Composition, form of production and packaging
Solution for ingestion of light yellow or yellow, transparent.
1 ml
lopinavir 80 mg
ritonavir 20 mg
Auxiliary substances: macrogol glyceryl hydroxy stearate - 10.2 mg, purified water - 69.2 mg, sodium chloride - 3.6 mg, sodium citrate - 2.0 mg, sodium saccharinate - 4.1 mg, potassium acesulfame - 4.1 mg, citric acid anhydrous 1.1 mg, ethanol 356.3 mg , propylene glycol 152.7 mg, levomentol 0.5 mg, povidone K-30 30.5 mg, glycerol 59.6 mg, corn syrup with a high content of fructose 168.6 mg, flavoring magnatosvit 110 (2X) 29.5 mg, menthol oil 3.1 mg , flavoring vanilla - 12.7 mg, flavored synthetic additive - 10.2 mg.
60 ml - bottles of polyethylene terephthalate (5) complete with dispensers (5 pcs.) - 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.
Mechanism of action
Lopinavir is an inhibitor of the HIV-1 and HIV-2 protease of the human immunodeficiency virus (HIV) and thus provides antiviral activity of the drug. Inhibition of HIV protease inhibits the synthesis of the 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
Isolates of HIV-1 with reduced sensitivity to lopinavir were isolated in vitro. The presence of ritonavir did not affect the isolation of lopinavir-resistant viruses in vitro.
In a clinical trial, viral isolates from each patient with plasma HIV RNA levels> 400 copies / ml at 24, 32, 40 and / or 48 weeks were analyzed during antiretroviral (ARV) treatment in previously untreated patients. All 37 evaluable patients treated with lopinavir / ritonavir had no evidence of genotypic or phenotypic resistance to lopinavir / ritonavir. In children who have not previously received ARV therapy, resistance to lopinavir / ritonavir has also not been identified.
In phase II clinical trials of Kaletra В®, among 227 HIV-infected patients who received and did not receive antiretroviral therapy before, 4 of 23 patients with virological inefficiency of therapy (HIV RNA> 400 copies / ml) showed a decrease in susceptibility to lopinavir through a 12- 100 weeks of therapy with Kaletra В® ; 3 of 4 patients received one of the HIV protease inhibitors (nelfinavir, saquinavir or indinavir) earlier, 1 in 4 patients received combination therapy with HIV protease inhibitors (indinavir, saquinavir and ritonavir). All 4 patients had at least 4 mutations associated with resistance to HIV protease inhibitors immediately prior to the initiation of therapy with Kaletra В® . A further increase in viral load was associated with the appearance of additional mutations associated with the development of resistance to HIV protease inhibitors. However, these data are insufficient to identify the mutations responsible for the development of resistance to lopinavir.
Cross-resistance
There is insufficient data on the development of cross-resistance during the therapy with lopinavir / ritonavir.
The virological response to lopinavir / ritonavir therapy has been altered in the presence of 3 or more of the following amino acid substitutions in the HIV protease gene: L10F / I / R / V, K20M / N / R, L24I, L33F, M36I, I47V, G48V, I54L / T / V, V82A / C / F / S / T, I84V.
The clinical significance of a decrease in 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 greater than 1000 copies / ml previously treated with nelfinavir, indinavir, saquinavir or ritonavir 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 EC 50 therapy (the concentration of the drug required to suppress the replication of 50% of the viruses), lopinavir with respect to 56 strains of the virus was 0.5-96 times higher than EC 50 for the wild type virus. In 55% (31/56) strains of the virus, the sensitivity to lopinavir was decreased by more than 4 times, with an average decrease in sensitivity to lopinavir among the 31 strains was 27.9 times.
Forty-eight weeks after initiation of lopinavir / ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, the HIV RNA concentration of 400 copies / ml was determined in 93% (25/27), 73% (11/15) and 25% (2/8) patients , in which the initial sensitivity to lopinavir was reduced by a factor of 10, 10-40, and 40 times, respectively. In these groups, the concentration of HIV RNA was? 50 copies / ml in 81% (22/27), 60% (9/15) and 25% (2/8) patients, respectively.
There is insufficient data to identify mutations that cause the development of resistance to lopinavir.
