KALETRA

Active material: Lopinavir, Ritonavir
When ATH: J05aa
CCF: Viricide, active against HIV
ICD-10 codes (testimony): B24
When CSF: 09.01.04.02
Manufacturer: ABBOTT LABORATORIES Ltd. (Great Britain)

Pharmaceutical form, composition and packaging

Pills, Film-coated of red color, Oval, embossed on one side of the trade mark and the company Abbott “AL”.

Excipients: povidone K28, sorbitan laurate, colloidal silicon dioxide; 2 layer (sodium fumarate, colloidal silicon dioxide).

The composition of the coating film: Opadry red dye (gipromelloza 6 mPa, Titanium dioxide, macrogol 400, giproloza, gipromelloza 15 mPa, talc, colloidal silicon dioxide, macrogol 3350, iron oxide colorant (E172), polysorbate 80.

120 PC. – plastic bottles (1) – packs cardboard.

Capsules soft gelatin, orange, Oval, Printed in black ink the trade mark and the firm Abbott “RK”; contents of capsules – transparent liquid without extraneous particles.

Excipients: oleic acid, propylene glycol, Macrogols glicerilgidroksistearat, Purified water.

The composition of the shell: gelatin, mixture of sorbitol and glycerol anhydrous, Titanium dioxide, colorant sunset yellow, triglycerides srednecepochnye, lecithin, ink black, Purified water.

90 PC. – plastic bottles (2) – packs cardboard.

Oral solution light yellow or yellow color, clear.

Excipients: Macrogols glicerilgidroksistearat, sodium chloride, sodium citrate, sodium saccharin, acesulfame potassium, Citric acid anhydrous, ethanol, propylene glycol, levomenthol, povidone K-30, glycerol, corn syrup, high fructose, flavor magnasvit 110 (2X), mentha oil, vanilla flavor, Flavor synthesized, Purified water.

60 ml – bottles made of polyethylene terephthalate amber (5) complete with dispensers (5 PC.) – packs cardboard.

Pharmacological action

Combined antiviral.

Lopinavir – HIV protease inhibitor-1 and HIV-2. Inhibition of HIV protease prevents the synthesis of viral proteins, that leads to the formation of immature and incapable to virus infection.

Ritonavir – an inhibitor of aspartyl proteases of HIV-1 and HIV-2, Active peptidomimetik. HIV protease inhibition prevents the tearing of the gag-pol connection poliproteina, which also leads to the formation of immature and unable to infection with virus. Ritonavir has selective affinity to proteaze HIV and shows little activity against human protease aspartil. It inhibits the isoenzyme CYP3A4-mediated metabolism of lopinavir in the liver, resulting in an increase of lopinavir plasma concentration.

Resistance

Development rezitentnosti to lopinavir / ritonavir has been studied in patients, naïve antiretroviral therapy (ARVT), and patients, ART-naïve (incl. protease inhibitors).

In clinical studies, the antiviral activity of lopinavir / ritonavir in HIV-infected adults and children, not receiving ART, It did not reveal any mutation, coupled with a decrease in sensitivity and the development of resistance to lopinavir.

That's Phase II clinical trials of the drug Kaletra among 227 HIV-infected patients, receiving and not receiving ARV therapy earlier, in 4 from 23 patients with virological treatment failure (HIV RNA>400 copies / ml) decrease in sensitivity was found to lopinavir through 12-100 weeks of therapy Kaletra; 3 from 4 patients received previously one protease inhibitor (Nelfinavir, saquinavir, indinavir), 1 from 4 patients – multiple protease inhibitor therapy (indinavir, saquinavir, ritonavir). Everything 4 patients had, at least, 4 mutations, assotsirovannye with resistance to protease inhibitors before therapy Kaletra. A further increase in viral load was associated with the introduction of additional mutations, related to the development of resistance to protease inhibitors. But, these data are insufficient to identify mutations, responsible for the development of resistance to ritonavir.

Cross-resistance

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

The study investigated the in vitro activity against lopinavir 112 clinical strains, isolated from patients, whose plasma HIV RNA levels greater than 1000 copies / ml, despite therapy with one or more protease inhibitors. The following protease gene mutations have been identified HIV, who were associated with a decrease in sensitivity in vitro to lopinavir: L10F / I / R / V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, L90M.

The clinical significance of decreased susceptibility to in vitro lopinavir studied based on viral response to therapy lopinavir / ritonavir depending on the original genotype and phenotype of virus from 56 patients with higher plasma HIV RNA 1000 copies / ml, previously treated with nelfinavir, indinavirom, sakvinavirom or ritonavirom (study M98-957). In this study of patients randomized circuit assigned lopinavir / ritonavir in one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Before the start of the EU therapy₅₀ (the concentration of the drug, necessary for the replication of suppressing 50% Virus) lopinavir against 56 strains was 0.5-96 times higher than the EU₅₀ for wild-type virus. In 55% (31/56) strains was determined by a decrease in sensitivity to more than lopinavir 4 times, wherein the average decrease sensitivity among lopinavir 31 strain – in 27.9 times.

