patients unsuccessfully treated with protease inhibitors
The clinical significance of the decrease in sensitivity to lopinavir in vitro was studied by the method of assessing the virologic response to Kaletra В® treatment, taking into account the initial viral genotype and phenotype, in 56 patients who had not benefited from treatment with various protease inhibitors. The EC 50 value of lopinavir on the basis of 56 initial strains of the virus exceeded the EC 50 value of wild types of HIV in the range from 0.6 to 98-fold. After 48 weeks of treatment with Kaletra В® , efavirenz and nucleoside reverse transcriptase inhibitors, the plasma HIV RNA level was? 400 copies / ml in 93% (25/27), 73% (11/15), and 25% (2/8) patients with less than 10-fold, 10-40-fold and more than 40-fold decrease in sensitivity to lopinavir, respectively, compared with the baseline level. The virologic response was also observed in 91% (21/23), 71% (15/21) and 33% (2/6) of patients with 0-5, 6-7, and 8-10 mutations in the above mutations in the HIV protease, associated with a decrease in sensitivity to lopinavir in vitro . Since these patients have not previously taken Kaletra В® or efavirenz, partial effect may be attributed to the antiviral activity of efavirenz, especially for patients with a highly resistant type of virus. The study does not involve a control group of patients who did not take Kaletra В® .
Cross-resistance
The effectiveness of other protease inhibitors against strains that developed increasing resistance to lopinavir after treatment with Kaletra В® in patients taking protease inhibitors: the presence of cross-resistance to other prosthetic inhibitors was analyzed in 18 recurring strains showing increased
resistance to lopinavir during three Phase II studies and one Phase II study of the Kaletra В® preparation in patients receiving protease inhibitors. Median IC 50 oflopinavir for the above 18 strains in the initial state and in the phenomenon of virologic recoil was higher in the range from 6.9 to 63 times, respectively, compared to wild types of the virus. As a rule, strains with virological recoil are preserved (with cross-resistance initially), and develop significant resistance to indinavir, saquinavir, atazanavir. A moderate decrease in amprenavir activity was observed with a median of an IC 50 of 3.7 to 8 for the initial and recurrent strains, respectively.The strains retained sensitivity to tipranavir with a median increase in IC 50 at baseline and in the virological response phenotype with a multiplicity of 1.9 to 1.8, respectively, compared to wild types of the virus. For more information on tipranavir, including the genotypic response rates for the treatment of HIV-1-resistant lopinavir, see the instructions for the use of tipranavir.
Results of clinical trials
Children
M98-940 was an open-label study of the liquid dosage form of the Kaletra В® preparation in 100 pediatric patients who did not take antiretroviral drugs (44%) and received antiretroviral drugs (56%). All patients did not receive non-nucleoside reverse transcriptase inhibitors. Patients were randomized to 230 mg lopinavir / 57.5 mg ritonavir per m 2 or 300 mg lopinavir / 75 mg ritonavir per m 2 . Previously untreated patients also received nucleoside reverse transcriptase inhibitors. Patients previously treated received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. For each patient, after 3 weeks of treatment, safety profiles, efficacy and pharmacokinetics were evaluated in two dosing regimens. Further, all patients continued to receive a dose of 300/75 mg per m 2 . The average age of the patients was 5 years (range from 6 months to 12 years), 14 patients were less than 2 years, 6 patients were one year or less. The mean baseline level of CD4 + T cell count was 838 cells / mm 3 , and the mean baseline HIV-1 RNA in plasma was 4.7 log 10 copies / ml.
