Generic Kaletra (Lopinavir 200mg/Ritonavir 50mg)
Kaletra

Generic Kaletra is a prescription drug that is used to treat HIV-1 in patients that include adults and children over the age of 14 days and contains Lopanovir 200mg and Ritonavir 50mg.

Package
Price
Per Bottles
Savings
Order
60 tab x 1 bottle
$280.99
$280.99
$0.00
Next orders 10% discount
+ Free standard airmail service
60 tab x 2 bottles
$526.99
$263.50
$34.98
Next orders 10% discount
+ Free standard airmail service
60 tab x 3 bottles
$718.99
$239.66
$123.99
Next orders 10% discount
+ Free standard airmail service
Product Description

Kaletra® (Kaletra) usage instructions

 

Form of production, packaging and the drug Kaletra®


The solution for the reception inside light yellow or yellow color, transparent.

  1 ml
lopinavir 80 mg
ritonavir 20 mg

Excipients: macrogol glycerylmonostearate - 10.2 mg, purified water - 69.2 mg, sodium chloride - 3.6 mg sodium citrate - 2.0 mg sodium saccharin - 4.1 mg of Acesulfame potassium is 4.1 mg, citric acid anhydrous - 1.1 mg, ethanol - 356.3 mg, propylene glycol - 152.7 mg, levomenthol - 0.5 mg, povidone K-30 - 30.5 mg, glycerol - 59.6 mg, corn syrup with high fructose - 168.6 mg, flavor of magnasweet-110 (2) - 29.5 mg, butter menthol - 3.1 mg, flavor vanilla - 12.7 mg, synthesized flavoring additive - 10.2 mg.

60 ml - bottles made of polyethylene terephthalate (5) complete with feeders (5 PCs.) - packs of cardboard.

Clinico-pharmacological group: Antiviral drug, active against HIV
Pharmaco-therapeutic group: Antiviral [HIV] means

Pharmacological action

Antiviral combo drug, which contains in its composition of lopinavir and ritonavir.

Mechanism of action

Lopinavir is a protease inhibitor of HIV-1 and HIV-2 human immunodeficiency virus (HIV) and thus ensures the antiviral activity of the drug. The inhibition of HIV protease prevents the synthesis of virus proteins and prevents cleavage of the polypeptide gag-pol, leading to the formation of immature and incapable to infection of the virus.

Ritonavir inhibits the CYP3A4-mediated metabolism of lopinavir in the liver, which leads to increased concentrations of lopinavir in plasma. Ritonavir is also an HIV protease inhibitor.

Resistance

Isolates of HIV-1 with reduced susceptibility to lopinavir have been selected in vitro. The presence of ritonavir did not influence the selection of lopinavir-resistant viruses in vitro.

In a clinical study during antiretroviral (ARV) treatment of patients, not previously treated, were analysed viral isolates from each patient with the concentration of HIV RNA in plasma more than 400 copies/ml at 24, 32, 40 and/or 48 week. All the 37 evaluated patients treated with lopinavir/ritonavir, there was no evidence of genotypic or phenotypic resistance to lopinavir/ritonavir. In children who had not previously received antiretroviral therapy, resistance to lopinavir/ritonavir were not revealed.

In phase II clinical studies of the drug Kaletra® among 227 HIV-infected patients who received and who had not previously received antiretroviral therapy, 4 of 23 patients with virological ineffectiveness of therapy (HIV RNA >400 copies/ml) was found reduced sensitivity to lopinavir 12-100 through weeks of therapy with the drug Kaletra®; 3 of 4 patients had previously received one of the HIV protease inhibitors (nelfinavir, saquinavir, or indinavir), 1 of 4 patients - combination therapy with protease inhibitors HIV (indinavir, saquinavir, and ritonavir). All 4 patients had at least 4 mutations associated with resistance to protease inhibitors HIV immediately before the commencement of drug therapy Kaletra®. A further increase in viral load was associated with the appearance of additional mutations associated with the development of resistance to inhibitors of HIV protease. However, these data are insufficient to identify the mutations responsible for the development of resistance to lopinavir.

Cross-resistance

Insufficient data on the development of cross-resistance during therapy with lopinavir/ritonavir.