Through 48 weeks after initiation of therapy lopinavir / ritonavir, efavirenz and nucleoside reverse transcriptase inhibitors VICH≤400 concentration of RNA copies / ml have determined 93% (25/27), 73% (11/15) and 25% (2/8) patients, in which the initial sensitivity to lopinavir was reduced to ≤10 times, 10-40 ≥40 times and once, respectively,. In these groups, the concentration of HIV RNA was ≤50 copies / mL 81% (22/27), 60% (9/15) and 25% (2/8) of patients, respectively.

Besides, HIV RNA concentrations in plasma was ≤400 copies / mL 91% (21/23) patients, whose original viral strains contained up 5 mutations, associated with resistance to protease inhibitors. IN 13 from 23 cases, mutations were determined in the provisions of 82, 84 and / or 90. Concentration HIV RNA ≤400 copies / ml have been observed 63% (17/27) patients, in which the initial strains of virus contained 6 or more mutations, incl. in positions 82, 84 and 90.

But, to identify mutations, associated with resistance to lopinavir, more research is needed.

Pharmacokinetics

Pharmacokinetic studies of lopinavir in combination with ritonavir in healthy volunteers and in HIV-infected patients did not reveal any significant differences between the two groups.

Lopinavir almost completely metabolized by the action of CYP3A isozymes. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its concentration in blood plasma.

In applying the lopinavir / ritonavir dose 400/100 mg 2 times / day mean C_ss lopinavir plasma HIV-infected patients 15-20 times higher than those of ritonavir in doses 600 mg 2 times / day.

EC₅₀ Lopinavir in vitro, e.g., in 10 times lower than that of ritonavir. Thus, Antiviral activity of the combination of lopinavir and ritonavir, lopinavir determined.

Absorption

In HIV-positive patients, receiving lopinavir / ritonavir at a dose of 400/100 m g 2 times / day with meals for a 3 weeks, middle C_max It was 9.8 ± 3.7 mcg / mL and was reached after about 4 h after administration.

The average threshold concentration (in the morning before taking the next dose) in an equilibrium state averaged 7.1 ± 2.9 mcg / ml, a C_min – 5.5± 2.7 pg / ml.

Lopinavir AUC over 12 h averaged 92.6 ± 36.7 pg / ml × h / ml. The absolute bioavailability of lopinavir in combination with ritonavir are not installed. In receive lopinavir / ritonavir then edы (500 kcal, 25% fat) in capsules or lopinavir solution concentration were similar. When accept simply entails lopinavir / ritonavir natoshtak hourly average AUC and C_max lopinavir were 22% below, than when the capsules.

Capsules and lopinavir / ritonavir bioequivalent after a meal solution (food with a moderate fat content). A single dose of lopinavir / ritonavir dose 400/100 mg capsules during the meal with moderate fat (500-682 kcal, 23-25% calories from fat) accompanied by an increase in AUC and C_max Lopinavir in a srednem 48 and 23% respectively, compared with those in the fasting state. When using a solution of lopinavir / ritonavir for oral corresponding increase in AUC and C_max lopinavir management services 80 and 54%. In receive lopinavir / ritonavir with zhirnoy Typewriter (872 kcal, 56% calories from fat) AUC и C_max lopinavir increased to 97 and 43% (capsules) and 130 and 56% (solution) compared with those in the employment drug on an empty stomach.

In order to increase the bioavailability and minimize variability in the pharmacokinetics of, Capsules and lopinavir / ritonavir solution should be taken with meals.

In single dose tablets lopinavir / ritonavir dose 400/100 mg with food AUC and C_max not significantly changed compared to those taking the drug on an empty stomach at. AUC is increased if the tablets with food moderate fat (500-682 kcal, 23-25% calories from fat) and a high fat content (872 kcal, 56% calories from fat) on 26.9% and 18.9% respectively, compared to the fasted. C_max increases by 17.6% when receiving tablets moderately greasy food, high fat content in the diet did not significantly change the C_max. Therefore, tablets lopinavir / ritonavir can be used regardless of the meal.

Distribution

При C_ss plasma lopinavir about 98-99% It binds to proteins. Lopinavir binds to both alpha₁-acid glycoprotein (Aag), and albumin, but it has a higher affinity for AAG. In a stable state of equilibrium protein binding remains constant at concentrations, which are installed in the blood after administration of the drug at a dose of 400/100 mg 2 times / day, and does not differ in healthy volunteers and HIV-infected.

Metabolism

Lopinavir primarily undergoes extensive oxidative metabolism involving the cytochrome P450 system hepatocytes almost exclusively under the influence of CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 and inhibits the metabolism of lopinavir, which increases the concentration of lopinavir in the blood plasma. The plasma is found not less than 13 lopinavir oxidative metabolites. The main metabolites, has antiviral activity, is 4-Hydroxy- and 4 gidroksimetabolitnye isomeric pair. After receiving a single dose 400/100 mg lopinavir / ritonavir, Spot ¹⁴C-lopinavirom, 89% radioactivity in plasma was due to unchanged drug. The concentrations of lopinavir before taking the next dose over time are reduced and stabilized within 10-16 days.