Table
Results at Point 48: Study M98-940
Those who did not receive antiretroviral therapy (N = 44) who received antiretroviral therapy (N = 56)
HIV RNA <400 copies / ml 84% 75%
The mean value of the increase in the value of the CD4 + T cell count (cells / mm 3 ) as compared to the baseline level 404 284
KONCERT / PENTA 18 is a prospective, multicenter, randomized, open-label study of the pharmacokinetic profile, efficacy and safety of taking 2 times a week, compared with 1 time per week of the lopinavir / ritonavir 100 mg / 25 mg dose, as part of a combination of antiretroviral therapy (CART) among children infected with HIV, with a suppressed virus (n = 173). Children were eligible for the study if their age was <18 years, body weight ≥15 kg if they received a cART that included lopinavir / ritonavir if the HIV-1 RNA concentration was <50 copies / ml for at least 24 weeks, and if they were able to swallow tablets. At week 24, efficacy and safety when taken 2 times / day (n = 87) in the pediatric population receiving lopinavir / ritonavir 100 mg / 25 mg tablets corresponded to the efficacy and safety observations in previous studies in adults and children with drugs lopinavir / ritonavir 2 times / day. The proportion of patients achieving HIV-1 RNA concentration <50 copies / ml at week 24 among patients in the pediatric population who received lopinavir / ritonavir 1 time (88.2%) was less than patients receiving a dose of 2 times / day (96.6%, p = 0.040), mainly due to a lower level of therapy in the admission group 1 time / day. Data on efficacy in favor of the 2-fold / day regimen are supported by differences in pharmacokinetic parameters, which significantly supports the regime 2 times / day
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 CYP3A isoenzymes. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its concentration in the blood plasma. When lopinavir / ritonavir was used at a dose of 400/100 mg 2 times / day, the average C ss 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 dose of 600 mg 2 times / day. EC 50 of lopinavir in vitro is about 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.
Suction
In a pharmacokinetic study involving HIV-positive patients (n = 19), when 400/100 mg lopinavir / ritonavir was taken 2 times / day during meals for 3 weeks, the mean C max was 9.8 В± 3.7 Ојg / ml and was achieved approximately 4 h after taking the drug.
The mean equilibrium concentration (C ss ) before the morning dose was 7.1 В± 2.9 Ојg / ml and the minimum concentration (C min ) within the dosing interval was 5.5 В± 2.7 Ојg / ml.
AUC of lopinavir for 12 hours after taking the drug averaged 92.6 В± 36.7 Ојg В· h / ml. Absolute bioavailability of lopinavir in combination with ritonavir in the human body has not been established.
Effect of food on intake when ingestion. The administration of a single dose of 400/100 mg of the preparation Kaletra В® in the tablet dosage form after ingestion (high fat content, 872 kcal, 56% fat) did not lead to significant changes in C max and AUC inf compared with fasting. Therefore, the preparation Kaletra В® in the dosage form of the tablet can be taken with or without food.
Distribution
In an equilibrium state, approximately 98-99% of lopinavir is in association with plasma proteins. Lopinavir binds to alpha- 1- acid glycoprotein (ACG) and albumin, however, lopinavir has a higher affinity for ACS. In an equilibrium state, binding of lopinavir to plasma proteins remains constant at concentrations that are established in the blood after taking the drug at a dose of 400/100 mg 2 times / day and is comparable in healthy volunteers and HIV-positive patients.
Metabolism
In vitro studies have shown that lopinavir is mainly exposed to oxidative metabolism involving the cytochrome P450 hepatocyte system, mainly under the influence of the CYP3A isoenzyme. Ritonavir is a potent inhibitor of the CYP3A isoenzyme, 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 (labeled with 14 C-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. During long-term use, the concentrations of lopinovir before the next dose were reduced with time and stabilized after about 10-16 days.
Excretion
After taking 400/100 mg of 14 C-lopinavir / ritonavir after 8 days, about 10.4 В± 2.3% and 82.6 В± 2.5% of the dose of 14 C-lopinavir is detected in urine and feces, respectively. And unchanged lopinavir is 2.2% and 19.8%, respectively. After prolonged use of less than 3% of the dose of lopinavir is excreted unchanged in kidneys.The clearance of lopinavir for oral administration is 5.98 В± 5.75 l / h.
