Kaletra pills 100mg+25mg, 60pcs

Composition

1 coated tablet contains:

active ingredients:

lopinavir-100 mg,

ritonavir-25 mg;

excipients:

copovidone K 28;

sorbitan laurate;

colloidal silicon dioxide;

second layer:

sodium oxaryl fumarate;

colloidal silicon dioxide

Pharmacological action

Pharmacodynamics

Kaletra is a combination drug that contains lopinavir and ritonavir. Lopinavir is an inhibitor of HIV-1 and HIV-2 protease of the human immunodeficiency virus (HIV) and provides antiviral activity of the drug Kaletra. Inhibition of HIV proteases prevents the synthesis of viral proteins, which leads to the formation of an immature and unable to infect the virus.

Ritonavir is an oral inhibitor of HIV-1 and HIV-2 aspartyl proteases and an active peptidomimetic. Inhibition of HIV proteases prevents the cleavage of the group-specific antigen-polymerase (gag-pol) polyprotein bond, which also leads to the formation of an immature and unable to infect virus. Ritonavir has a selective affinity for HIV protease and shows little activity against human aspartyl protease.

It inhibits the CYP3A-mediated metabolism of lopinavir in the liver, resulting in increased plasma concentrations of lopinavir.

Resistance.

The development of resistance to lopinavir/ritonavir was studied both in patients who had not previously received antiretroviral therapy, and in patients who had previously received antiretroviral drugs, including protease inhibitors.

In clinical studies of the antiviral activity of lopinavir/ritonavir in HIV-infected adults and children who have not previously received antiretroviral therapy, no mutations associated with reduced sensitivity and development of resistance to lopinavir were detected.

In phase II clinical trials of Kaletra, among 227 HIV-infected patients who received and did not receive previously antiretroviral therapy,4 out of 23 patients with virologic ineffectiveness of therapy (HIV RNA >400 copies/ml) showed a decrease in sensitivity to lopinavir after 12-100 weeks of Kaletra therapy; 3 out of 4 patients previously received one protease inhibitor (nelfinavir, saquinavir or indinavir),1 out of 4 patients — multiple therapy with protease inhibitors (indinavir, saquinavir and ritonavir).

All 4 patients had at least 4 mutations associated with resistance to protease inhibitors before starting Kaletra therapy. Further increase in the viral load was associated with the appearance of additional mutations associated with the development of resistance to protease inhibitors. However, these data are not sufficient to identify mutations responsible for the development of resistance to lopinavir.

Cross-resistance

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

The virological response to lopinavir/ritonavir therapy was altered in the presence of three or more listed amino acid substitutions in the HIV protease gene: (L10F/I/R/V, K20M/N/R, L24I, M36I, I54L/T/V, I84V, G48V, L33F,147V,82A/C/F/S/T).

The clinical significance of reduced sensitivity to lopinavir in vitro was studied based on the virological response to lopinavir/ritonavir therapy depending on the initial genotype and phenotype of the virus in 56 patients with HIV RNA above 1000 copies/ml who had previously received therapy with nelfinavir, indinavir, saquinavir or ritonavir (study M 98-957). In this randomized trial, patients were given lopinavir/ritonavir at one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors.

Prior to initiation of EC50 therapy (the drug concentration required to inhibit replication of 50% of viruses) of lopinavir for 56 virus strains was 0.5-96 times higher than EC50 for wild-type virus. 55% (31/56) of the virus strains showed a decrease in sensitivity to lopinavir by more than 4 times, while the average decrease in sensitivity to lopinavir among 31 strains was 27.9 times.

After 48 weeks after the start 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 whose initial sensitivity to lopinavir has been reduced to ≤10,10-40 times and ≥40, 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.

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

Pharmacokinetics

The pharmacokinetics of lopinavir in combination with ritonavir were studied in healthy volunteers and HIV-infected patients; no significant differences were found between the two groups. Lopinavir is almost completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir and causes an increase in its plasma levels. When using lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, the average steady-state plasma concentrations of lopinavir in HIV-infected patients were 15-20 times higher than those of ritonavir, and the plasma concentration of ritonavir was less than 7% of the concentration when taking ritonavir at a dose of 600 mg 2 times a day. The EC50 of lopinavir in vitro is approximately 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

Suction

In HIV-positive patients who received lopinavir / ritonavir 400/100 mg twice daily with meals for 3 weeks, the average maximum plasma concentration of lopinavir (Cmax) was 9.8±3.7 mcg/ml and reached approximately 4 hours after use. The average residual concentration (in the morning before the next dose) at steady state averaged 7.1±2.9 mcg/ml, and the minimum concentration was 5.5±2.7 mcg/ml. The AUC of lopinavir for 12 hours averaged 92.6±36.7 mcg * h / ml. The absolute bioavailability of lopinavir in combination with ritonavir has not been established.