PHARMACOKINETICS
Suction
The pharmacokinetics of lopinavir in combination with ritonavir was studied in healthy volunteers and in 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 plasma. When lopinavir / ritonavir was used at a dose of 400/100 mg 2 times / day, the average equilibrium concentrations (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 when taking ritonavir in a 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.
Effect of food on drug absorption
When using lopinavir / ritonavir (in the form of a solution for ingestion) with fatty foods (872 kcal, 56% of calories due to fat), the AUC and C max of lopinavir increased by 130% and 56%, respectively, compared with those when taking the drug on an empty stomach. To increase bioavailability and minimize the variability of pharmacokinetics, lopinavir / ritonavir solution should be taken with meals.
Distribution
In an equilibrium state, approximately 98-99% of lopinavir binds to plasma proteins. Lopinavir binds to alpha 1- acid glycoprotein (ACT) and albumin, but lopinavir has a higher affinity for ACS. In an equilibrium state, the binding of lopinavir to plasma proteins remains constant in the range of registered concentrations produced after taking lopinavir / ritonavir 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 undergoes oxidative metabolism mainly involving the cytochrome P450 system of hepatocytes, 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 metabolites of lopinavir were detected. Ritonavir is able to induce isoenzymes of cytochrome P450, which leads to the induction of its own metabolism. During long-term use, concentrations of lopinovir decreased with time, before application, the next dose, stabilizing after about 10-16 days.
Excretion
8 days after the application of 14 C-lopinavir / ritonavir in a dose of 400/100 mg, approximately 10.4 В± 2.3% and 82.6 В± 2.5% of the dose of 14 C-lopinavir are detected in urine and feces, respectively. Moreover, lopinavir in unchanged form is 2.2% and 19.8%, respectively. After prolonged use, less than 3% of the dose of lopinavir is excreted unchanged by the kidneys. The clearance of lopinavir for oral administration is 5.98 В± 5.75 l / h.
Special Groups
The pharmacokinetics of lopinavir has not been studied in elderly patients. There are no sex-dependent pharmacokinetic differences in adult patients. No clinically significant pharmacokinetic differences depending on the race are also established.
Children. The pharmacokinetics of lopinavir / ritonavir 300/75 mg / m 2 / day and 230/57.5 mg / m 2 2 times / day were studied in a total of 53 patients aged 6 months to 12 years. The use of lopinavir / ritonavir at a dose of 230/57.5 mg / m 2 2 times / day without nevirapine and at a dose of 300/75 mg / m 2 2 times / day with nevirapine had similar concentrations of lopinavir in plasma similar to those obtained in adult patients taking lopinavir / ritonavir in a dose of 400/100 mg 2 times / day (without nevirapine). The use of lopinavir / ritonavir 1 time / day in children has not been studied.
The mean equilibrium AUC, C max , and C min of lopinavir after application of lopinavir / ritonavir at a dose of 230/57.5 mg / m 2 2 times / day without nevirapine (n = 12) were 72.6 В± 31.1 Ојg / h; 8.2 В± 2.9 and 3.4 В± 2.1 Ојg / ml, respectively; and 85.8 В± 36.9 Ојg В· h / ml, 10 В± 3.3 and 3.6 В± 3.5 Ојg / ml, respectively, after application of 300/75 mg / m 2 times / day with nevirapine (n = 12). Nevirapine was used according to the following regimens: 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 has not been studied in patients with renal insufficiency; since Lipinavir's renal clearance is insignificant, a reduction in overall clearance in patients with renal insufficiency is not expected.
Liver failure. Lopinavir is mainly metabolized and excreted by the liver. Multiple application of lopinavir / ritonavir at a dose of 400/100 mg 2 times / day in patients simultaneously infected with HIV and hepatitis C with mild and moderate hepatic insufficiency resulted in a 30% increase in lupinavir AUC and a 20% increase in Cmax in comparison with HIV-infected patients with normal liver function. The binding of lopinavir to plasma proteins was lower for mild to moderate hepatic insufficiency compared to control groups (99.09% vs. 99.31%, respectively). The use of lopinavir / ritonavir in patients with severe hepatic insufficiency has not been studied (see the section "Contraindications").
Drug Interactions
Lopinavir / ritonavir inhibits the isoenzyme CYP3A in vitro. The simultaneous use of lopinavir / ritonavir and drugs metabolized by the CYP3A isoenzyme may lead to an increase in the concentration of this drug in the blood plasma, which may enhance or prolong its therapeutic or side effects (see the section "Contraindications").