Deduction

After a single dose of lopinavir / ritonavir dose 400/100 mg after 8 days, about 10.4 ± 2.3% from the accepted dose of lopinavir detected in urine and 82.6 ± 2.5% of the dose is found in faeces, wherein the lopinavir is suitably unmodified 2.2% and 19.8%. Following multiple administration of less, than 3% lopinavir dose is excreted unchanged by the kidneys. The clearance of lopinavir ingestion of 5.98 ± 5.75 l / h.

Application 1 time / day

Pharmacokinetics Lopinavir / ritonavir accept 1 time / day has been studied in HIV-infected patients, ART-naïve. Lopinavir / ritonavir doze 800/200 mg administered in combination with emtricitabine in a dose of 200 mg tenofovir DF and in a dose 300 mg. All the drugs used 1 time / day. In applying the lopinavir / ritonavir dose 800/200 mg 1 times / day with meals for a 4 C Weeks_max Lopinavir was achieved after about 6 h after administration and was on average 11.8 ± 3.7 pg / ml. The threshold concentration at steady state (before taking the morning dose) averaged 3.2 ± 2.1 mcg / ml, a C_min within the dosing interval – 1.7± 1.6 pg / ml. Lopinavir AUC during day was equal in average 154.1 ± 61.4 pg × h / ml.

Pharmacokinetics in special clinical situations

According to the age, by sex and race differences in the pharmacokinetics in adults has not been found. Pharmacokinetics in lopinavir elderly patients I have not been studied.

The pharmacokinetics of lopinavir / ritonavir oral solution at a dose of 300/75 mg / m² 2 times / day and 230/57.5 mg / m² 2 times / day was studied in 53 children aged 6 Months before 12 years. In applying the drug in a dose 230/57.5 mg / m² 2 times / day without a dose of nevirapine and 300/75 mg / m² 2 times / day with nevirapine concentrations of lopinavir plasma was similar to that in adult patients, receiving lopinavir / ritonavir at a dose of 400/100 mg 2 times / day (without nevirapine). Farmakokinetiku Lopinavir / ritonavir accept 1 time / day in children has not been evaluated.

equilibrium AUC, C_max and C_min lopinavir were respectively 72.6 ± 31.1 pg × h / ml, 8.2± 2.9 and 3.4 ± 2.1 mcg / mL after administration of lopinavir / ritonavir dose 230/57.5 mg / m² 2 times / day without nevirapine (n=12), and after application of the preparation at a dose of 300/75 mg / m² 2 times / day with nevirapine (n=12) – 85/8± 36/9 × ug h / mL, 10± 3.3 and 3.6 ± 3.5 mcg / ml, respectively.

Pharmacokinetics lopinavir in patsientov with renal failure I have 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.

Lopinavir metabolized and excreted primarily in the liver. Repeated application of lopinavir / ritonavir dose 400/100 mg 2 times / day for patients, infected with HIV and hepatitis C virus, from umerennymm easy or hepatic impairment was an increase in AUC and C_max lopinavir of 30 and 20%, respectively, compared with those of HIV-infected patients with normal liver function. lopinavir plasma protein binding in patients with mild to moderate hepatic impairment was somewhat lower, than patients in the control group (99.09 and 99.31% respectively). The pharmacokinetics of lopinavir has not been studied in patients with severe hepatic impairment.

Testimony

Acquired Immune Deficiency Syndrome (HIV infection), in a combination therapy:

- adults and children 3 and older (tablets, capsules, oral solution);

- in children aged from 6 Months (oral solution).

Dosage regimen

The tablets should be taken orally, regardless of the meal: swallowed whole, they can not chew or crush.

Capsules and solution for the reception inside should be taken with food.

Table doses of different drug forms Kaletra adult

In children with a body weight ≥40 kg (or body surface area >1.3 m²) Kaletra tablets used in a dose 400/100 mg (2 tab.) 2 times / day. In children weighing ≤40 kg (or body surface area <1.3 m²) Kaletra recommended oral solution.

Kaletra solution recommended dose for oral administration in children aged 6 Months before 12 years with a body weight of 7 to 15 kg is 12/3 mg / kg; weighing from 15 to 40 kg The recommended dose is 10/2.5 mg / kg (equivalent 230/57.5 mg / m²). The maximum dose in children with a body weight ≥ 40 kg should not exceed 400/100 mg (5 Kaletra ml oral solution). The drug is prescribed 2 times / day at mealtime.

Table dose calculation Kaletra oral solution according to the child's body weight.

*dose is selected taking into account the content of lopinavir in lopinavir / ritonavir solution (80/20 mg / ml).

**children over the age of 12 s dosing recommendations correspond to those in adults.

The use of Kaletra 1 time / day in children has not been studied.

Dosing recommendations Kaletra oral solution on the basis of body surface area (m²)

In children aged 6 Months before 12 years Kaletra recommended dose oral solution is 230/57.5 mg / m² 2 times / day at mealtime. The maximum dose – 400/100 mg 2 times / day.

* body surface area (BSA) It can be calculated by the following formula: BSA (m²)= the square root of (height in cm x body weight in kg / 3600).