Effect of food on drug absorption

With a single dose of lopinavir/ritonavir tablets at a dose of 400/100 mg with food, AUC and Cmax did not change significantly compared to those when taking the drug on an empty stomach. AUC increases when tablets are taken together with moderate-fat (500-682 kcal,23-25% caloric content due to fat) and high-fat (872 kcal,56% caloric content due to fat) foods by 26.9 and 18.9%, respectively, compared to fasting. Cmax increases by 17.6% when taking tablets with moderately fatty foods, high fat content in food does not significantly change Cmax. Therefore, lopinavir/ritonavir tablets can be used regardless of food intake.

Distribution

At steady state, lopinavir binds approximately 98-99% to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein and albumins, but it has a greater affinity for alpha-1-acid glycoprotein. At steady state, the binding of lopinavir to proteins remains constant in the range of registered concentrations created after taking lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

Lopinavir primarily undergoes intensive oxidative metabolism involving the cytochrome P450 system of hepatocytes almost exclusively under the influence of the CYP3A isoenzyme. Ritonavir is a potent CYP3A inhibitor and interferes with the metabolism of lopinavir, which increases the level of lopinavir in blood plasma. 13 oxidative metabolites of lopinavir were detected in human blood plasma; 4-oxo-and 4-hydroxymetabolite isomeric pairs are the main metabolites with antiviral activity. After a single dose of 400/100 mg of lopinavir/ritonavir labeled with 14C-lopinavir,89% of plasma radioactivity was associated with the unchanged drug. Concentrations of lopinavir before taking the next dose decrease over time and stabilize after about 10-16 days.

Deduction

After a single dose of lopinavir / ritonavir 400/100 mg after 8 days, approximately 10.4±2.3% of the lopinavir dose is detected in the urine and 82.6±2.5% of lopinavir is detected in the faeces, with unchanged lopinavir accounting for 2.2% and 19.8%, respectively. After repeated use, less than 3% of the lopinavir dose is excreted unchanged through the kidneys. The oral clearance of lopinavir is 5.98±5.75 l / h.

Once-daily use The pharmacokinetics of lopinavir/ritonavir with a once-daily dose multiplicity have been studied in HIV-infected patients who have not previously received antiretroviral therapy. Lopinavir / ritonavir 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg. All drugs were used once a day. When using lopinavir / ritonavir at a dose of 800/200 mg once a day with meals for 4 weeks, the maximum concentration of lopinavir was reached approximately 6 hours after use and averaged 11.8±3.7 mcg / ml. The residual concentration at steady state (before taking the morning dose) averaged 3.2±2.1 mcg / ml, and the minimum concentration within the dosage interval was 1.7±1.6 mcg / ml. The AUC of lopinavir during the day averaged 154.1±61.4 mcg * h / ml.

Special groups

Gender, race and age

The pharmacokinetics of lopinavir in the elderly have not been studied. In adults, the pharmacokinetics of lopinavir were gender-independent. Clinically significant race-dependent pharmacokinetics have also not been established.

Kidney failure

The pharmacokinetics of lopinavir have not been studied in patients with renal insufficiency. However, the renal clearance of lopinavir is insignificant, so there is no reason to expect a decrease in the total clearance of the drug in the presence of renal insufficiency.

Impaired liver function

Lopinavir is mainly metabolized and excreted by the liver. When repeated use of lopinavir / ritonavir at a dose of 400/100 mg 2 times a day in patients infected with HIV and hepatitis C virus, with mild or moderate hepatic impairment, an increase in the AUC and Cmax of lopinavir was noted by 30 and 20%, respectively, compared with those in HIV-infected patients with normal liver function. The plasma protein binding of lopinavir in patients with mild and moderate hepatic impairment was slightly lower than in the control group (99.09% and 99.31%, respectively). The pharmacokinetics of lopinavir/ritonavir have not been studied in patients with severe hepatic impairment.

Indications

Acquired human immunodeficiency syndrome (HIV infection) in adults and children over 3 years of age in combination therapy.

Use during pregnancy and lactation

During pregnancy, the potential benefits of taking the drug should be analyzed in relation to the possible risks to the mother and child.

Women should stop breastfeeding.

Contraindications

• Hypersensitivity to lopinavir, ritonavir or to the auxiliary components of the drug Kaletra.
• Severe liver failure.
• Concomitant use of drugs whose clearance is significantly dependent on metabolism by the CYP3A isoenzyme. These drugs include: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, salmeterol, sildenafil (only for the treatment of pulmonary hypertension), vardenafil, voriconazole, ergot alkaloids (for example, ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA inhibitors reductases (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone.
• Concomitant use with St. John’s wort, boceprevir.
• Concomitant use of a standard dose of Kaletra with rifampicin.
• Concomitant use of Kaletra and tipranavir with a low dose of ritonavir.
• Children under 3 years of age (children aged 6 months to 3 years are prescribed the drug in the dosage form “solution for oral use”).
• Use of Kaletra once daily in combination with carbamazepine, phenobarbital or phenytoin.
• Use of Kaletra once daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

With caution

• Viral hepatitis B and C.
• Cirrhosis of the liver.
• Mild to moderate hepatic insufficiency.
• Increased activity of “liver” enzymes.
• Pancreatitis.
• Hemophilia A and B.
• Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).
• Older age (over 65 years).
• Patients with organic heart diseases, patients with a history of cardiac conduction disorders, or patients taking medications that extend the PR interval (such as verapamil or atazanavir).
• Concomitant use with drugs for the treatment of erectile dysfunction, namely with sildenafil, tadalafil.
• Concomitant use with fentanyl, rosuvastatin, atorvastatin, bupropion, inhaled or nasal glucocorticosteroids (e. g. fluticasone, budesonide), antiarrhythmic drugs (e. g. bepridil, lidocaine, quinidine), digoxin, rifampicin, lamotrigine, valproic acid.
• Concomitant use with drugs that prolong the QT interval.