Virologic response to therapy with lopinavir/ritonavir was changed in the presence of 3 or more of the following amino acid substitutions in the gene for HIV protease: 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 decrease in susceptibility to lopinavir in vitro was studied on the basis of the virological response to therapy with lopinavir/ritonavir depending on the source of the genotype and phenotype of the virus in 56 patients with HIV RNA above 1000 copies/ml who received prior therapy with nelfinavir, indinavir, or saquinavir with a ritonavir (study M98-957). In this study, patients prescribed lopinavir/ritonavir at one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Before therapy EU50 (the concentration of drug needed to suppress replication of 50% of viruses) of lopinavir against the 56 strains of the virus was in 0.5-96 times higher than the EU50 for wild-type virus. In 55% (31/56) of the virus strains was determined by the decreased sensitivity to lopinavir is more than 4 times, and the average decreased sensitivity to lopinavir among 31 strain was 27.9 times.

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

Not enough data to identify the mutations causing 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; significant differences between the two groups is not revealed. Lopinavir is almost completely metabolized by the action of isoenzyme CYP3A. Ritonavir inhibits the metabolism of lopinavir and increases its concentration in plasma. When using lopinavir/ritonavir dose 400/100 mg 2 times/day average equilibrium concentrations (Css)of lopinavir in plasma from HIV-infected patients is 15-20 times higher than those of ritonavir, and ritonavir concentration in the plasma was less than 7% of the concentrations in the ritonavir dose of 600 mg 2 times/day. EC50 lopinavir in vitro is about 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir lopinavir is determined.

The impact of food on drug absorption

When using lopinavir/ritonavir (dosage form solution for the reception inside) with a fat meal (872 kcal, 56 % calorie from fat) AUC and Cmax lopinavir increased by 130% and 56% respectively as compared to those when taking the drug on an empty stomach. To improve the bioavailability and minimize variability of pharmacokinetics, the solution of lopinavir/ritonavir should be taken with food.

Distribution

At steady state, approximately 98-99% of the lopinavir bound to plasma proteins. Lopinavir binds to alpha1-acid glycoprotein (ACT) and albumin, but the lopinavir higher affinity for ACS. In equilibrium the binding of lopinavir plasma proteins remains constant in the range of concentrations was created after administration of the lopinavir/ritonavir dose 400/100 mg 2 times/day, and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

In vitro studies showed that lopinavir undergoes primarily oxidative metabolism involving cytochrome P450 of hepatocytes, mainly under the influence of isoenzyme CYP3A. Ritonavir is a powerful inhibitor of the isoenzyme CYP3A, which inhibits the metabolism of lopinavir, which provides for the increase of the concentrations of lopinavir in plasma. After a single dose of 400/100 mg lopinavir/ritonavir (with labeled 14C-lopinavir), 89% of the radioactivity provided the original drug. In the human body have been identified, at least 13 metabolites of lopinavir. Ritonavir is capable of inducing the cytochrome P450 isoenzymes, leading to induction of its own metabolism. During prolonged use concentrations of lopinavir before applying the next dose decreased with time, stabilizing after approximately 10 to 16 days.

Excretion

8 days after application 14C-lopinavir/ritonavir 400/100 mg dose, approximately 10.4±2.3% and 82.6±2.5% of the dose 14C-lopinavir found in the urine and feces, respectively. And lopinavir in an unmodified form is respectively 2.2% and 19.8%. After prolonged use, less than 3% of the lopinavir dose are excreted unchanged by the kidneys. Clearance of lopinavir when administered is 5.98±5.75 l/h.

Special groups

Lopinavir pharmacokinetics have not been studied in elderly patients. No sex-dependent pharmacokinetic differences in adults is not established. No clinically significant pharmacokinetic differences depend on race also found.

Children. The pharmacokinetics of lopinavir/ritonavir when using 300/75 mg/m 2 times/day and 230/57.5 mg/m2 2 times/day were studied in a total of 53 patients aged from 6 months to 12 years. The use of lopinavir/ritonavir dose of 230/57.5 mg/m2 2 times per day without nevirapine and the dose of 300/75 mg/m2 2 times/day with nevirapine had similar concentrations of lopinavir in plasma to those obtained in adult patients taking lopinavir/ritonavir dose 400/100 mg 2 times/day (without nevirapine). The use of lopinavir/ritonavir 1 times/day in children has not been studied.