In therapeutic concentrations, lopinavir / ritonavir does not inhibit the isoenzymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2.
Lopinavir / ritonavir in vivo induces its own metabolism and enhances the biotransformation of some drugs metabolized by enzymes of the cytochrome P450 system and by glucuronation.
Lopinavir / ritonavir is metabolized with the participation of the CYP3A isoenzyme. It is expected that drugs that induce the activity of the CYP3A isoenzyme may increase the clearance of lopinavir, which may lead to a decrease in plasma concentrations of lopinavir. The simultaneous use of lopinavir / ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir.
INDICATIONS
- acquired human immunodeficiency syndrome (HIV infection) in adults and children aged 6 months as part of combined antiretroviral therapy.
DOSING MODE
Inside. The solution for oral administration of Kaletra В® should be taken with food.
The dose is measured with a calibrated syringe (dispenser).
Adults
The preparation Kaletra В® is applied in a dose:
- 400/100 mg (5 ml solution) 2 times / day or
- 800/200 mg (10 ml solution) 1 time / day in patients with no more than 2 mutations associated with the development of resistance to lopinavir. The use of the preparation Kaletra В® 1 time / day in patients with more than 2 mutations associated with the development of resistance to lopinavir, has been studied insufficiently, and therefore contraindicated.
Concomitant therapy
The combined use of the preparation Kaletra В® 1 time / day with drugs carbamazepine, phenobarbital or phenytoin is contraindicated.
Omeprazole and ranitidine. The use of the preparation Kaletra В® in a dosage form solution for ingestion in combination with omeprazole and ranitidine does not require dose adjustment.
Efavirenz, nevirapine, amprenavir or nelfinavir. If a decrease in susceptibility to lopinavir is suggested (based on anamnesis or laboratory data), an increase in the dose of Kaletra В® up to 533/133 mg (6.5 ml of solution) 2 times / day is recommended when combined with efavirenz, nevirapine, amprenavir or nelfinavir.Simultaneous application of Kaletra В® 1 time / day with efavirenz, nevirapine, amprenavir or nelfinavir is contraindicated
Children
To avoid the toxic effects of ethanol and propylene glycol when using the preparation Kaletra В® (solution for ingestion) in children, the total amount of these substances entering the body should be taken into account when using medicines containing them, including. preparation Kaletra В® .
In children aged 6 months to 12 years with a body weight of 7 kg to 15 kg, the recommended dose of the preparation Kaletra В® (solution for ingestion) is 12/3 mg / kg, and with a body weight of 15 kg to 40 kg - 10 /2.5 mg / kg (equivalent to 230 / 57.5 mg / m 2 ); the preparation Kaletra В® is prescribed during meals; the maximum dose in children with a body weight of more than 40 kg should not exceed 400/100 mg (5 ml of solution) 2 times / day. The use of the preparation Kaletra В® 1 time / day in children has not been studied.
The doctor should calculate an adequate dose in mg for each child under 12 years of age and determine the appropriate volume of the solution. Table 1 contains recommendations for the selection of a dose of Kaletra В® (oral solution) depending on the body weight in children.
Table 1. Recommendations for the selection of a dose of the preparation Kaletra В® , depending on the body weight in children.
Body weight (kg) Dose (mg / kg) * Volume of oral solution (80 mg of lopinavir / 20 mg of ritonavir in 1 ml)
Without efavirenz, nevirapine, amprenavir or nelfinavir
7-15 kg 12 mg / kg 2 times / day
7-10 kg 1.25 ml 2 times / day
10-15 kg 1.75 ml 2 times / day
15-40 kg 10 mg / kg 2 times / day
15-20 kg 2.25 ml 2 times / day
20-25 kg 2.75 ml 2 times / day
25-30 kg 3.5 ml 2 times / day
30-35 kg 4.0 ml 2 times / day
35-40 kg 4.75 ml 2 times / day
More than 40 kg dose for an adult 5.0 ml 2 times / day
* The dose is selected taking into account the content of lopinavir in a solution of lopinavir / ritonavir (80/20 mg / ml).
Note: in children over the age of 12, the dosage recommendations correspond to those of adults.
