Preparation which contains in its composition lopinavir and ritonavir. Lopinavir is an inhibitor of the protease of , human liquid anavar immunodeficiency virus and provides antiviral activity of the drug. The inhibition of HIV protease prevents the synthesis of viral proteins and prevents cleavage of the polypeptide gag-pol, which leads to the formation of immature and unable to infection by the virus. Ritonavir inhibits isoenzyme metabolism of lopinavir in the liver, leading to an increase of lopinavir plasma concentration. Ritonavir is also an inhibitor of HIV protease. Resistance isolates with reduced susceptibility to lopinavir have been selected presence of ritonavir does not influence the selection of lopinavir-resistant viruses in treatment in patients not previously treated with therapy were analyzed viral isolates from each patient with a . A further increase in viral load was associated with the introduction of additional mutations associated with the development of resistance to protease inhibitors of HIV. However, these data are insufficient to identify the mutations responsible for the development liquid anavar of resistance to lopinavir. Cross-resistance of today is not enough of cross-resistance during therapy with the development of data . lopinavir / ritonavir virologic response to therapy with lopinavir .
The pharmacokinetics of lopinavir in combination with ritonavir was studied in healthy volunteers and HIV-infected patients; significant differences between the two groups did not reveal. Lopinavir is almost completely metabolized by the action of liquid anavar isoenzyme CYP3A. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its concentration in plasma. In the application of lopinavir / ritonavir 400/100 mg dose twice daily average equilibrium lopinavir plasma concentration in HIV infected patients is 15-20 times higher than those of ritonavir and ritonavir plasma concentration was less than 7% of the concentration at reception in ritonavir 600 mg twice daily. EC 50 lopinavir in vitro is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir, lopinavir is determined.
When the meal concentration of lopinavir and ritonavir in the blood plasma after taking two tablets 200/50 mg is equivalent to three capsules at 133/33 mg with minimal variability in pharmacokinetics.Absorption In a pharmacokinetic study in HIV -positive patients (n = 19), when receiving the 400/100 mg lopinavir / ritonavir twice daily together with food for three weeks, the average value of the maximum quantity of lopinavir plasma concentration (C max ) 3.7 ± 9,8 g / ml, it was noted after about four hours after taking the drug. The average equilibrium concentration before the morning dose was 7.1 ± 2.9 mg / ml and the minimum concentration within the dosing interval was 5.5 ± 2.7 pg / ml. The area under the curve “concentration-time» (AUC) for lopinavir 12 hours after taking the drug averaged 92,6 ± 36,7 mkg⋅ch / ml. The absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established. Distribution In the equilibrium state of about 98 – 99% of lopinavir are in communication with the plasma proteins. Lopinavir binds to alpha 1-acid glycoprotein (ACS) and albumin, however, lopinavir higher affinity for ACS. In equilibrium binding of lopinavir plasma proteins remains constant in the range of reported concentrations, poses after receiving the 400/100 mg lopinavir / rntonavira twice a day, and is comparable in healthy volunteers and HIV-positive patients. Metabolism Studies in vitrodemonstrated that lopinavir predominantly undergoes oxidative metabolism involving liquid anavar cytochrome P450 hepatocytes, mainly under the influence of isoenzyme CYP3A. Ritonavir – a potent inhibitor of isoenzyme CYP3A, which inhibits the metabolism of lopinavir, lopinavir that provides an increase in plasma concentrations. After a single dose of 400/100 mg lopinavir / ritonavir (labeled with 14 C- lopinavir), 89% of the radioactivity provided the original drug. In humans, it has been revealed at least 13 lopinavir oxidative metabolites. Ritonavir is able to induce the cytochrome P450 isozymes, which leads to the induction of its own metabolism. During prolonged use lopinovira concentration before taking the next dose decreased over time, stabilizing after approximately 10-16 days. Withdrawal After receiving 400/100 mg 14 C-lopinavir / ritonavir eight days approximately 10,4 ± 2,3%, and 82, 6 ± 2,5% of the administered dose of 14 C-lopinavir found in the urine