Average equilibrium AUC, Withmaxand Cmin lopinavir after application of the lopinavir/ritonavir dose of 230/57.5 mg/m2 2 times per day without nevirapine (n=12) were 72.6±31.1 µg×h/ml; 8.2±2.9 and 3.4±2.1 µg/ml, respectively; and 85.8±36.9 µg×h/ml, 10±3.3 and 3.6±3.5 µg/ml, respectively, after the application of 300/75 mg/m 2 times/day with nevirapine (n=12). Nevirapine was used in the following schemes: 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. Lopinavir pharmacokinetics have not been studied in patients with renal failure because renal clearance of lopinavir is negligible, decrease in total clearance in patients with renal impairment is not expected.

Liver failure. Lopinavir is metabolized and excreted by the liver. Repeated use of lopinavir/ritonavir dose 400/100 mg 2 times/day in patients, simultaneously infected with HIV and hepatitis C, with liver failure mild and moderate severity resulted in a 30% increase in lopinavir AUC and 20% increase Withmax compared with HIV-infected patients with normal hepatic function. The binding of lopinavir with blood plasma proteins was lower when liver failure mild and moderate in comparison with the control groups (99.09%, compared to 99.31%, respectively). The use of lopinavir/ritonavir in patients with hepatic insufficiency of severe degree has not been studied (see section "Contraindications").

Drug interactions

Lopinavir/ritonavir in vitro inhibits the isoenzyme CYP3A. Concomitant use of lopinavir/ritonavir and drugs metabolized by the CYP3A isoenzyme, can lead to increased concentrations of this drug in plasma, which could increase or prolong its therapeutic or adverse effect (see "Contraindications").

In therapeutic concentrations of lopinavir/ritonavir does not inhibit the isoenzyme CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2.

Lopinavir/ritonavir in vivo induces its own metabolism and increases the biotransformation of some drugs metabolized by the enzymes cytochrome P450 and by glukuronirovania.

Lopinavir/ritonavir is metabolized with the participation of isoenzyme CYP3A. It is expected that drugs that induce isoenzyme CYP3A activity may increase the clearance of lopinavir, which may lead to lower concentrations of lopinavir in plasma. Concomitant use of lopinavir/ritonavir and other drugs that inhibit the isoenzyme CYP3A may increase plasma concentrations of lopinavir.

The testimony of the drug Kaletra®

  • the syndrome of acquired immunodeficiency (HIV) infection in adults and children 6 months of age as part of combination antiretroviral therapy.

 

The dosage regimen

Inside. The oral solution Kaletra® should be taken during meals.

Measure dose with a calibrated syringe (batcher).

Adults

The Drug Kaletra® used in a dose:

  • 400/100 mg ( 5 ml) 2 times/day or
  • 800/200 mg (10 ml) 1 times/day in patients with no more than 2 mutations associated with development of resistance to lopinavir. The use of the drug Kaletra® 1 time/day in patients with more than 2 mutations associated with development of resistance to lopinavir, not well understood, and therefore contraindicated.

Concomitant therapy

The combined use of the drug Kaletra® 1 time/day with the drugs carbamazepine, phenobarbital or phenytoin is contraindicated.

Omeprazole and ranitidine. The use of the drug Kaletra® in the pharmaceutical form solution for oral administration in combination with omeprazole and ranitidine does not require dose adjustment.

Efavirenz, nevirapine, amprenavir or nelfinavir. If it reduced sensitivity to lopinavir (based on history or lab data) in combination with efavirenz, nevirapine, amprenavir or nelfinavir, it is recommended increasing the dose of the drug Kaletra® to 533/133 mg (6.5 ml) 2 times/day. The simultaneous use of the drug Kaletra® 1 time/day with efavirenz, nevirapine, amprenavir or nelfinavir is contraindicated

Children

To avoid toxic effects of ethanol and propylene glycol with the use of the drug Kaletra® (solution for the reception inside) in children should consider the total amount of these substances entering the body in the application containing medicines, including the drug Kaletra®.