Concomitant therapy
If children of 6 months to 12 years are suspected of a decrease in susceptibility to lopinavir (based on anamnesis or laboratory data), when combined with efavirenz, nevirapine, amprenavir or nelfinavir, an increase in the dose of Kaletra В® to 13 / 3.25 mg / kg 2 times / day in children weighing from 7 kg to 15 kg and up to 11 / 2.75 mg / kg 2 times / day in children weighing from 15 kg to 45 kg (approximately 300/75 mg / m 2 ). The maximum dose for children weighing more than 45 kg should not exceed 533/133 mg 2 times / day. Table 2 contains recommendations for the selection of doses of the preparation Kaletra В® (oral solution) depending on the body weight when the drug is used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in children.
Table 2. Recommendations for the selection of a dose of Kaletra В® in combination with efavirenz, nevirapine, amprenavir or nelfinavir, depending on body weight in children.
Body weight (kg) Dose (mg / kg) * Volume of oral solution (80 mg of lopinavir / 20 mg of ritonavir) in 1 ml
With efavirenz, nevirapine, amprenavir, or nelfinavir
7-15 kg 13 mg / kg 2 times / day
7-10 kg 1.5 ml 2 times / day
10-15 kg 2 ml 2 times / day
15-45 kg 11 mg / kg 2 times / day
15-20 kg 2.5 ml 2 times / day
20-25 kg 3.25 ml 2 times / day
25-30 kg 4 ml 2 times / day
30-35 kg 4.5 ml 2 times / day
35-40 kg 5 ml 2 times / day
40-45 kg 5.75 ml 2 times / day
More than 45 kg Adult dose 6.5 ml 2 times / day
* Dose is selected taking into account the content of lopinavir in a solution of lopinavir / ritonavir (80/20 mg / ml). Note: in children over the age of 12, the dosage recommendations correspond to those of adults.
Recommendations for dosing based on body surface area (m 2 )
Children aged 6 months: the recommended dose of Kaletra В® is 230 / 57.5 mg / m 2 2 times / day during meals, the maximum dose is 400/100 mg 2 times / day. For some children who are simultaneously receiving efavirenz, nevirapine, amprenavir or nelfinavir, this dose may not be sufficient. In such cases, it is possible to increase it to 300/75 mg / m 2 .
Table 3. Recommendations for the use of a solution for oral administration of Kaletra В® in children.
Body surface area (m 2 ) * 230 / 57.5 mg / m 2 2 times / day
0.25 0.7 ml (57.5 / 14.4 mg) 2 times / day
0.4 1.2 ml (92/23 mg) 2 times / day
0.5 1.4 ml (115 / 28.8 mg) 2 times / day
0.75 2.2 ml (172.5 / 43.1 mg) 2 times / day
0.8 2.3 ml (184/46 mg) 2 times / day
1 2.9 ml (230 / 57.5 mg) 2 times / day
1.25 3.6 ml (287.5 / 71.9 mg) 2 times / day
1.3 3.7 ml (299 / 74.8 mg) 2 times / day
1.4 4 ml (322 / 80.5 mg) 2 times / day
1.5 4.3 ml (345 / 86.3 mg) 2 times / day
1.75 5 ml (402.5 / 100.6 mg) 2 times / day
* 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?).
Specific patient groups
Use in elderly patients. The number of patients aged 65 years and older was insufficient to assess the possible differences in their response to the treatment of lopinavir / ritonavir as compared to those of younger patients. In applying lopinavir / ritonavir in elderly patients should be careful because of the increased frequency of decreased liver function, kidney or heart related diseases and concomitant therapy.
Liver failure.Lopinavir / Ritonavir predominantly metabolized and excreted by the liver, so caution should be exercised when applying lopinavir / ritonavir in patients with hepatic failure. The use of lopinavir / ritonavir in patients with hepatic insufficiency, severe has not been studied (see. Section "Contraindications").
SIDE EFFECT
Adults
most frequent adverse reactions associated with taking 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 adverse reactions 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 divisions), gastroenteritis, colitis, dyspepsia, pancreatitis, gastroesophageal reflux disease, haemorrhoids, flatulence, bloating; infrequently - constipation, stomatitis, ulcer of the oral mucosa, duodenitis, gastritis, gastrointestinal bleeding (including rectal bleeding), dry mouth, stomach and bowel disease, faecal incontinence.