For some children,, receiving concomitant nevirapine or efavirenz, you may need to increase the dose to 300/75 mg / m². The dose is metered from a calibrated syringe (dispenser).

Soputstvuyushtaya therapy

In Adult tablets use, capsules and oral solution Kaletra in combination with omeprazole and ranitidine does not require dose adjustments.

In combination with efavirenz, nevirapine, amprenavir, nelfinavir pill Kaletra can be used at a dose of 400/100 mg (2 tab.) 2 times / day dose without correction.

If you expect a decrease in sensitivity to lopinavir (Based on the anamnesis data or laboratory), then increasing the dose is recommended, while the use of the drug efavirenz or nevirapine to 533/133 mg (4 caps. or 6.5 ml oral solution).

In an application with efavirenz, nevirapine, amprenavir, nelfinavir drug Kaletra should not be administered 1 time / day.

If children from 6 Months before 12 years weighing from 7 to 15 kg It expected to decrease in sensitivity to lopinavir (Based on the anamnesis data or laboratory), then the solution increase in dose is recommended, while the use efavirenz or nevirapine for ingestion to 13/3.25 mg / kg 2 times / day; weighing from 15 to 45 kg recommended dose increase to 11 / 2.75 mg / kg 2 times / day; weighing ≥ 45 kg maximum dose should not exceed 533/133 mg / kg 2 times / day.

Table calculation Kaletra dose oral solution depending on the body weight of the drug when used in combination with nevirapine efvirenzom or children.

*dose is selected taking into account the content of lopinavir in lopinavir / ritonavir solution (80/20 mg / ml).

** children over the age of 12 s dosing recommendations correspond to those in adults.

Side effect

Most often in patients, prinimavshih lopinavir / ritonavir, diarrhea was observed and mild to moderate severity.

More than 2% Adult patients had the following moderately pronounced and serious side effects.

From the digestive system: abdominal pain, diarrhea, dysphagia, dyspepsia, flatulence, vomiting, nausea.

From the central and peripheral nervous system: insomnia, headache, depression, paresthesia.

Cardio-vascular system: arterial hypertension, vascular disorders.

The respiratory system: bronchitis.

On the part of the endocrine system: male hypogonadism, amenorrhea.

Metabolism: anorexia, weight loss.

On the part of the musculoskeletal system: myalgia.

On the part of the reproductive system: decreased libido.

Skin and subcutaneous fat: lipodystrophy, skin rash.

Other: asthenia, fever, chills.

Side effects, observed in less than 2% adult patients (connection with the use of Kaletra has not been established).

From the digestive system: gastritis, gastroenteritis, gemorragicheskiy colitis, constipation, scatacratia, belching, pancreatitis, periodontitis, sialadenitis, stomatitis, dry mouth, kholangit, cholecystitis, esophagitis, enteritis, enterocolitis, ulcerative stomatitis, hepatitis, gepatomegaliya, fat deposits in the liver, liver tenderness, jaundice.

The respiratory system: breathlessness, increased cough, pulmonary edema, rhinitis, sinusitis, pharyngitis, bronchial asthma.

From the central and peripheral nervous system: dizziness, dyskinesias, stroke, migraine, taste disturbances, disturbances of thought processes, amnesia, apathy, ataxia, sleep disorders, neuropathies, nervousness, peripheral neuritis, drowsiness, convulsions, tremor, emotional lability, encephalopathy, ažitaciâ, confusion, alarm, extrapyramidal syndrome, Bell's paralysis, Muscle hypertonicity.

Cardio-vascular system: phlebeurysm, vasculitis, atrial fibrillation, orthostatic hypotension, deep vein thrombosis, tromboflebit, myocardial infarction, palpitations; isolated cases – ʙradiaritmija.

From the senses: blurred vision, otitis media, noise in ears.

On the part of the endocrine system: gipotireoz, diabetes, Cushing's syndrome, gynecomastia, breast enlargement.

From the urinary system: nefrourolitiaz, jade.

On the part of the musculoskeletal system: arthralgia, arthrosis, back pain, osteonecrosis, changes in the joints, muscular weakness.

Metabolism: beri, Lactic acidosis, degidratatsiya, increased appetite, weight gain, obesity.

From the hematopoietic system: anemia, leukopenia, lymphadenopathy, neutropenia.

On the part of the reproductive system: abnormal ejaculation, impotence.

Dermatological reactions: acne, benign tumors of the skin, changes in the structure of nails, changes in skin color, skin ulceration, itching, Sweating, maculo-papular rash, seborrhea, xerosis, furunculosis, eczema, exfoliative dermatitis, alopecia, striae; isolated cases – erythema multiforme, Stevens-Johnson syndrome.

From the laboratory parameters: glucose increase, total cholesterol, triglycerides, bilirubin, uric acid in blood plasma, increased activity of AST, GOLD, GGT, amilazы, reduction of inorganic phosphorus.

Other: allergic reactions, malaise, chest pain, retrosternal pain, flu-like symptoms, swelling of the face, general and peripheral edema, bacterial infection, viral infections, cyst.

The profile of adverse events in children aged 6 Months before 12 years was similar to that in adults. Most often observed rash, dysgeusia, vomiting and diarrhea.