Have children aged 6 months to 12 years with body weight from 7 kg to 15 kg recommended dose Kaletra®(solution for the reception inside) is 12/3 mg/kg and body weight between 15 kg and 40 kg - 10/2.5 mg/kg (equivalent to 230/57.5 mg/m2); the drug Kaletra® administered during meals; maximum dose children weighing more than 40 kg shall not exceed 400/100 mg (5 ml) 2 times/day. The use of the drug Kaletra® 1 time/day in children has not been studied.

The doctor should calculate the appropriate dose in mg for each child under the age of 12 years old and determine the corresponding volume of solution. Table 1 provides guidance on the selection of the dose Kaletra® (solution for the reception inside) depending on the body mass in children.

Table 1. Recommendations on the selection of the dose Kaletra® depending on the body mass in children.

Body weight (kg) Dose (mg/kg)* The volume of the oral solution (80 mg lopinavir/20 mg ritonavir per 1 ml)
Without efavirenz, nevirapine, and nelfinavir amprenavir or
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 with regard to the content of lopinavir in solution lopinavir/ritonavir (80/20 mg/ml).

Note: children under the age of 12 recommendations for dosing comply with those of the adults.

Concomitant therapy

If children from 6 months to 12 years it reduced sensitivity to lopinavir (based on history or lab data) in combination with efavirenz, nevirapine, amprenavir or nelfinavir, it is recommended increasing the dose of the drug Kaletra® to 13/3.25 mg/kg 2 times/day at children with body mass from 7 kg to 15 kg until 11/2.75 mg/kg 2 times/day at children weighing from 15 kg to 45 kg (approximately 300/75 mg/m2). Maximum dose children weighing more than 45 kg should not exceed 533/133 mg 2 times/day. Table 2 provides guidance on the selection of doses of the drug Kaletra® (solution for the reception inside), depending on body mass when using the drug in combination with efavirenz, nevirapine, amprenavir or nelfinavir in children.

Table 2. Recommendations on the selection of the dose Kaletra® in combination with efavirenz, nevirapine, amprenavir or nelfinavir depending on the body mass in children.

Body weight (kg) Dose (mg/kg)* The volume of the oral solution (80 mg lopinavir/20 mg ritonavir) in 1 ml
With efavirenz, nevirapine, amprenavir or nelfinavir
7-15 kg 13 mg/kg2 times/day  
7-10 kg   1.5 ml 2 times/day
10-15 kg   2 ml 2 times/day
15-45 kg 11 mg/kg2 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

* The dose is selected with regard to the content of lopinavir in solution lopinavir/ritonavir (80/20 mg/ml).
Note: children under the age of 12 recommendations for dosing comply with those of the adults.

Recommendations for dosing on the basis of the body surface area (m2)

Children under the age of 6 months: recommended dose Kaletra® is 230/57.5 mg/m2 2 times/day during meals, a maximum dose of 400/100 mg 2 times/day. For some children, while receiving efavirenz, nevirapine, amprenavir or nelfinavir, this dose may be insufficient. In such cases it may increase to 300/75 mg/m2.

Table 3. Recommendations for use of oral solution Kaletra® in children.

The surface area of the body (m2)* 230/57.5 mg/m2 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

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

Special groups of patients

Use in elderly patients. The number of patients aged 65 years and older was insufficient to assess the possible differences in their response to treatment with lopinavir/ritonavir compared with that of patients of younger age. When using lopinavir/ritonavir in patients of advanced age should be careful, given the increased frequency of the liver function is reduced, renal or cardiac comorbidities and concomitant therapy.

Liver failure. Lopinavir/ritonavir is primarily metabolized and excreted by the liver, so caution should be exercised when using lopinavir/ritonavir in patients with hepatic insufficiency. The use of lopinavir/ritonavir in patients with hepatic insufficiency of severe degree not studied (see section "Contraindications").

Side effects

Adults

The most common adverse reactions associated with taking lopinavir/ritonavir were diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting can occur already in the start of therapy while hypertriglyceridemia and hypercholesterolemia may develop later.

Moderately severe and serious adverse reactions is given below, with an indication of frequency: very common (≥1/10), often (≥1/100 but <1/10), infrequently (≥1/1000 but <1/100).