Side effects

Adults

The most common side effects associated with taking lopinavir/ritonavir were diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea, and vomiting may occur as early as the beginning of therapy, while hypertriglyceridemia and hypercholesterolemia may develop later.

From the immune system

Often: hypersensitivity reactions, including urticaria and angioedema; infrequently: immune recovery syndrome.

From the digestive system

Very common: diarrhea, nausea; often: vomiting, abdominal pain (upper and lower parts), gastroenteritis, colitis, dyspepsia, pancreatitis, gastroesophageal reflux, hemorrhoids, flatulence, bloating, hepatitis, hepatomegaly, cholangitis, liver steatosis; Infrequently: constipation, stomatitis, ulcers of the oral mucosa, duodenitis, gastritis, gastrointestinal tract intestinal bleeding, including rectal bleeding, dry mouth, stomach and intestinal ulcers, and fecal incontinence.

From the nervous system

Often: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety; Infrequently: ageusia, convulsions, tremor, cerebrovascular disorders, sleep disorders, decreased libido.

From the cardiovascular

system Often: arterial hypertension; infrequently: atherosclerosis, myocardial infarction, atrioventricular block, tricuspid valve insufficiency, deep vein thrombosis.

From the side of the skin and subcutaneous adipose tissue

Often: rash, including maculopapular, lipodystrophy, including depletion of subcutaneous fat in the face, dermatitis, eczema, seborrhea, increased sweating at night, pruritus; infrequently: alopecia, capillaritis, vasculitis.

From the musculoskeletal

system Often: musculoskeletal pain, including arthralgia and back pain, myalgia, muscle weakness, muscle spasms; infrequently: rhabdomyolysis, osteonecrosis.

Metabolic and endocrine disorders

Common: hypercholesterolemia, hypertriglyceridemia, weight loss, decreased appetite, diabetes mellitus; infrequently: weight gain, lactic acidosis, increased appetite, male hypogonadism.

From the side of the kidneys and urinary tract

Often: renal failure; infrequently: hematuria, nephritis.

From the reproductive system

Often: erectile dysfunction, amenorrhea, menorrhagia.

From the blood system and hematopoietic organs

Often: anemia, leukopenia, neutropenia, lymphadenopathy.

From the side of the senses

Infrequently: vestibular vertigo, tinnitus, visual impairment.

Infections

Very common: upper respiratory tract infections; common: lower respiratory tract infections, skin and subcutaneous fat infections, including cellulitis, folliculitis and furunculosis.

Common Symptoms: weakness, asthenia.

Changes in laboratory parameters: increased concentration of glucose, uric acid, total cholesterol, total bilirubin, triglycerides, increased activity of serum aspartate aminotransferase( AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGTP), lipase, amylase, creatine phosphokinase, decreased concentration of inorganic phosphorus, hemoglobin, decreased creatinine clearance.

Children

The profile of side effects in children aged 6 months to 12 years was similar to that in adults. The most common symptoms were rash, dysgeusia, vomiting, and diarrhea.

From the side of laboratory parameters, the following changes were registered in children: an increase in the content of total bilirubin, total cholesterol, an increase in amylase activity, an increase in the activity of AST, ALT, neutropenia, thrombocytopenia, an increase or decrease in sodium content. Isolated cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and bradyarrhythmia have also been reported with lopinavir/ritonavir.

Interaction

Lopinavir / ritonavir is an in vitro and in vivo inhibitor of the CYP3A isoenzyme. Concomitant use of lopinavir / ritonavir and drugs primarily metabolized by the CYP3A isoenzyme (for example, dihydropyridine slow calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase 5 (PDE-5) inhibitors) may lead to an increase in plasma concentrations of these drugs, the therapeutic or side effects of which may increase or last. In drugs that are actively metabolized by the CYP3A isoenzyme and have a high presystemic metabolism, when taken simultaneously with lopinavir/ritonavir, a significant increase in AUC (more than 3-fold) is more often observed. Drugs that are contraindicated precisely because of undesirable interactions and the possibility of developing serious side effects are listed in the section “Contraindications”.

Lopinavir / ritonavir is metabolized by the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs that induce the CYP3A isoenzyme may reduce plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes were not observed when co-administered with ketoconazole.

Concomitant use of lopinavir / ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir.

Drugs used to treat HIV

Nucleoside reverse transcriptase inhibitors (NRTIs)

Stavudine and lamivudine

There were no changes in the pharmacokinetics of lopinavir when lopinavir/ritonavir was co-administered with stavudine and lamivudine compared to lopinavir/ritonavir monotherapy.