From the laboratory parameters: increase of total bilirubin, IS, GOLD, total cholesterol, amilazы, increasing or decreasing sodium content.

From the hematopoietic system: thrombocytopenia, neutropenia.

Contraindications

- severe degree of liver failure;

- simultaneous application of astemizole, terfenadine, midazolamom, triazolamom, cizapridom, pimozidom, ergot alkaloids (incl. ergotamin, digidroergotamin, ergometrine, methylergometrine), lovastatin, simvastatin, Hypericum perforatum, rifampicin, vorikonazolom;

- Children up to age 6 Months (for oral solution);

- Children up to age 3 years (for capsules and tablets);

- hypersensitivity to lopinavir, ritonavir and other ingredients.

FROM caution use in patients with viral hepatitis B and C., cirrhosis, mild to moderate hepatic insufficiency, elevated liver enzymes, hemophilia A and B, dyslipidaemia (incl. hypercholesterolemia, gipertrigliceridemii), in elderly patients (senior 65 years).

Pregnancy and lactation

Use of the drug during pregnancy is possible only in case, when the intended benefits to the mother outweighs the potential risk to the fetus.

If necessary, use during lactation should decide the issue of termination of breastfeeding.

Cautions

GCS

Systemic corticosteroid effects, including Cushing's syndrome and suppression of adrenocortical function, were described, while the application Kaletra with intranasal and inhaled fluticasone propionate. The development of similar symptoms when used Kaletra with other inhaled glucocorticosteroids, which are metabolized similar to flutikazonom, such as budesonide, cannot be deleted. Particular caution should be observed when using Kaletra with any GCS by inhalation or inatranzalnym. It is advisable to consider the possibility of appointing another SCS, especially when the need for long-term treatment.

Funds, improve erectile function

Particular caution should be observed when using sildenafil, tadalafil or vardenafil in patients, taking Kaletra, because, while the use of these drugs may be a significant increase in their concentration in plasma and the development of side effects (incl. hypotension, prolonged erection).

Abnormal liver function

Lopinavir / ritonavir primarily metabolized in the liver. Therefore, caution should be exercised in the appointment of the drug to patients with impaired liver function. The use of Kaletra has not been studied in patients with severe hepatic impairment. Pharmacokinetic data indicate that, that HIV-positive patients with the HCV-infection and mild or moderate hepatic impairment may increase lopinavir plasma concentrations of approximately 30%, and decrease its binding to plasma proteins. In the presence of hepatitis B or C, or a significant increase in transaminases before treatment increased the risk of further increasing their. In clinical practice, reported cases of liver function abnormalities, incl. fatal. Typically, they have been observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis, treated with various drugs. Communication of such cases with Kaletra 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 the drug.

Diabetes mellitus / hyperglycemia

During postmarketing surveillance in HIV-infected patients, receiving protease inhibitors, We have reported cases of decompensation of diabetes mellitus and hyperglycemia. In some cases, it had to appoint insulin or oral hypoglycemic agents (or increase their dose). Sometimes developing diabetic ketoacidosis. In some patients, hyperglycemia persisted after the abolition of the protease inhibitor. Reports of these incidents have been reported on a voluntary basis, therefore estimate their frequency and communication with protease inhibitors is not possible.

Pancreatitis

Patients, receiving Kaletra, observed the development of pancreatitis, incl. amid the severe hypertriglyceridemia. Cases of fatal. The connection of this adverse event with Kaletra has not been established, Nonetheless, a significant increase in the level of triglycerides is a risk factor for pancreatitis. In patients with advanced HIV infection increased the risk of developing hypertriglyceridemia and pancreatitis, in patients with a history of pancreatitis are at increased risk of its worsening during treatment with Kaletra.

Resistance / cross-resistance

In the study of protease inhibitors has been fixed cross-resistance of varying severity. Currently, we study the effect of lopinavir / ritonavir on the efficiency of subsequent therapy other protease inhibitors.

hemophilia

Patients with hemophilia A and B in the treatment of protease inhibitors described cases of bleeding, including spontaneous formation of subcutaneous hematoma and hemarthrosis development. Some patients received an additional dose of factor VIII. More than half the cases, treatment with protease inhibitors was continued. The causal relationship, or the mechanism of development of such adverse events in the treatment of protease inhibitors have not been established.

fat Redistribution

Against the background of ART was observed redistribution / accumulation of body fat deposition in the central parts of his body, in the back area, Neck, appearance “gorʙa ʙujvola”, a decrease in body fat in the face and extremities, breast enlargement and kushingoidom. The mechanism and long-term consequences of these adverse effects are unknown. Their connection with therapy is not installed.

Increasing the level of lipids

Kaletra treatment resulted in an increase in total cholesterol and triglyceride concentrations. Before beginning treatment and at regular intervals during treatment should control the levels of triglycerides and cholesterol. In the presence of lipid disorders shows the corresponding therapy.