Of the liver and biliary tract: hepatitis, including ACT increasing activity, ALT, GGT, hepatomegaly, cholangitis, hepatic steatosis.
From the nervous system: often - headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness; infrequently - ageusia, convulsions, tremors, cerebrovascular disorders.
Mental disorders:often - anxiety; infrequently - abnormal dreams, decreased libido.
Cardio-vascular system: frequently - hypertension; infrequently - atherosclerosis, myocardial infarction, AV-block, tricuspid valve insufficiency, deep venous thrombosis.
With the skin side and subcutaneous fat: often - a rash (including maculo-papular), lipodystrophy (including depletion of subcutaneous fat in the face), dermatitis, eczema, seborrhea, sweating at night itching; rare - alopecia, capillaries, vasculitis.
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 kidneys and mochevodyaschih ways: 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 and furunculosis.
General reactions: often - fatigue, asthenia.
Changes in laboratory parameters: increase of concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, lipase, amylase, creatine kinase, reduction of inorganic phosphorus concentration of hemoglobin, reduced KK.
Post-registration experience
Children
The profile of adverse events in children aged 6 months to 12 years was similar to that 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 ACT, 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 exudative, bradyarrhythmia and hypersensitivity reactions (characterized by fever, rash, and jaundice).
CONTRAINDICATIONS
- increased sensitivity to lopinavir, ritonavir or auxiliary components of the drug;
- hepatic failure, severe;
- simultaneous use of drugs, which significantly clearance depends on metabolism by isozyme CYP3A. Such drugs include: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, salmeterol, sildenafil (only in case of its application for the treatment of pulmonary hypertension, see "Drug Interactions."), Tadalafil (only in case of its application for treatment of pulmonary hypertension. see section "Drug interactions"), vardenafil, AVANAFIL, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine and metilergometrin), inhibitors of HMG-CoA reductase inhibitors (lovastatin, simvastatin) Vos prenavir, alfuzosin, fusidic acid, amiodarone, quetiapine;
- simultaneous application of drugs Hypericum boceprevir;
- simultaneous application of ketoconazole and itraconazole in high doses (over 200 mg / day);
- simultaneous administration of the preparation Kaletra В® standard dose rifampicin;
- simultaneous administration of the preparation Kaletra В® and tipranavir with low dose ritonavir;
- Children up to age 6 months;
- 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;
- application of the drug Kaletra В®1 time / day in patients with more than two mutations associated with the development of resistance to lopinavir;
- fructose intolerance.
Precautions:
- viral hepatitis B and C;
- cirrhosis of the liver;
- hepatic insufficiency mild and moderate severity;
- increase in liver enzymes;
- renal failure;
- pancreatitis;
- hemophilia A and B;
- dyslipidemia (hypercholesterolemia, hypertriglyceridemia);
- Pregnancy;
- alcoholism;
- epilepsy;
- traumatic brain injury;
- diseases of the brain;
- children's age till 18 years;
- 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);
- simultaneous application of drugs for the treatment of erectile dysfunction, namely sildenafil (see "Drug Interactions."), Tadalafil;
- simultaneous application of fentanyl, rosuvastatin, bupropion, inhaled or administered nasally glucocorticoids (e.g., fluticasone, budesonide), antiarrhythmic drugs (e.g., bepridilom, lidocaine, quinidine), digoxin, lamotrigine, valproic acid (see "Drug Interactions".) ;
- simultaneous use with drugs that prolong the interval QT;
- simultaneous administration of drugs disulfiram or metronidazole (see "Drug Interactions.").
PREGNANCY AND LACTATION
Pregnancy
In pregnancy, the drug is used only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding period
If necessary, the drug Kaletra В® lactation breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
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.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Lopinavir / Ritonavir predominantly metabolized and excreted by the liver, so caution should be exercised when applying lopinavir / ritonavir y with hepatic failure patients . The use of lopinavir / ritonavir in patients with hepatic insufficiency, severe contraindicated.
With caution should be used drug in viral hepatitis B and C; cirrhosis; liver failure mild to moderate; increase in liver enzymes.
APPLICATION FOR CHILDREN
Use of the drug is contraindicated in children younger than 6 months.