Didanosine

It is recommended to take didanosine on an empty stomach; therefore, in combination with didanosine, lopinavir/ritonavir tablets should be taken one hour before or two hours after a meal.

Zidovudine and abacavir

Lopinavir / ritonavir induces glucuronidation, so the drug can reduce the plasma concentrations of zidovudine and abacavir.The clinical significance of this potential interaction is unknown.

Tenofovir

The study showed that lopinavir / ritonavir increases the concentration of tenofovir in blood plasma. The mechanism of this interaction is unknown. Patients taking lopinavir / ritonavir and tenofovir should be monitored for tenofovir-related side effects.

Other NRTs

Increased creatine phosphokinase (CPK) activity, myalgia, myositis and, rarely, rhabdomyolysis have been reported with HIV protease inhibitors, especially in combination with NRTIs.

Non-nucleoside reverse transcriptase inhibitors(NNRTIs)

Nevirapine

There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. The results of a study involving HIV-positive children showed a decrease in lopinavir concentrations during concomitant use with nevirapine. It is believed that the effect of nevirapine on HIV-positive adult patients may be similar to that in children, which may lead to a decrease in the concentration of lopinavir. The clinical significance of the pharmacokinetic interaction is unknown.

In patients who have previously received antiretroviral therapy or who have phenotypic or genotypic signs of a significant decrease in sensitivity to lopinavir, when lopinavir / ritonavir is co-administered with nevirapine, it may be necessary to increase the dose of lopinavir / ritonavir to 500/125 mg twice daily. Lopinavir / ritonavir in combination with nevirapine should not be used once a day.

Efavirenz

Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg (two Kaletra tablets 200/50 mg + one Kaletra tablet 100/25 mg) twice a day does not affect the concentration of lopinavir in blood plasma in comparison with the use of lopinavir/ritonavir 400/100 mg twice a day without efavirenz. Increasing the dose of lopinavir/ritonavir tablets to 600/150 mg (three (3) 200/50 mg tablets) twice daily when co-administered with efavirenz increased the plasma concentration of lopinavir by approximately 36% and the concentration of ritonavir by approximately 56%-92% compared to the dose of lopinavir/ritonavir 400/100 mg (two (2) 200/50 mg tablets) when taken twice daily without efavirenz (see section “Dosage and use”).

Efavirenz and nevirapine induce the CYP3A isoenzyme and, thus, can reduce the plasma concentrations of other viral protease inhibitors when used in combination with lopinavir/ritonavir. Concomitant use of lopinavir / ritonavir with both efavirenz and nevirapine once daily is contraindicated.

Delavirdin

Delavirdine is able to increase the concentration of lopinavir in plasma.

HIV protease inhibitors

Amprenavir

Lopinavir / ritonavir may increase the concentration of amprenavir (taking amprenavir at a dose of 750 mg twice a day plus lopinavir / ritonavir leads to an increase in AUC, similar to Cmax, an increase in Cmin relative to amprenavir at a dose of 1200 mg twice a day). Concomitant use of lopinavir / ritonavir and amprenavir reduces the concentration of lopinavir (see section “Dosage and use”). Concomitant use of lopinavir / ritonavir with amprenavir once daily is contraindicated.

Fosamprenavir

The study showed that concomitant use of lopinavir / ritonavir with fosamprenavir reduces the concentrations of fosamprenavir and lopinavir. Adequate safety and efficacy doses of fosamprenavir and lopinavir/ritonavir in combination have not been established.

Indinavir

Lopinavir/ritonavir may increase the concentration of indinavir (when combined with indinavir at a dose of 600 mg twice a day with simultaneous use of lopinavir/ritonavir, a decrease in Cmax is observed, an increase in Cmin compared to taking indinavir three times a day at a dose of 800 mg, while AUC is similar). The indinavir dose may need to be reduced when lopinavir/ritonavir is co-administered 400/100 mg twice daily. use of lopinavir / ritonavir in combination with indinavir once daily has not been studied.

Nelfinavir

Lopinavir / ritonavir may increase the concentrations of nelfinavir and the nelfinavir metabolite M8 (when taking nelfinavir 1000 mg twice daily and lopinavir/ritonavir compared to taking nelfinavir 1250 mg twice daily, similar AUC, similar Cmax, increased Cmin are observed). Concomitant use of lopinavir / ritonavir and nelfinavir leads to a decrease in lopinavir concentrations (see section “Dosage and use”). Concomitant use of lopinavir / ritonavir with nelfinavir once daily is contraindicated.

Ritonavir

When lopinavir/ritonavir was co-administered with an additional 100 mg of ritonavir twice daily, the AUC of lopinavir increased by 33% and Cmin increased by 64% compared to lopinavir/ritonavir 400/100 mg twice daily.

Saquinavir

Lopinavir / ritonavir increases saquinavir concentrations (saquinavir 800 mg twice daily plus lopinavir / ritonavir compared to saquinavir 1200 mg three times daily leads to an increase in AUC, Cmax and Cmin). The dose of saquinavir co-administered with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. use of lopinavir / ritonavir in combination with saquinavir once daily has not been studied.