The immune system: often hypersensitivity reactions, including urticaria and angioedema; rarely, 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, hemorrhoids, flatulence, bloating; rare - constipation, stomatitis, ulcers of the mucous membrane of the mouth, duodenitis, gastritis, gastrointestinal bleeding (including rectal bleeding), dry mouth, peptic ulcer disease of the stomach and intestines, fecal incontinence.

The liver and biliary tract: hepatitis, including increased activity ACT, ALT, GGT, hepatomegaly, cholangitis, hepatic steatosis.

From the nervous system: often - headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness; rare - ageusia, convulsions, tremor, cerebrovascular.

Mental disorders: often anxiety; rarely, unusual dreams, decreased libido.

From the side of cardiovascular system: often - arterial hypertension; rarely, atherosclerosis, myocardial infarction, AV-blockade, tricuspid valve insufficiency, deep vein thrombosis.

The skin and subcutaneous fat: often - rash (including macula-papular), lipodystrophy (including the depletion of subcutaneous fat in the face), dermatitis, eczema, seborrhea, sweating at night, itching; rare - alopecia, capillary vasculitis.

From the musculoskeletal: often, musculoskeletal pain including arthralgia and back pain, myalgia, muscle weakness, muscle spasms; rare - rhabdomyolysis, osteonecrosis of the.

Metabolic disorders and disorders of the endocrine system: often, hypercholesterolemia, hypertriglyceridemia, reduced body mass, decreased appetite, diabetes mellitus; rarely, weight gain, lactic acidosis, increased appetite, male hypogonadism.

The kidneys and mcevaddy ways: often kidney failure; rarely, hematuria, nephritis.

From the reproductive system: often - erectile dysfunction, amenorrhea, menorrhagia.

With the hematopoietic system: often - anemia, leukopenia, neutropenia, lymphadenopathy.

From the senses: rarely, vestibular vertigo, tinnitus, blurred vision.

Infection: very often infection of the upper respiratory tract; often - infection of the lower respiratory tract, infections of skin and subcutaneous fat, including cellulite, folliculitis and furunculosis.

General reaction: often weakness, fatigue.

Changes in laboratory parameters: the increased concentrations of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, lipase, amylase, CPK, reducing the concentration of inorganic phosphorus, haemoglobin, decrease in KK.

Post-registration experience of application

Children

The side effect profile in children aged 6 months to 12 years were similar to those in adults. Often observed rash, dysgeusia, vomiting, diarrhea.

From the laboratory parameters children registered the following changes: the increase in the content of total bilirubin, total cholesterol, increase of amylase activity, increased activity ACT, ALT, neutropenia, thrombocytopenia, increase or decrease in sodium.

When using lopinavir/ritonavir were also registered some cases of hepatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome, erythema multiforme exudative, of bradiaritmii and hypersensitivity reactions (characterized by fever, rash and jaundice).

Contraindications

  • hypersensitivity to lopinavir, ritonavir or auxiliary component drug;
  • hepatic insufficiency of severe degree;
  • the simultaneous use of drugs, whose clearance is highly dependent on metabolism via the isoenzyme CYP3A. Such medicines include: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, salmeterol, sildenafil (only in case of its use for the treatment of pulmonary hypertension, see "Drug interactions"), tadalafil (only in case of its use for the treatment of pulmonary hypertension, see section "Drug interactions"), vardenafil, avanafil, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine, and methylergometrine), inhibitors of HMG-COA reductase inhibitors (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine;
  • concurrent use with drugs St. John's wort, boceprevir;
  • concurrent use of ketoconazole and Itraconazole in high doses (over 200 mg/day);
  • the simultaneous use of the drug Kaletra® in the standard dose with rifampicin;
  • the simultaneous use of the drug Kaletra® and tipranavir with low dose of ritonavir;
  • children up to age 6 months;
  • the use of the drug Kaletra® 1 times/day in combination with carbamazepine, phenobarbital or phenytoin;
  • the use of the drug Kaletra® 1 times/day in combination with drugs efavirenz, nevirapine, amprenavir or nelfinavir;
  • the use of the drug Kaletra® 1 time/day in patients with more than two mutations associated with the development of resistance to lopinavir;
  • the fructose intolerance.