Immune reconstitution syndrome

Patients, treated with combination ARV therapy, incl. using drug Kaletra, observed the development of immune reconstitution syndrome. Against the background of the restoration of immune function in the beginning of combination ARV therapy may increase asymptomatic or residual opportunistic infections (incl. Mycobacterium avium, Mycobacterium tuberculosis, Pneumocystis carinii, Cytomegalovirus), which may require additional examination and treatment.

Antimikobakterialynыe funds

Purpose Rifampicin simultaneously with Kaletra in tablet form is accompanied by a dose dependent decrease of lopinavir plasma concentration in comparison with a standard dose Kaletra 400/100 mg without rifampicin. Increased ALT and AST was observed when using Kaletra at higher doses in combination with rifampicin. With simultaneous use of Kaletra with rifampicin should be administered at the standard dose, at least, during 10 days prior to the appointment of rifampicin, Only then can further titration of the dose of Kaletra upwards. It is necessary to carefully monitor liver function.

osteonecrosis

Known, Many factors play a role in the etiology of osteonecrosis (incl. GCS, alcohol abuse, High BMI, severe immunosuppression). In particular, reported cases of osteonecrosis in patients with advanced HIV infection and / or long-term use of combination ART. Therefore, such patients should be advised to appeal to the doctor if you have pain, stiffness in the joints and impaired motor function.

Number older patients 65 years It was insufficient to assess the possible differences in the treatment lopinvirom / ritonavir compared to those of younger patients. In applying the lopinavir / ritonavir in the elderly should be careful, given the increased frequency of decreased hepatic, kidney or heart, comorbidities and concomitant therapy.

Use in Pediatrics

Bezopasnosty and pharmacokinetics of lopinavir / ritonavir in children aged less 6 Months not set. In HIV-infected patients children aged 6 Months before 12 years the profile of adverse events in clinical trials was similar to that in adults. The use of lopinavir / ritonavir 1 time / day has not been studied in children.

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of the drug Kaletra on the ability to drive a car or work with moving mechanisms have not been conducted.

Overdose

Currently, the clinical experience of acute overdose in humans is limited.

Treatment: Events, aimed at maintaining the body's life support, including monitoring of vital systems and monitor the patient's clinical condition. If necessary, – gastric lavage, administration of activated charcoal. Dialysis maloeffyektivyen (High-protein binding). No specific antidote.

Kaletra oral solution comprising 42.4% (volume percent) alcohol. Random welcome the child of the solution may cause alcohol intoxication.

Drug Interactions

Lopinavir / ritonavir in vitro and in vivo inhibit the CYP3A4 isoenzyme of cytochrome P450. Concomitant use of drugs and drug Kaletra, метаболизирующихся изоферментами CYP3A (incl. dihydropyridine calcium antagonists, inhibitors of HMG-CoA reductase, immunosuppressants and sildenafilom) It can lead to an increase in their concentration in the plasma and enhance or prolong the therapeutic actions and side effects.

The risk of a significant increase in AUC (≥3 times) during treatment with lopinavir / ritonavir is highest, while the use of drugs, It is extensively metabolized by the action of CYP3A isozymes and are metabolized during the first pass through the liver.

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

Lopinavir / ritonavir in vivo to induce its own metabolism and causes an increase in the biotransformation of some drugs, metabolized by the action of isoenzymes under the influence of cytochrome P450 isoenzymes, and by glyukuronirovaniya.

Lopinavir / ritonavir metaboliziruetsya under deystviem izofermentov CYP3A. Concomitant use of lopinavir / ritonavir with inducers of this isoenzyme may reduce plasma concentrations of lopinavir and its therapeutic effect. Other drugs, inhibiting isoenzymes CYRZA, can cause an increase in plasma concentrations of lopinavir, although these changes were not observed while applying ketoconazole.

Nucleoside reverse transcriptase inhibitors (NNRTI)

In an application with the use of ritonavir or lopinavir / ritonavir in combination with stavudine and lamivudine was not observed changes in the pharmacokinetics of lopinavir.

Didanosine is recommended to take an empty stomach. In this regard, didanosine may be administered with lopinavir / ritonavir without meals.

Lopinavir / ritonavir indutsiruet glyukuronirovanie, however possible to reduce the concentrations of zidovudine, and abacavir while the use of the drug Kaletra. The clinical significance of possible interactions unknown.

Lopinavir / ritonavir causes an increase tenofovir concentrations. The mechanism of interaction is not known. Patients, poluchayushtih lopinavir / ritonavir odnovremenno with tenofovirom, should monitor the side effects of the latter.

In the treatment of protease inhibitors, particularly in combination with NRTIs, observed: Increase CPK activity, mialgii, myositis, rarely – raʙdomioliz.

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

In healthy volunteers, poluchavshih nevirapine and lopinavir / ritonavir, not observed changes in the pharmacokinetics of lopinavir. In HIV-infected children showed decreased concentrations of lopinavir, while the use of nevirapine. The effect of nevirapine in HIV-positive adults may be similar to that in children, which may lead to decrease in the concentration of lopinavir. The clinical significance of the pharmacokinetic interaction is unknown. Lopinavir / ritonavir sleduet primenyaty 1 times / day in combination with nevirapine.