Tipranavir

When tipranavir (500 mg twice daily) is co-administered with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily), the AUC and Cmin of lopinavir decrease by 55% and 70%, respectively. Concomitant use of lopinavir / ritonavir and tipranavir with a low dose of ritonavir is contraindicated.

Hepatitis C virus protease inhibitors

Telaprevir

Concomitant use of lopinavir / ritonavir with telaprevir leads to a decrease in the steady-state concentration of telaprevir without changing the steady-state concentration of lopinavir.

Boceprevir

Concomitant use of lopinavir / ritonavir with boceprevir leads to a decrease in the steady-state concentrations of boceprevir and lopinavir. Concomitant use of lopinavir / ritonavir with boceprevir is contraindicated.

Antiviral drugs — inhibitors of the CCR5 chemokine receptor

Maravirok

Simultaneous use of maraviroc with lopinavir / ritonavir leads to an increase in the concentration of maraviroc. When used concomitantly with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced. The dosage of maraviroc should be selected in accordance with its instructions for use.

Other medications

Narcotic analgesics

Fentanyl

Since lopinavir / ritonavir inhibits the CYP3A4 isoenzyme, it is possible to increase the concentration of fentanyl in blood plasma.

Therapeutic and side effects (including respiratory depression) should be carefully monitored when lopinavir/ritonavir and fentanyl are co-administered.

Antiarrhythmic drugs (bepridil, lidocaine and quinidine)

Concomitant use with lopinavir / ritonavir may increase the concentrations of these drugs. Caution should be exercised when using these drugs and monitoring therapeutic concentrations, if possible.

Digoxin

An analysis of the literature showed that concomitant use of ritonavir (300 mg every 12 hours) and digoxin resulted in a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin, while monitoring serum digoxin concentrations.

Medications that extend the QT interval

Under the influence of lopinavir / ritonavir, concentrations of phenyramine, quinidine, erythromycin, clarithromycin may increase, followed by prolongation of the QT interval and the development of cardiac side effects. Special care should be taken when using lopinavir/ritonavir concomitantly with drugs that prolong the QT interval.

Anticancer agents (e. g. dasatinib, nilotinib, vincristine, vinblastine)

It is possible to increase their serum concentrations when used simultaneously with lopinavir/ritonavir, which can lead to side effects usually associated with these antitumor drugs.

The dosage of nilotinib and dasatinib should be selected in accordance with the instructions for use of these drugs.

Anticoagulants

Possible effect on warfarin concentrations when used concomitantly with lopinavir / ritonavir. It is recommended to monitor the INR (International Normalized ratio).

Rivaroxaban

Concomitant use of rivaroxaban with lopinavir / ritonavir may increase the concentration of rivaroxaban, which may lead to an increased risk of bleeding.

Antidepressants

Bupropion

Concomitant use of bupropion with lopinavir/ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, then it should be carried out under close clinical monitoring of the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.

Trazodone

Concomitant use of ritonavir and trazodone may increase the concentration of trazodone. Side effects were observed: nausea, dizziness, hypotension and fainting. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, should be used with caution and reduce the dose of trazodone.

Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

It is known that these drugs can induce the CYP3A4 isoenzyme and, thus, reduce the concentration of lopinavir.Concomitant use of lopinavir / ritonavir once daily in combination with phenobarbital, phenytoin or carbamazepine is contraindicated.

In addition, the concomitant use of phenytoin and lopinavir / ritonavir leads to a moderate decrease in steady-state concentrations of phenytoin. Phenytoin concentrations should be monitored when the drug is administered concomitantly with lopinavir / ritonavir.

Lamotrigine and valproic acid

Concomitant use of these drugs with lopinavir/ritonavir resulted in a decrease in lamotrigine and valproic acid concentrations. The decrease in lamotrigine concentration reached 50%. These drug combinations should be used with caution. When these drugs are co-administered with lopinavir/ritonavir, especially during the dose selection period, it may be necessary to increase the dose of lamotrigine or valproic acid, as well as monitor their concentration in blood plasma.

Antifungal products

Serum concentrations of ketoconazole and itraconazole may increase under the influence of lopinavir/ritonavir. The use of ketoconazole and itraconazole in high doses (more than 200 mg / day) together with lopinavir / ritonavir is not recommended.

Voriconazole

The study showed that concomitant use of ritonavir at a dose of 100 mg every 12 hours reduces the steady-state AUC of voriconazole by an average of 39%; concomitant use of lopinavir/ritonavir and voriconazole is contraindicated.

Medications for the treatment of gout

Concomitant use of colchicine with lopinavir / ritonavir may increase the concentration of colchicine. use and dose selection of colchicine should be carried out in accordance with its instructions for use.

Antibacterial agents

Lopinavir/ritonavir may cause a moderate increase in clarithromycin AUC. In patients with impaired renal or hepatic function, the dose of clarithromycin should be reduced when used concomitantly with lopinavir / ritonavir.