With caution:

  • viral hepatitis b and C;
  • cirrhosis of the liver;
  • liver failure mild and moderate severity;
  • increased activity of liver enzymes;
  • kidney failure;
  • pancreatitis;
  • hemophilia A and b;
  • dyslipidemia (hypercholesterolemia, hypertriglyceridemia);
  • pregnancy;
  • alcoholism;
  • epilepsy;
  • traumatic brain injury;
  • diseases of the brain;
  • children up to age 18;
  • elderly patients over 65 years old.
  • patients with organic heart disease, patients with disorders of the cardiac conduction system in anamnesis or to patients receiving drugs, lengthening of the PR interval (such as verapamil or atazanavir);
  • concurrent use of drugs for the treatment of erectile dysfunction, namely sildenafilom (see "Drug interactions"), tadalafilum;
  • concurrent use of fentanyl, a rosuvastatin, bupropion, inhaled or introduced through the nose with glucocorticoids (e.g. fluticasone, budesonide), antiarrhythmic drugs (e.g., bepridil, lidocaine, quinidine), digoxin, lamotrigine, valproic acid (see "Drug interactions");
  • the simultaneous use of drugs, extension QT interval;
  • concomitant use of drugs disulfiram or metronidazole (see "Drug interactions").

Application of pregnancy and breastfeeding

Pregnancy

When pregnancy drug is used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

If necessary, use of the drug Kaletra® during lactation breastfeeding should be discontinued.

Application for violations of liver function

Lopinavir/ritonavir is primarily metabolized and excreted by the liver, so caution should be exercised when using lopinavir/ritonavir have patients with hepatic insufficiency. The use of lopinavir/ritonavir have patients with hepatic insufficiency, severe contraindicated.

Withcaution the drug should be used in viral hepatitis b and C; liver cirrhosis; liver failure mild and moderate; increase in liver enzymes.

Application for violations of renal function

Pharmacokinetics of lopinavir in patients with renal insufficiency have not been studied. But due to the fact that the renal clearance of lopinavir is negligible, should not be expected to reduce the overall clearance of the drug in renal failure.

The children

The drug is contraindicated in children under the age of 6 months.

Withcaution the drug should be used in children and adolescents under 18 years.

Use in elderly patients

When using lopinavir/ritonavir have elderly patients care should be taken, given the increased frequency of the liver function is reduced, renal or cardiac comorbidities and concomitant therapy.

Special instructions

The liver

Lopinavir/ritonavir is mainly metabolized in the liver. In this regard, care should be taken when administering the drug Kaletra® patients with impaired hepatic function mild to moderate. The use of lopinavir/ritonavir have not been studied in patients with impaired liver function severe. Pharmacokinetic data indicate that HIV-positive patients with hepatitis C and impaired liver function or moderate may increase the concentration of lopinavir in plasma is approximately 30%, and reducing its binding to blood plasma proteins. If the patient has hepatitis b or C or a significant increase in transaminases before treatment increased the risk further increases. In post-licensure studies reported cases of liver dysfunction (including fatal outcome), which are usually observed in patients with progressive HIV infection and concomitant chronic hepatitis or cirrhosis of the liver treated with excessive medication. A causal relationship of these cases with therapy lopinavir/ritonavir is not installed.

There were cases of increase in transaminases while increasing the concentration of bilirubin or not within 7 days after the first use of lopinavir/ritonavir in combination with other antiviral drugs. In some cases, disturbances of liver function was serious, but the causality of such cases therapy with lopinavir/ritonavir is not installed. 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.

Violation of kidney function

Since the renal clearance of lopinavir and ritonavir is negligible, in patients with renal impairment is not expected to increase plasma concentrations of lopinavir/ritonavir. Because lopinavir and ritonavir are actively associated with blood plasma proteins, it is unlikely that they will be displayed with hemodialysis or peritoneal dialysis.

Ethanol and propylene glycol

The oral solution of lopinavir/ritonavir containing ethanol (42.4% vol./vol.) and propylene glycol (15.3% wt/vol.). In 1 ml contains 356.3 mg ethanol and 152.7 mg of propylene glycol. Competitive ethanol inhibits the metabolism of propylene glycol in common use, which may lead to increased concentrations of propylene glycol.