Application 1 time / day
The pharmacokinetics of lopinavir / ritonavir once a day was studied in HIV-infected patients who had not previously received antiretroviral therapy. Lopinavir / ritonavir 800/200 mg was used in combination with emtricitabine at a dose of 200 mg and tenofovir 300 mg once a day daily. With the long-term use of 800/200 mg lopinavir / ritonavir 1 time / day during meals for 4 weeks C max lopinavir was reached approximately 6 hours after administration and averaged 11.8 В± 3.7 Ојg / ml.The mean C ss, before taking the morning dose, averaged 3.2 В± 2.1 Ојg / ml, and C min within the dosing interval was 1.7 В± 1.6 Ојg / ml. AUC of lopinavir at a 24-hour interval of reception averaged 154.1 В± 61.4 Ојg В· h / ml.
Special patient groups
Sex, race, age. The pharmacokinetics of lopinavir has not been studied in elderly patients. No sex-dependent pharmacokinetic differences were observed in adult patients. No clinically relevant pharmacokinetic differences depending on the race are established.
Children. The pharmacokinetics of lopinavir / ritonavir for oral administration at a dose of 300/75 mg / m 2 2 times / day and 230/57.5 mg / m 2 2 times / day were studied in a total of 53 children under the age of 12 years. The dosing regimen of 230 / 57.5 mg / m2 2 times / day without nevirapine and 300/75 mg / m 2 2 times / day with nevirapine provided plasma lopinavir concentrations similar to those obtained in adult patients taking 400/100 mg twice / day (without nevirapine). The pharmacokinetics of lopinavir / ritonavir was not studied in children 1 time / day in children.
In the equilibrium state, AUC, Cmax and Cmin of lopinavir were 72.6 В± 31.1 Ојg / h, 8.2 В± 2.9 and 3.4 В± 2.1 Ојg / ml, respectively, after application of lopinavir / ritonavir in a dose of 230/57.5 mg / m 2 2 times / day without nevirapine (n = 12), and after application of the drug at a dose of 300/75 mg / m 2 2 times / day with nevirapine (n = 12) - 85.8 В± 36.9 Ојg / h, 10 В± 3.3 and 3.6 В± 3.5 Ојg / ml, respectively. The nevirapine regimen was 7 mg / kg 2 times / day (in patients from 6 months to 8 years) or 4 mg / kg 2 times / day (in patients older than 8 years).
Renal failure. The pharmacokinetics of lopinavir in patients with renal insufficiency has not been studied. But due to the fact that the renal clearance of lopinavir is negligible, should not be expected to reduce the total clearance of the drug in patients with renal insufficiency.
Liver failure. Lopinavir is metabolized and eliminated primarily by the liver. Combined dosing lopinavir / ritonavir 400/100 mg of 2 times / day in patients coinfected with HIV and hepatitis C virus with impaired liver medium and low severity function leads to 30% increase AUClopinavira and 20% increase in C maxcompared to HIV-infected patients with normal liver function. Lopinavir plasma protein binding was lower with mild to moderate hepatic impairment compared to controls (99.09% compared to 99.31%, respectively). Lopinavir / ritonavir has not been studied in patients with hepatic insufficiency, severe patients (see. Section "Contraindications").
Pregnancy and the postpartum period
Pharmacokinetic data indicate that there is a slight decrease in AUC and C max of lopinavir in pregnant women in the III trimester of pregnancy compared with the II trimester of pregnancy.
Pharmacokinetic data obtained in an HIV-1 infected pregnant women receiving lopinavir / ritonavir tablets, film-coated 400/100 mg 2 times a day, are presented in the following table:
Average (the coefficient of variation,%) pharmacokinetic parameters of lopinavir in the equilibrium state HIV-1 infected pregnant women
pharmacokinetic parameter II trimester n = 17 1 III trimester n = 23 Postpartum n = 17 2
AUC 0-12 (pg? h / mL) 68.7 (20.6) 61.3 (22.7 ) 94.3 (30.3)
C max 7.9 (21.1) 7.5 (18.7) 9.8 (24.3)
C predose (mcg / ml) 4.7 (25.2) 4.3 (39.0) 6.5 (40.4)
C predose- the concentration of drug in the blood before receiving the next dose. 1 - n = 18 for C max . 2 - n = 16 C predose .