Anti-tuberculosis drugs

Rifabutin

When rifabutin and lopinavir/ritonavir were co-administered for ten days, the Cmax and AUC of rifabutin (unchanged drug and active 25-O-deacetyl metabolite) increased 3.5-fold and 5.7-fold, respectively. Based on these data, it is recommended to reduce the dose of rifabutin by 75% (i. e. 150 mg every other day or three times a week) when used with lopinavir/ritonavir. Further dose reduction of rifabutin may be necessary.

Rifampicin

Concomitant use of rifampicin with lopinavir / ritonavir is accompanied by a dose-dependent decrease in the plasma concentration of lopinavir compared to the use of lopinavir/ritonavir at a standard dose of 400/100 mg without rifampicin. The use of rifampicin with a standard dose of lopinavir / ritonavir may lead to a loss of virological response and possible development of resistance to lopinavir/ritonavir or to a class of HIV protease inhibitors or other antiretroviral drugs used simultaneously.

When rifampicin is co-administered with lopinavir / ritonavir (800/200 mg twice daily) the decrease in plasma concentrations of lopinavir reached 57% compared to the use of lopinavir/ritonavir at a dose of 400/100 mg twice a day without simultaneous use of rifampicin. When rifampicin was co-administered with lopinavir / ritonavir at a dose of 400/400 mg twice daily, the corresponding decrease in the concentration of lopinavir in blood plasma reached 7%.

In studies with higher doses of lopinavir/ritonavir when used concomitantly with rifampicin, an increase in ALT and AST activity was observed, this phenomenon may depend on the sequence of dose use.

If the concomitant use of lopinavir/ritonavir and rifampicin is necessary, lopinavir/ritonavir should be started at a standard dose of 400/100 mg twice daily approximately 10 days before the start of rifampicin, and the dose of lopinavir/ritonavir should be gradually increased. Careful monitoring of liver function is necessary.

Antiparasitic agents

It is possible to reduce the therapeutic concentration of atovahone when used simultaneously with lopinavir / ritonavir. It may be necessary to increase the doses of atovahone.

Glucocorticosteroids (corticosteroids)

Dexamethasone may cause an increase in CYP3A4 activity and a decrease in lopinavir concentrations.

Fluticasone: concomitant use of lopinavir / ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and lower serum cortisol concentrations. Use with caution. It is recommended to consider alternatives to fluticasone, especially for long-term use.

Systemic effects of glucocorticosteroids, including Itsenko-Cushing syndrome and adrenal suppression, have been reported when ritonavir is co-administered with intranasal and inhaled forms of fluticasone and budesonide.

Concomitant use of lopinavir/ritonavir and fluticasone, as well as other CORTICOSTEROIDS that are metabolized by CYP3A4, such as budesonide, is not recommended, unless the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.

Special caution should be exercised when lopinavir/ritonavir is co-administered with any of the inhaled or nasal glucocorticosteroids.

Consideration should be given to reducing the dose of glucocorticosteroid with careful monitoring of local and general reactions, or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (e. g. Beclomethasone). Also, in case of discontinuation of glucocorticoid therapy, a gradual dose reduction should be carried out over a long period.

Slow calcium channel blockers (for example, felodipine, nifedipine, nicardipine).

There may be an increase in serum concentrations of these drugs when used concomitantly with lopinavir/ritonavir.

PDE5 inhibitors

Special care should be taken when using sildenafil and tadalafil for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir, since when taking these drugs simultaneously, you can expect a significant increase in their concentrations and the development of side effects such as hypotension and prolonged erection.

Sildenafil

Use of sildenafil for the treatment of erectile dysfunction should be carefully reduced in doses (25 mg every 48 hours) and more often monitor side effects.

The use of sildenafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.

Tadalafil

Tadalafil should be used cautiously in reduced doses (no more than 10 mg every 72 hours) and side effects should be monitored more often.

The use of tadalafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is not recommended.

Vardenafil

Concomitant use of vardenafil with lopinavir / ritonavir is contraindicated.

Medicinal products of plant origin

Concomitant use of drugs containing St. John’s wort is contraindicated in patients receiving treatment with lopinavir/ritonavir, as this combination may reduce the concentrations of lopinavir/ritonavir in plasma. This effect may occur due to the induction of the CYP3A4 isoenzyme and may lead to a loss of therapeutic effect and the development of resistance.

HMG-CoA reductase inhibitors

Lopinavir/ritonavir may cause a significant increase in plasma concentrations of HMG-CoA reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin. Increased concentrations of these statins can lead to the development of myopathy, including rhabdomyolysis, so their combination with lopinavir / ritonavir is contraindicated. Rosuvastatin and atorvastatin, whose metabolism is less dependent on the CYP3A4 enzyme, should be used together with ritonavir/lopinavir with caution in minimal doses. When taken in combination with lopinavir/ritonavir, an increase in Cmax and AUC of atorvastatin was observed by 4.7 and 5.9 times, respectively, which increases the risk of serious adverse reactions of myopathy and rhabdomyolysis.

No clinically significant interaction of lopinavir / ritonavir with pravastatin was detected. The metabolism of pravastatin and fluvastatin is independent of CYP3A4, so they should not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated during the use of lopinavir/ritonavir, it is recommended to use pravastatin or fluvastatin.