Increasing the dose of lopinavir / ritonavir to 600/150 mg (3 tab.) 2 times / day in combination with evafirenzom leads to an increase of lopinavir plasma concentration of at 36% and ritonavir 56-92% compared with dosing lopinavir / ritonavir dose 400/100 mg 2 times / day without evafirenza.

Evafirenz and nevirapine can induce CYP3A isoenzyme and, respectively, lower concentrations of other protease inhibitors, when used in combination with lopinavir / ritonavir. We do not recommend the use of lopinavir / ritonavir 1 times / day in combination with evafirenzom.

Delavirdine may increase lopinavir plasma concentrations.

Protease inhibitors

Lopinavir / ritonavir may cause a rise in the concentration of amprenavir. In the treatment at a dose of amprenavir 750 mg 2 times / day in combination with lopinavir / ritonavir marked increase in AUC and C_min compared to those when using a dose of amprenavir 1200 mg 2 times / day, wherein C_max It does not change significantly. Simultaneous treatment lopinavir / ritonavir, amprenavir and lopinavir concentration causes a decrease in. Lopinavir / ritonavir sleduet primenyaty 1 times / day in combination with amprenavir.

Combined use of lopinavir / ritonavir, fosamprenavir, and is accompanied by a decrease in the concentrations of lopinavir and fosamprenavir. Adequate doses of drugs in combined use is not installed (in terms of safety and efficacy).

Lopinavir / Ritonavir may increase the concentration of indinavir (indinavir in combination at a dose of 600 mg 2 times / day with lopinavir / ritonavir marked decrease in C_max With the increase and_min compared to those when using a dose of Indinavir 800 mg 3 times / day, wherein AUC is not altered. In applying the lopinavir / ritonavir dose 400/100 mg 2 times / day may require dose reduction of indinavir. Lopinavir / ritonavir sleduet primenyaty 1 times / day in combination with indinavir.

Lopinavir / ritonavir may cause a rise in the concentration of nelfinavir and its M8 metabolite. With simultaneous application of a dose of nelfinavir 1000 mg 2 times / day with lopinavir / ritonavir marked increase in C_min compared with those in the treatment at a dose of nelfinavir 1250 mg 2 times / day, wherein the AUC and C_max do not change significantly. The combination of lopinavir / ritonavir with nelfinavir reduces the concentration of lopinavir. Lopinavir / ritonavir sleduet primenyaty 1 times / day in combination with nelfinavir.

In applying nelfinavir may require increasing the dose of lopinavir / ritonavir, especially in HIV-infected patients, treated with various protease inhibitors or having reduced sensitivity to lopinavir.

With simultaneous use of lopinavir / ritonavir, ritonavir at a dose of 100 mg 2 times / day there was an increase in the AUC of lopinavir 33% and C_min on 64% in comparison with those when using only lopinavir / ritonavir dose 400/100 mg (3 caps.) 2 times / day.

Lopinavir / ritonavir may cause a rise in the concentration of saquinavir. In an application in a dose of saquinavir 800 mg 2 times / day with lopinavir / ritonavir was an increase in AUC, C_max and C_min compared to those when using a dose of saquinavir 1200 mg 3 times / day. In applying the lopinavir / ritonavir dose 400/100 mg 2 times / day may require dose reduction of saquinavir. The use of lopinavir / ritonavir in combination with saquinavir 1 time / day has not been evaluated.

With simultaneous application of a dose of tipranavir 500 mg 2 times / day with ritonavir at a dose of 200 mg 2 times / day and lopinavir / ritonavir dose 400/100 mg 2 times / day reduction occurs AUCi C_min on 47% and 70% respectively. The simultaneous use of lopinavir / ritonavir, tipranavir and ritonavir with a low dose is not recommended.

Antiarrhythmics

Concentrations of amiodarone, bepridil, lidocaine and quinidine may be increased with concomitant administration with lopinavir / ritonavir. Caution must be exercised combination Kaletra preparation with the above drugs and, possibly, to monitor their concentrations in plasma.

While the use of ritonavir dose 300 mg every 12 h increases significantly ANALYSIS OF digoxin. Caution must be exercised when applying a combination of drug with digoxin Kaletra, as well as to control the concentration of digoxin in serum.

Drugs, prolonging the QT interval

Concentrations pheniramine, xinidina, erythromycin and clarithromycin can increase followed QT prolongation and development of side effects of the cardiovascular system while the use of lopinavir / ritonavir. It should be used with caution Kaletra drug in combination with drugs, prolonging the QT interval.

Antineoplastic agents

While the use of ritonavir / lopinavir may increase plasma concentrations of vincristine and vinblastine followed by a potential increase in the frequency of side effects, are characteristic of these drugs.

Antykoahulyantы

Lopinavir / ritonavir may cause a decrease in the concentration of warfarin. It is recommended to monitor the international normalized ratio (INR).

Antidepressants

The combination of ritonavir and trazodone may increase concentrations of trazodone and the development of side effects (incl. nausea, dizziness, hypotension, fainting). Simultaneously isoenzyme CYP3A inhibitor, Takima how lopinavir / ritonavir, trazodone should be used cautiously, perhaps, with decreasing doses.