With caution should use the drug in children and adolescents up to 18 years.
APPLICATION IN ELDERLY PATIENTS
In applying lopinavir / ritonavir in elderly patients should be careful because of the increased frequency of decreased liver function, kidney or heart related diseases and concomitant therapy.
SPECIAL INSTRUCTIONS
Abnormal liver function
Lopinavir / ritonavir is mainly metabolized by the liver. In this regard should be taken when assigning the drug Kaletra В®patients with impaired liver function mild to moderate. The use of lopinavir / ritonavir has not been studied in patients with impaired liver function severe. Pharmacokinetic data indicate that HIV-positive patients with hepatitis C, and human liver mild or moderate may increase lopinavir plasma concentration of about 30% and a reduction of its binding to plasma proteins. If a patient of hepatitis B or C, or a significant increase in activity of aminotransferases before treatment increased the risk of further increasing them. In cases of post-marketing study liver function abnormalities account (including fatal) that usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis,receiving excessive medication. The causal relationship of these cases with lopinavir / ritonavir therapy has not been established.
Cases increase transaminase activity were recorded while increasing the concentration of bilirubin or without it for 7 days after initiation of lopinavir / ritonavir in combination with other antiviral agents. In some cases, liver function abnormalities were serious, but the causal relationship of these cases with lopinavir / ritonavir therapy has not been established. In such situations, it is advisable to frequently monitor the activity of AST / ALT, especially in the first months after the appointment of lopinavir / ritonavir.
Renal dysfunction
Since renal clearance of lopinavir and ritonavir is negligible, in patients with renal failure patients is not expected to increase the plasma concentrations of lopinavir / ritonavir. Because lopinavir and ritonavir actively bind to plasma proteins, it is unlikely that they will be significantly displayed in hemodialysis or peritoneal dialysis.
Ethanol and propylene glycol
solution for oral administration of lopinavir / ritonavir contains ethanol (42.4% v. / V.) And propylene glycol (15.3% w / v.). 1 ml of the preparation contains 356.3 mg of ethanol and 152.7 mg of propylene glycol. Ethanol competitively inhibits metabolism propylene at their joint application, which can lead to increased propylene concentration.
Ethanol can be potentially dangerous for patients with liver disease, alcoholism, epilepsy, brain injury, brain diseases, pregnant women and children.
To avoid the toxic effects of ethanol and propylene glycol in children, to consider the total amount of these substances released into the body by the application of medicaments containing them. In children receiving lopinavir / ritonavir in the form of solution for oral administration, careful monitoring of reactions such as increase in osmolarity (with lactic acidosis or without it), and creatinine concentration in blood plasma, kidney, CNS depression (including pomrachnenie consciousness, coma and apnea ), convulsions, hypotension, cardiac arrhythmias, ECG changes, and hemolysis.
The standard dose of the drug Kaletra В® (for oral solution) contained 0.8 g of fructose, which should be taken into consideration when administering the drug to patients with hereditary fructose intolerance.
Contained in a solution for oral glycerol (0.3 g per unit dose) may be in the case of drug overdose cause headache and gastrointestinal upset.
Contained in the solution for intake acesulfame potassium in the case of overdose can cause gastrointestinal disorder. The presence of acesulfame potassium preparation should also be considered in patients who are prescribed a diet low in potassium.
Premature babies are
safe and effective dose of the drug Kaletra В® (oral solution) in preterm infants has not been determined. Taking into account the potential toxic effects of ethanol and propylene glycol, the drug Kaletra В®(Solution for oral administration) is contraindicated for preterm infants in the early postpartum period.
Premature infants are at risk of the emergence of adverse reactions caused by propylene glycol, as a result of reduced ability to metabolize it, which leads to the accumulation of propylene glycol in the body.
The post-marketing studies, mainly in premature infants receiving the drug Kaletra В® (oral solution), described life-threatening cases of cardiac toxicity (including complete atrioventricular block, bradycardia and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and cases breathing difficulties with fatal
diabetes mellitus / hyperglycemia
In the post-registration period in HIV-infected patients receiving protease inhibitors, cases of decompensation of diabetes mellitus and hyperglycemia have been reported. For the treatment of these conditions in some cases had to appoint insulin or oral hypoglycemic agents, or increase their dose. In some cases, developed diabetic ketoacidosis. some