Immunosuppressants

Concentrations of these drugs (e. g. cyclosporine, tacrolimus, and sirolimus) may increase when used concomitantly with lopinavir / ritonavir. More frequent monitoring of therapeutic concentrations is recommended until the concentrations of these drugs in the blood are stabilized.

Methadone

Lopinavir/ritonavir has been shown to reduce plasma concentrations of methadone. Monitoring of methadone plasma concentrations is recommended.

Buprenorphine

Buprenorphine at a dose of 16 mg once a day does not require a dose change.

Oral contraceptives or contraceptives in the form of a patch

Since ethinyl estradiol concentrations may be reduced by concomitant use of lopinavir / ritonavir and estrogen-containing oral contraceptives or patch-based contraceptives, alternative or complementary contraceptive measures should be used.

Vasodilators

When bosentan was co-administered with lopinavir/ritonavir, the Cmax and AUC of bosentan increased by 6 and 5 times, respectively.Bosentan should be prescribed and selected in accordance with its instructions for use.

No clinically significant interaction is expected

No clinically significant interactions of lopinavir / ritonavir with desipramine, raltegravir, omeprazole, or ranitidine have been reported. Based on the data on metabolism, no clinically significant interaction of lopinavir/ritonavir with fluvastatin, dapsone, trimethoprim sulfamethoxazole, azithromycin or fluconazole is expected in patients with normal renal and hepatic function.

How to take, course of use and dosage

Inside, regardless of food intake. Kaletra tablets should be swallowed whole, without chewing, breaking or crushing. Adult patientsrecommended oral dose of Kaletra is:

Four tablets of Kaletra 100/25 mg (400/100 mg) twice a day, regardless of food intake.

Eight tablets of Kaletra 100/25 mg (800/200 mg) once a day, regardless of food intake, for patients with less than 3 mutations associated with the development of resistance to lopinavir. There are insufficient data for the use of lopinavir / rntonavir 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 ranntndine does not require dose adjustment.

In patients with suspected low sensitivity to lopinavir (clinically or laboratory-indicated) who have previously received antiretroviral therapy, in combination with efavirenz, nevirapine, amprenavir or nelfinavir, the dose of Kaletra tablets should be increased to 500/125 mg (5 tablets of 100/25 mg) 2 times a day. When used concomitantly with these drugs, Kaletra tablets should not be prescribed 1 time a day.

The children’s mode of taking Kaletra tablets once a day in children has not been studied. An adult dose of Kaletra tablets (400/100 mg twice daily) without concomitant use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children with a body weight of 35 kg or more or with a body surface area of 1.4 m2 or more. It is recommended to use the following tables to determine the dose for children with a body weight of less than 35 kg or with a BMI of 0.6 to 1.4 m2. For children with a PTA of less than 0.6 m or for children under 3 years of age, there is a solution of Kaletra for oral use.

Overdose

Currently, the clinical experience of acute overdose with lopinavir/ritonavir in humans is limited. There is no specific antidote.

Treatment consists of activities aimed at maintaining the body’s life support, including monitoring vital systems and monitoring the patient’s clinical condition.

If necessary, remove unabsorbed drugs by gastric lavage, for which the appointment of activated carbon may be useful. Since lopinavir/ritonavir is highly bound to plasma proteins, the use of dialysis is impractical.

Special instructions

Impaired liver function

Lopinavir/ritonavir is mainly metabolized in the liver. In this regard, caution should be exercised when prescribing this drug to patients with mild to moderate hepatic impairment. The use of lopinavir/ritonavir has not been studied in patients with severe hepatic impairment. Pharmacokinetic data indicate that in HIV-positive patients with HCV infection and mild to moderate hepatic impairment, lopinavir may increase plasma concentrations by approximately 30%, as well as reduce its binding to plasma proteins.

If you have hepatitis B or C or a significant increase in the activity of aminotransferases before starting treatment, the risk of further increase is increased. In clinical practice, cases of impaired liver function, including those with a fatal outcome, have been reported. They were usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis of the liver, who received excessive drug therapy. The association of these cases with lopinavir/ritonavir therapy has not been established.

Cases of increased transaminase activity have been reported with or without a concomitant increase in bilirubin concentrations within seven days of starting lopinavir / ritonavir in combination with other antiviral agents. In some cases, liver function disorders were severe, but a causal relationship between these cases and lopinavir/ritonavir therapy has not been established.

In such situations, it is advisable to monitor the activity of AST/ALT more often, especially in the first months after the appointment of lopinavir/ritonavir.

Diabetes mellitus/hyperglycemia

In the course of post-marketing surveillance, cases of development and decompensation of diabetes mellitus and hyperglycemia were reported in HIV-infected patients treated with protease inhibitors. In some cases, it was necessary to prescribe insulin or oral hypoglycemic agents or increase their doses. Sometimes diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after discontinuation of the protease inhibitor. These cases were reported on a voluntary basis, so it was not possible to assess their frequency and association with protease inhibitor therapy.