Ethanol may be potentially dangerous for patients with liver disease, alcoholism, epilepsy, brain injury, brain diseases, pregnant women and children.

To avoid toxic effects of ethanol and propylene glycol in children should take into account the total amount of these substances entering the body with the use of containing medications. In children receiving lopinavir/ritonavir in oral solution, careful monitoring of such reactions, as an increase in osmolarity (with or without lactic acidosis) and creatinine concentration in plasma, kidney damage, CNS depression (including paracrine consciousness, coma, and apnea), seizures, hypotension, cardiac arrhythmias, ECG changes, and hemolysis.

In the standard dose Kaletra® (solution for the reception inside) contains 0.8 g of fructose that should be taken into consideration when prescribing the drug to patients with hereditary fructose intolerance.

Contained in the oral solution glycerol (up to 0.3 g in one dose) may, in case of drug overdose cause headache and gastrointestinal upset.

Contained in the oral solution potassium Acesulfame in case of overdose of the drug can cause gastrointestinal upset. The presence of the drug Acesulfame potassium also should be considered in patients assigned to a diet low in potassium content.

Premature infants

Safe and effective dose of Kaletra® (solution for the reception inside) in preterm infants is not defined. Taking into account the potential toxic effects of ethanol and propylene glycol, the drug Kaletra® (the oral solution) is contraindicated in preterm infants in the early postpartum period.

Premature infants are at risk for the occurrence of side reactions caused by the propylene glycol, because of the reduced ability to its metabolism leading to accumulation of propylene glycol in the body.

In post-marketing studies, primarily in preterm infants treated with the drug Kaletra® (solution for the reception inside), has been described life-threatening cases of cardiotoxicity (including complete atrioventricular blockade, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and cases of breathing difficulties fatal

Diabetes mellitus/hyperglycemia

In the post-marketing period in HIV-infected patients receiving protease inhibitors were registered cases of development and decompensation of diabetes mellitus and hyperglycemia. For the treatment of these conditions in some cases had to prescribe insulin or oral hypoglycemic drugs, or increase their dose. In some cases, developed diabetic ketoacidosis. Some patients have hyperglycemia persisted after the lifting of a protease inhibitor. Reports of such cases came voluntarily, therefore, to assess their frequency and connection to therapy with protease inhibitors is not possible.

Pancreatitis

In patients receiving lopinavir/ritonavir, including patients who have observed the severe hypertriglyceridemia, observed the development of pancreatitis. Cases with a fatal outcome. Although the relationship of this adverse reactions with the use of lopinavir/ritonavir not established, a significant increase in the concentration of triglycerides is a risk factor for development of pancreatitis. In patients with progressive HIV infection, increased risk of hypertriglyceridemia and pancreatitis, and patients with pancreatitis in the anamnesis increased risk of relapse during treatment with the drug Kaletra®.

Should consider the possibility of developing pancreatitis when the clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (e.g., increased activity of lipase or amylase of serum). Patients who develop these signs or symptoms should be examined; if there is clinical evidence should temporarily discontinue treatment with the drug Kaletra® and/or other antiretroviral drugs.

Resistance/cross-resistance

In the study of protease inhibitors observed cross-resistance various degrees of severity. In the present study the influence of lopinavir/ritonavir on the efficiency of subsequent therapy with other protease inhibitors.

Hemophilia

In patients with hemophilia type A and type b in the treatment of protease inhibitors described cases of bleeding, including spontaneous formation of subcutaneous hematomas and the development of hemarthrosis. Some patients were administered additional doses of coagulation factor VIII. More than half of the described cases, treatment with protease inhibitors was continued or resumed. Causation or mechanism of development of such adverse reactions during treatment with protease inhibitors is not established.

Elongation of PR interval

On the background of the use of lopinavir/ritonavir, some patients noted moderate asymptomatic prolongation of the PR interval. It was reported about rare cases of AV blockade II and III extent in the use of lopinavir/ritonavir in patients with organic heart disease and pre-existing disorders of the conduction system of the heart or in patients taking drugs, lengthening of the PR interval (such as verapamil or atazanavir). In such patients, the drug Kaletra® should be used with caution.