INDICATIONS
- the treatment of HIV infection in adults and children from 3 years as part of combination therapy.
DOSING MODE
Inside, regardless of the meal. Tablets Kaletra В® should be swallowed whole, not chewed without crushing or breaking a.
Adult
recommended dose drug Kaletra В® is:
-by 4 tablets Kaletra В® 100/25 mg (400/100 mg), 2 times / day independently of food intake;
-by 8 tablets Kaletra В® 100/25 mg (400/100 mg), 1 time / day independently of food intake for patients who showed less than 3 mutations associated with the development of resistance to lopinavir. Insufficient data for use lopinavir / ritonavir 1 time / day in adult patients with three or more mutations associated with the development of resistance to lopinavir.
Concomitant therapy
The use of Kaletra В® in combination with omeprazole and ranitidine requires no dose adjustment.
Patients with suspected reduced sensitivity to lopinavir (shown clinically or laboratory), previously treated with antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir or nelfinavir necessary to increase the dose Kaletra В® to 500/125 mg (5 pi. For 100/25 mg ) 2 times / day. While the use of these drugs drug Kaletra В® should not be given 1 time / day.
Children
Use of the drug Kaletra В® 1 time / day pediatric patients contraindicated.
The dose of drug Kaletra В® for adults (400/100 mg of 2 times / day) without a simultaneous application of efavirenz, nevirapine, amprenavir or nelfinavir can be used in children weighing? 35 kg or body surface area (BSA)? 1.4 m 2 . To determine the dosage for children weighing <35 kg or PPT from 0.6 to 1.4 m 2 is recommended to use the following tables.
In children with BSA less than 0.6 m 2 or children under 3 years recommended drug Kaletra В® as oral solution.
Tables 1 and 2 comprise the preparation of dosing guide Kaletra В® 100/25 mg, based on a TIC.
Table 1. Principles of dosing children, based on PPT, without the simultaneous application of efavirenz, nevirapine, amprenavir or nelfinavir
Body surface area * (m 2 ) The recommended number of 100/25 mg tablet when 2 times / d
? 0.6 to <0.9 Table 2 . (200/50 mg)
? 0.9 to <1.4 Table 3. (300/75 mg)
? 1.4 Table 4. (400/100 mg)
* Body surface area (BSA) can be calculated by the following formula: BSA (m 2 ) = square root of (height in cm of body weight in kg / 3600?).
Table 2. Principles of dosing children, based on PPT, while the use of drugs efavirenz, nevirapine, amprenavir or nelfinavir
Body surface area * (m 2 ) The recommended number of 100/25 mg tablet when 2 times / d
? 0.6 0.8 Table 2 . (200/50 mg)
? 0.8 to 1.2 3 tab. (300/75 mg)
? 1.2 to 1.7 4 tab. (400/100 mg)
? 1.7 Table 5. (500/125 mg)
Tables 3 and 4 contain the drug dosing guide Kaletra В® 100/25 mg of body weight.
Table 3. Principles of dosing children in body weight without a simultaneous application of drugs efavirenz, nevirapine, nelfinavir or amprenavir
Body weight (kg) Number of 100/25 mg tablets for receiving 2 times / day
from 7 to <15 kg tablets reception is not recommended. The solution should be used for oral administration.
from 15 to 25 kg 2
> 25 3 to 30 kg
> 35 kg 4 *
* Alternatively, patients who can swallow large tablets, it is possible to apply two 200/50 mg tablet.
Table 4. Principles of dosing children in body weight while the use of drugs efavirenz, nevirapine, amprenavir or nelfinavir
Body weight (kg) Number of 100/25 mg tablets for receiving 2 times / day
from 7 to <15 kg tablets reception is not recommended. The solution should be used for oral administration.
from 15 to 20 kg 2
> 20 3 to 30 kg
> 30 kg to 45 4 *
> 45 5 kg
* Alternatively, patients who can swallow large tablets, it is possible to apply two 200/50 mg tablet.