Pancreatitis

Patients treated with lopinavir/ritonavir were observed to develop pancreatitis, including against the background of severe hypertriglyceridemia. Fatal cases have been reported. Although the association of this side effect with lopinavir/ritonavir has not been established, however, a significant increase in triglyceride concentrations is a risk factor for pancreatitis. Patients with advanced HIV infection have an increased risk of developing hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis have an increased risk of its exacerbation during treatment with lopinavir/ritonavir.

Resistance/cross-resistance

When studying protease inhibitors, cross-resistance of varying severity was observed. The effect of lopinavir/ritonavir on the effectiveness of subsequent therapy with other protease inhibitors is currently being studied.

Hemophilia

Cases of bleeding, including spontaneous subcutaneous hematoma formation and development of hemarthrosis, have been reported in patients with type A and B hemophilia treated with protease inhibitors. Some patients were given additional doses of factor VIII. In more than half of the cases described, treatment with protease inhibitors was continued or resumed. The causal relationship or mechanism of development of such adverse events during treatment with protease inhibitors has not been established.

Lengthening the PR interval

When taking lopinavir/ritonavir, some patients showed a moderate asymptomatic prolongation of the PR interval. When taking lopinavir/ritonavir, rare cases of grade II and III atrioventricular block have been reported in patients with organic heart disease and pre-existing disorders of the cardiac conduction system or in patients taking drugs that extend the PR interval (such as verapamil or atazanavir). Lopinavir / ritonavir should be used with caution in these patients.

Electrocardiogram

The QTcF interval (adjusted for Fridericia) was evaluated in a randomized, placebo-controlled cross – sectional study with active control (moxifloxacin 400 mg once daily) in 39 healthy adult volunteers. 10 measurements were performed for 12 hours on day 3 of the study. The mean maximum difference in QTcF compared to placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for doses of 400/100 mg twice daily and 800/200 mg twice daily of lopinavir/ritonavir, respectively. The changes observed when using the above two dosage regimens were approximately 1.5 and 3 times higher than those observed when taking the recommended doses of lopinavir/ritonavir once a day or twice a day at steady state. None of the patients showed an increase in the QTcF interval >60 ms compared to the baseline value; the QTcF interval did not exceed the potentially clinically significant threshold of 500 ms. >

In the same study, a moderate increase in the PR interval was also observed in patients taking lopinavir/ritonavir on day 3. The maximum PR interval was 286 ms, and there was no development of grade II or III atrioventricular block.

Fat redistribution

On the background of antiretroviral therapy, fat redistribution/accumulation was observed with its deposition in the central parts of the body, in the back and neck, the appearance of a “buffalo hump”, a decrease in fat deposits on the face and limbs, an increase in mammary glands and kushingoid. The mechanism and long-term consequences of these adverse events are not known. Their connection with therapy has not been established.

Increased lipid concentrations

Lopinavir/ritonavir treatment resulted in increased total cholesterol and triglyceride concentrations. Before starting treatment with lopinavir/ritonavir and regularly during therapy, triglyceride and cholesterol concentrations should be monitored. In the presence of lipid disorders, appropriate therapy is indicated.

Immune recovery syndrome

Patients who received combined antiretroviral therapy, including lopinavir/ritonavir, developed a syndrome of restoring immunity. When immune function is restored at the beginning of combined antiretroviral therapy, asymptomatic or residual opportunistic infections (such as Mycobacterium avium, cytomegalovirus, Pneumocystis jiroveci (Pneumocystis carinii) or Mycobacterium tuberculosis) may worsen, which may require additional examination and treatment.

Autoimmune diseases, such as Graves ‘ disease, polymyositis, and Guillain-Barre syndrome, have been observed with the development of immune recovery syndrome, but the duration of occurrence of these phenomena can vary significantly and can be several months from the start of therapy.

Osteonecrosis

It is known that many factors play a role in the etiology of osteonecrosis (taking corticosteroids, alcohol abuse, high body mass index, severe immunosuppression, etc. ). In particular, cases of osteonecrosis have been reported in patients with advanced HIV infection and / or long-term use of combined antiretroviral therapy. Therefore, these patients should be advised to consult a doctor if they experience pain, stiffness in the joints and impaired motor function.

Use in the elderly

The number of patients aged 65 years and older was insufficient to assess the possible differences in their response to lopinavir/ritonavir treatment compared to those in younger patients. Caution should be exercised when using lopinavir/ritonavir in the elderly, given the increased incidence of decreased liver, kidney or heart function, comorbidities, and concomitant therapy.

Use in children

The safety and pharmacokinetics of lopinavir/ritonavir in children less than 6 months of age have not been established. In HIV-infected children aged 6 months to 12 years, the side effect profile in the clinical study was similar to that in adults.

The use of lopinavir/ritonavir once daily has not been studied in children.

Influence on the ability to drive motor vehicles, manage mechanisms

During the treatment period, care should be taken when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions. If you develop side effects that may affect these abilities, such as dizziness, it is recommended to refrain from driving vehicles and operating mechanisms. Studies of the ability to drive motor vehicles and manage mechanisms have not been conducted.

Form of production

Film-coated tablets

Storage conditions

At a temperature of 15 to 30 °C

Shelf life

2 years

Active ingredient

Lopinavir, Ritonavir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Indications

HIV infection