and feces, respectively. Moreover unmodified lopinavir is respectively 2.2 and 19.8%. After prolonged use of less than 3% of the dose of lopinavir is excreted in unchanged form via the kidneys. The clearance (CL / F) of lopinavir ingestion of 5.98 +/- 5.75 l / h. The reception once daily pharmacokinetics of lopinavir / ritonavir, with a multiplicity of receiving once daily was evaluated in HIV-infected patients not receiving prior antiretroviral therapy. Lopinavir / ritonavir 800/200 mg was used in combination with emtricitabine and tenofovir 200 mg 300 mg once a day daily. Chronic administration of 800/200 mg lopinavir / rntonavira once a day for 4 weeks during a meal the average maximum plasma concentration of lopinavir in (the C max ) was 11,8 ± 3,7 mg / ml and reaches about 6 hours after administration. Lopinavir liquid anavar average equilibrium concentration before taking the morning dose was 3.2 ± 2.1 mg / ml, the lowest concentration within the dosing interval was 1.7 ± 1.6 pg / ml. Lopinavir AUC at 24-hour reception interval averaged 154,1 ± 61,4 mkg⋅ch / ml. Special group sex, race and age of the pharmacokinetics of lopinavir has not been studied in elderly patients. No sex-dependent pharmacokinetic differences were observed in adult patients. No clinically significant pharmacokinetic differences depending on race also has been established. Children Pharmacokinetics lopinavir / ritonavir 300/75 reception mg / m 2 twice daily and 230 / 57.5 mg / m 2 twice daily were studied for a total of 53 patients aged 12 years. Driving dosing 230 / 57.5 mg / m 2 twice daily without nevirapine and the 300/75 mg / m 2 twice daily with nevirapine provided lopinavir plasma concentrations similar to those obtained in liquid anavar adult patients receiving 400/100 mg for twice a day (without nevirapine). Receiving Lopinavir / ritonavir once a day in children has not been studied. Average equilibrium AUC, C max, and C min lopinavir after administration of lopinavir / ritonavir 230 / 57.5 mg / m 2 twice daily without nevirapine (n = 12) were 72.6 ± 31,1mkg⋅ch / ml; 8.2 ± 2.9 and 3.4 ± 2.1 mcg / mL, respectively; and 85.8 ± 36.9 mkg⋅ch / ml, 10.0 ± 3.3 and 3.6 ± 3.5 mcg / ml, respectively, after receiving 300/75 mg / m 2 twice daily with nevirapine (n = 12). Scheme NVP was 7 mg / kg twice a day (in patients from six months up to eight years) or 4 mg / kg twice a day (in patients older than eight years). Renal insufficiency Pharmacokinetics lopinavir has not been studied in patients with renal failure; however, since the renal clearance of lopinavir is negligible, lower total clearance in patients with renal insufficiency is not expected. Liver failure Lopinavir predominantly metabolized and excreted by the liver. The combined dosing of lopinavir / ritonavir at 400/100 mg twice daily in patients co-infected with HIV and hepatitis C, liver failure resulting in moderate 30% increase in AUC of lopinavir and 20% increase in the C max as compared to the HIV-infected patients with normal liver function. Lopinavir liquid anavar plasma protein binding was lower when compared to the control groups mild to moderate hepatic impairment (99.09 compared with 99.31%, respectively). Lopinavir / ritonavir has not been studied in patients with hepatic impairment, severe (see “Contraindications” section.). Drug Interactions (See also:. “Contra,” “Precautions,” “Special instructions”, “Interactions with other drugs “). Lopinavir / ritonavir in vitro inhibits the isoenzyme of CYP3A. The simultaneous use of lopinavir / rntonavira and drugs metabolized isoenzyme CYP3A, may lead to increased concentrations of the drug in the plasma, which can enhance or prolong the therapeutic or side effect (cm. “Contraindications”). Lopinavir / ritonavir does not inhibit isoenzymes CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at therapeutic concentrations. Lopinavir / ritonavir in vivo to induce its own metabolism and enhances the biotransformation of some drugs metabolized by cytochrome P450 and glyukuronirovaniya. Lopnnavir / ritonavir is metabolized with the participation of isoenzyme of CYP3A. It is expected that agents that induce isoenzyme CYP3A, lopinavir clearance may increase, which may lead to a decrease in plasma concentrations of lopinavir. Concomitant liquid anavar use of lopinavir / ritonavir and other drugs that inhibit the isoenzyme of CYP3A, may increase plasma concentrations of lopinavir. Clinical guidelines refer to “Interactions with other drugs.”