Application during pregnancy and postpartum
According to several clinical studies are not required drug dose correction Kaletra В®during pregnancy and the postpartum period. Use of the drug 1 time / day contraindicated in pregnant women due to insufficiency pharmacokinetic and clinical data.
SIDE EFFECT
Adults
most common side effects associated with the use of lopinavir / ritonavir were diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of therapy, while hypertriglyceridemia and hypercholesterolemia may develop later.
Moderate and severe side effects are listed below with an indication of frequency: very common (1/10?), Common (1/100 but <1/10?), Rare (1/1000, but <1/100?).
Immune system: often - hypersensitivity reactions, including urticaria and angioedema; infrequently - immune reconstitution syndrome.
From the digestive system:very often - diarrhea, nausea; often - vomiting, abdominal pain (upper and lower sections), gastroenteritis, colitis, dyspepsia, pancreatitis, gastro-oesophageal reflux, hemorrhoids, flatulence, bloating, hepatitis, hepatomegaly, cholangitis, hepatic steatosis; infrequently - constipation, stomatitis, ulcer of the oral mucosa, duodenitis, gastritis, gastrointestinal bleeding (including rectal bleeding), dry mouth, stomach and intestinal ulcers, faecal incontinence.
From the nervous system: often - headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety; infrequently - ageusia, convulsions, tremors, cerebrovascular disorders, sleep disorders, decreased libido.
Cardio-vascular system:frequently - hypertension; infrequently - atherosclerosis, myocardial infarction, AV-block, tricuspid valve insufficiency, deep vein thrombosis; frequency is unknown - increasing interval PR.
Skin and subcutaneous tissue: often - a rash (including maculo-papular), dermatitis, eczema, seborrhea, sweating at night, itching; rare - alopecia, capillaries, vasculitis; the frequency is unknown - lipodystrophy and redistribution of subcutaneous fat.
On the part of the musculoskeletal system: often - musculoskeletal pain (including arthralgia and back pain), myalgia, muscle weakness, muscle cramps; rarely - rhabdomyolysis, osteonecrosis.
Metabolic disorders and disorders of the endocrine system:often - hypercholesterolemia, hypertriglyceridemia, weight loss, decreased appetite, diabetes mellitus; rarely - weight gain, lactic acidosis, increased appetite, male hypogonadism; the frequency is unknown - insulin resistance.
The kidneys and the urinary tract: often - renal failure; rarely - hematuria, nephritis.
Reproductive system: often - erectile dysfunction, amenorrhea, menorrhagia.
From hemopoiesis system: often - anemia, leukopenia, neutropenia, lymphadenopathy.
From the sensory organs: rarely - vestibular vertigo, ringing in the ears, blurred vision.
infections:very often - upper respiratory tract infection; often - lower respiratory tract infections, infections of skin and subcutaneous fat, including cellulitis, folliculitis, furunculosis.
General reactions: often - fatigue, asthenia.
Changes in laboratory parameters: increase of concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, elevated AST, ALT, GGT, lipase, amylase, creatine kinase, reduction of inorganic phosphorus concentration of hemoglobin, reduced KK.
Children
The profile of adverse events in children aged 6 months to 12 years were similar to those in adults. Most often observed rash, dysgeusia, vomiting, diarrhea.
From the laboratory parameters in children registered following changes: increase of total bilirubin, total cholesterol, increased amylase, increased activity of AST, ALT, neutropenia, thrombocytopenia, increase or decrease the sodium content.
In applying lopinavir / ritonavir were also reported some cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and bradyarrhythmias.
Description of the individual adverse events
Cushing's syndrome has been observed in patients receiving ritonavir and inhaled or intranasally receiving fluticasone propionate. This effect can potentially occur in the case of other corticosteroids metabolized by cytochrome P450, such as budesonide.