Anticonvulsants

Phenobarbital, phenytoin and carbamazepine induce CYP3A isoenzyme and may cause a decrease in the concentration of lopinavir. Lopinavir / ritonavir sleduet primenyaty 1 times / day in combination with the above drugs. The simultaneous use of phenytoin and lopinavir / ritonavir may be accompanied by moderate decrease in C_ss phenytoin. It should control the concentration of phenytoin in the plasma of combined treatment with lopinavir / ritonavir.

antifungals

Serum concentrations of ketoconazole and itraconazole may be increased while the use of lopinavir / ritonavir. Apply itraconazole, ketoconazole, and in high doses (>200 mg / day) in combination with lopinavir / ritonavir is not recommended.

Ritonavir at a dose of 400 mg every 12 h caused a decrease in equilibrium AUC of voriconazole by an average of 39%. Not recommended simultaneous use of voriconazole with drug Kaletra.

Antibacterials

Lopinavir / ritonavir may cause a moderate increase in AUC of clarithromycin. Patients with impaired renal or hepatic function is expedient to decrease the dose of clarithromycin while the use of lopinavir / ritonavir.

Antimikobakterialynыe funds

With simultaneous use of rifabutin and lopinavir / ritonavir for 10 days C_max and AUC rifabutin (of the drug and active 25-O-metabolite dezatsetilovogo) increase in 3.5 and 5.7 times, respectively,. Given these data in the treatment of lopinavir / ritonavir is recommended to decrease the dose of rifabutin 75% (ie. to 150 mg a day or 3 times a week). May require additional reduction of the dose of rifabutin.

Given the significant reduction in lopinavir concentrations while the use of rifampicin, appoint rifampicin in combination with the drug Kaletra should not. Such combination may result in a deterioration of viral response and potential development of resistance to lopinavir / ritonavir, the entire class of protease inhibitors or other anti-retroviral drugs.

antiparasitics

In the treatment of lopinavir / ritonavir may reduce the therapeutic concentration of atovaquone. You may need to increase the concentration of the latter.

GCS

Dexamethasone can induce CYP3A isoenzyme increased activity and reduced concentration of lopinavir.

The combination with lopinavir / ritonavir may result in increased concentrations of fluticasone and reduce serum cortisol concentrations.

Dihydropyridine calcium antagonists

Serum concentrations of felodipine, nifedipine and nicardipine may increase while the use of lopinavir / ritonavir.

Funds, improve erectile function

Funds, improve erectile function, should apply with frequent monitoring of side effects and lower doses: sildenafil – 25 mg every 48 no; tadalafil – not >10 mg every 72 no; Vardenafil – not >2.5 mg every 72 no.

HMG-CoA reductase

Lopinavir / ritonavir may cause a significant increase in plasma levels of HMG-CoA reductase, metaboliziryuschihsya under isoenzyme CYP3A, Taki how lovastatin and simvastatin. We do not recommend the combination of lopinavir / ritonavir with statins, because increasing concentrations of statins can lead to the development of myopathies, incl. rhabdomyolysis.

Metabolism Atorvastatin is less dependent on CYP3A isoenzyme. With simultaneous use of atorvastatin with lopinavir / ritonavir experienced higher C_max and AUC atorvastatin 4.7 and 5.9 times, respectively,. In combination with lopinavir / ritonavir atorvastatin should be used in minimal doses.

No evidence of clinically significant interaction between lopinavir / ritonavir with pravastatin were found. Metabolism of pravastatin and fluvastatin is not dependent on CYP3A isozymes, therefore they should not engage in the lopinavir / ritonavir. If treatment is indicated inhibitors of HMG-CoA reductase inhibitor during therapy with Kaletra, recommended pravastatin or fluvastatin.

Immunosuppressive

The concentrations of cyclosporine, tacrolimus and sirolimus may increase while the use of lopinavir / ritonavir. Recommended more frequent monitoring of immunosuppressant concentrations in plasma, while their blood levels are stabilized.

Methadone

Lopinavir / ritonavir is a decrease in plasma concentrations of methadone. It is recommended to control the plasma concentration of methadone.

Oral contraceptives and patches

Given the possibility of reducing the plasma concentration of ethinyl estradiol while applying lopinavir / ritonavir with oral contraceptives or patches, containing estrogens, suitable other or additional contraceptive measures.

Clinically significant interactions are not expected

The studies did not reveal clinically significant interactions of lopinavir / ritonavir with desipramine, omeprazolom and ranitidinom.

Taking into account the information about the metabolism is not expected clinically significant interaction with fluvastatin, dapsone, trimetoprimom / sulyfametoksazolom, azithromycin or fluconazole in patients with normal liver function or renal.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Capsules for oral solution should be kept out of the reach of children at a temperature of from 2 ° to 8 ° C. (in a refrigerator). Shelf life - 2 year.

Outside the refrigerator preparation can be stored at temperatures not above 25 ° C for 42 d (6 weeks), then the residue should be destroyed. It is recommended to leave a bottle with a solution for oral administration date, when the drug has been removed from the refrigerator.

Kaletra tablets should be stored in reach of children at a temperature not higher than 25 ° C. Shelf life - 2 year.