Treatment of HIV infection in adults and children from 3 years as part of combination therapy.
- Hypersensitivity to lopinavir, ritonavir or auxiliary ingredients.
- Severe hepatic insufficiency.
- Concomitant use of drugs, clearance is significantly dependent on metabolism by isoenzyme CYP3A. These medications include: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, rifampicin, salmeterol, sildenafil (only in the case of the treatment of pulmonary hypertension, see “Interaction with other medicinal products.”), Vardenafil, voriconazole, ergot alkaloids ( eg, ergotamine and dihydroergotamine, ergometrine and metilergometrin) reductase inhibitors Z-hydroxy-Z-CoA metilglutaril- (lovastatin, simvastatin), St. John’s wort preparations, fosamprenavir.
- Children under 3 years of age (for children aged from 6 months to 3 years old is prescribed drug in dosage form “for oral solution”).
- Use of the drug Kaletra ® once daily in combination with carbamazepine, phenobarbital or phenytoin.Carefully
- Viral hepatitis B and C.
- Cirrhosis of the liver.
- Mild to moderate hepatic insufficiency.
- The increased activity of “liver” enzymes.
- Hemophilia A and B.
- Dyslipidemia (giperholesterinemnya, hypertriglyceridemia).
- Older age (over 65 years).
- Patients with organic heart disease, and pre-existing disorders of the cardiac conduction system or patients taking medications, lengthening the interval PR (such as verapamil or atazanavir).
- The simultaneous use of drugs for the treatment of erectile dysfunction, namely with sildenafil (see. “Contraindications”), tadalafil.
- Concomitant use of fentanyl, rosuvastatin, atorvastatin, bupropion, or inhaled glucocorticosteroids administered through the nose.(See. “Interaction with other medicinal products”).Pregnancy and lactation
During pregnancy, the drug should be taken only if the potential benefit to the mother outweighs the potential risk to the fetus. Women should stop breast-feeding during the use of lopinavir / rntonavira.
Dosing and Administration
Inside, regardless of meals. Tablets Kaletra ® should be swallowed whole without chewing, without breaking or crushing. Adult patients The recommended oral dose of Kaletra ® is:
- On four tablets Kaletra ® 100/25 mg (400/100 mg) twice daily without regard to meals.
- On eight tablets of Kaletra ® 100/25 mg (800/200 mg) once daily without regard to meals for patients who showed less than 3 mutations associated with the development of resistance to lopinavir.Insufficient data for use of lopinavir / rntonavira once daily in adult patients with 3 or more mutations associated with the development of resistance to lopinavir. Concomitant therapy The use of Kaletra tablets ® in combination with omeprazole and ranntndinom does not require dose adjustment. In patients with suspected reduced sensitivity to lopinavir (shown clinically or laboratory), previously treated with antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir or nelfinavir need to increase the dose tablets Kaletra ® to 500/125 mg (5 100/25 mg tablets) twice a day 2 . While the use of these drugs pill Kaletra ® should not be administered 1 time per day. Children mode receiving Kaletra tablets ® once daily pediatric patients has not been studied. The adult dosage tablets Kaletra ® (400/100 mg twice daily) without the simultaneous application of efavirenz, nevirapine, amprenavir or nelfinavir can be used for children weighing more than 35 kg or body surface area (BSA) of 1.4 m 2 or more . To determine the dose for children weighing less than 35 kg or with a BSA between 0.6 and 1.4 m 2 is recommended to use the following table. For children with a BSA less than 0.6m or for children under 3 years of age there is a solution of the drug Kaletra ® for oral administration.