Increased activity of CK, myalgia, myositis and rhabdomyolysis in rare cases were reported in the treatment with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
In HIV-infected patients with severe immune deficiency at the time of the start of combination antiretroviral therapy (cART) can be asymptomatic or residual opportunistic infections. Also reported autoimmune disorders (such as Graves' disease), the start of which, however, is more variable - the disease can begin in a long time after the start of treatment.
Cases of osteonecrosis have been noted, especially in patients with risk factors in the history of progressive HIV infection or after prolonged use of antiretroviral therapy. The frequency of their occurrence is unknown. For information about redistribution of subcutaneous fat cm. In section "Special instructions".
metabolic parameters
Body weight and plasma lipid and glucose in the blood plasma can rise during antiretroviral therapy.
CONTRAINDICATIONS
- increased sensitivity to lopinavir, ritonavir or auxiliary components of the drug;
- severe hepatic impairment;
- simultaneous use of drugs, which significantly clearance depends on metabolism by isozyme CYP3A. Such drugs include astemizole, blonanserin, terfenadine, midazolam (for oral application), triazolam, cisapride, pimozide, salmeterol, sildenafil (only in the case of treatment of pulmonary hypertension, see. "Drug Interactions"), tadalafil (only in the case of treatment of pulmonary hypertension see. "Drug interactions"), vardenafil, AVANAFIL, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine and metilergometrin), inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin, atorvastatin), fosamprenavir, alfuzosin, fusidic acid (in the treatment of skin infections), amiodarone, quetiapine;
- simultaneous application of drugs Hypericum, boceprevir,simeprevirom;
- simultaneous application of ketoconazole and itraconazole in high doses (over 200 mg / day);
- simultaneous application of the standard dose Kaletra В® with rifampicin;
- simultaneous administration of the preparation Kaletra В® and tipranavir with low dose ritonavir (see "Drug Interactions.");
- children under 3 years of age (children aged 6 months to 3 years prescribed drug in the dosage form of oral solution);
- use of the drug Kaletra В® 1 time / day in combination with carbamazepine, phenobarbital or phenytoin;
- use of the drug Kaletra В® 1 time / day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir;
- use of the drug Kaletra В® 1 time / day in children and adolescents up to 18 years;
- the use of lopinavir / ritonavir, 1 time / day for pregnant women.
Precautions:
- viral hepatitis B and C;
- cirrhosis of the liver;
- hepatic insufficiency mild and moderate severity;
- increase in liver enzymes;
- pancreatitis;
- hemophilia A and B;
- dyslipidemia (hypercholesterolemia, hypertriglyceridemia);
- Patients older than 65 years;
- Patients with organic heart disease, patients with disorders of the cardiac conduction system a history or patients taking drugs, lengthening the interval PR (such as verapamil or atazanavir) or drugs, lengthening the interval QT (pheniramine, quinidine, erythromycin, clarithromycin);
- simultaneous application of drugs for the treatment of erectile dysfunction, namely sildenafil (see "Drug Interactions."), Tadalafil;
- simultaneous application of fentanyl, rosuvastatin, bupropion, inhalable or nasally administered by glucocorticoids, e.g., fluticasone, budesonide (see "Drug Interactions.");
- simultaneous application of antiarrhythmic drugs such as bepridil, lidokainomi and quinidine;
- simultaneous application with digoxin;
- simultaneous application with lamotrigine, valproic acid;
- simultaneous application bedakvilinom;
- simultaneous application of trazodone.
PREGNANCY AND LACTATION
Pregnancy
Influence of lopinavir / ritonavir was assessed in 3366 women during pregnancy. Available data indicate that lopinavir / ritonavir did not increase the risk of overall major congenital malformations compared with the initial rate of congenital malformations. If necessary, lopinavir / ritonavir can be used during pregnancy.
Breastfeeding period
Studies in rats revealed that lopinavir is excreted in the mother's milk. It is not known whether this drug in human milk is released. Women should stop breast-feeding.
USE IN H