Electrocardiogram

The QT intervalcF (corrected for Fridericia) was evaluated in a randomized, placebo-controlled cross-over study with an active control (moxifloxacin 400 mg 1 times/day) with the participation of 39 healthy adult volunteers. Made 10 measurements over 12 hours on the 3rd day of the study. The maximum standard deviation of QTcF compared with placebo was 3.6 (6.3) msec and 13.1 (15.8) msec for doses of lopinavir/ritonavir 400/100 mg 2 times/day and 800/200 mg 2 times/day, respectively. Developments in the application of the above two schemes dosing, was approximately 1.5 and 3 times higher than observed while taking lopinavir/ritonavir at the recommended dose, 1 time/day or 2 times/day at steady state. None of the patients did not have increased QT intervalcF >60 MS compared to baseline value; the QT intervalcF not exceeding the potentially clinically relevant threshold of 500 msec.

In this study, on the 3rd day in patients taking lopinavir/ritonavir has been observed a mild increase in the PR interval. Maximum PR interval was 286 msec; there was no development of AV blockade II or III extent.

The redistribution of adipose tissue

On the background of antiretroviral therapy, the observed redistribution/accumulation of adipose tissue deposition in the Central parts of the body in the back, the neck, the appearance of a "Buffalo hump", decrease fat deposits on the face and limbs, breast enlargement and cushingoid. The mechanism and long-term consequences of these adverse events is unknown. Their relationship to therapy with Kaletra® is not installed.

Increasing the concentration of lipids

Treatment with lopinavir/ritonavir resulted in increased concentrations of total cholesterol and triglycerides. Before starting treatment with lopinavir/ritonavir and regularly during treatment should monitor the concentration of triglycerides and cholesterol. In the presence of lipid disorders shown appropriate therapy.

The immune reconstitution syndrome

Patients treated with combination antiretroviral therapy, including with the use of lopinavir/ritonavir have watched the development of immune reconstitution syndrome. Against the background of restoration of immune function in early combination antiretroviral therapy may exacerbate asymptomatic or residual opportunistic infections (caused by such pathogens as Mycobacterium avium, cytomegalovirus, Pneumocystis jiroveci (Pneumocystis carinii) or Mycobacterium tuberculosis), which may require additional examination and treatment.

On the background of the development of immune reconstitution syndrome were observed in the development of autoimmune diseases such as graves ' disease, polymyositis, and Guillain-Barre syndrome, however, the period of emergence of these phenomena may vary considerably and can amount to several months of therapy.

Avascular necrosis

It is known that many factors play a role in the etiology of osteonecrosis (receiving corticosteroids, alcohol, high BMI, severe immunosuppression and others). In particular, reported cases of osteonecrosis in patients with progressive HIV infection and/or long-term use of combination antiretroviral therapy. Therefore, such patients should consult a doctor when pain, stiffness in joints and impaired mobility.

Use in elderly patients

The number of patients aged 65 years and older was insufficient to assess the possible differences in their response to treatment with lopinavir/ritonavir compared with that of patients of younger age. When using lopinavir/ritonavir in elderly patients should proceed with caution, given the increased frequency reduction function of the liver, kidneys and heart, comorbidities and concomitant therapy.

The children

The safety and pharmacokinetic profile of lopinavir/ritonavir in children under 6 months not established. In HIV-infected children aged 6 months to 12 years side effect profile in the clinical study were similar to those in adults.

The use of lopinavir/ritonavir 1 times/day in children has not been studied.

Interaction

Drugs concurrent use with lopinavir/ritonavir is contraindicated: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, salmeterol, sildenafil (only in case of its use for the treatment of pulmonary hypertension, see "Drug interactions"), tadalafil (only in case of its use for the treatment of pulmonary hypertension, see "Drug interactions"), vardenafil, avanafil, voriconazole, ergot alkaloids (e.g., ergotamine and dihydroergotamine, ergometrine, and methylergometrine), inhibitors of HMG-COA reductase inhibitors (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone, quetiapine, St. John's wort preparations, boceprevir; use with ketoconazole and Itraconazole in high doses (over 200 mg/day), the use of a standard dose Kaletra® with rifampicin, the use of the drug Kaletra® and of tipranavir with ritonavir in a low dose, the drug Kaletra® 1 times/day in combination with carbamazepine, phenobarbital or phenytoin, the drug Kaletra