Kaletra, 100 mg+25 mg 60 pcs

Pharmacodynamics

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

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

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

Resistance.

The development of lopinavir/ritonavir resistance has been studied both in patients who have not previously received antiretroviral therapy and in patients who were previously treated with antiretrovirals, including protease inhibitors.

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

In phase II clinical trials of Kaletra among 227 HIV-infected patients receiving and not receiving prior antiretroviral therapy, 4 of 23 patients with virologic ineffectiveness of therapy (HIV RNA >400 copies/mL) were found to decrease sensitivity to lopinavir after 12-100 weeks of Kaletra therapy; 3 of 4 patients had previously received a single protease inhibitor (nelfinavir, saquinavir, or indinavir) and 1 of 4 patients had received multiple protease inhibitor therapy (indinavir, saquinavir, and ritonavir).

All 4 patients had at least 4 mutations associated with resistance to protease inhibitors before starting therapy with Kaletra. A further increase in viral load was associated with additional mutations associated with the development of resistance to protease inhibitors. However, these data are insufficient to identify the mutations responsible for the development of lopinavir resistance.

Cross-resistance

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

The virologic 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 was studied in vitro based on virologic response to lopinavir/ritonavir therapy depending on baseline genotype and virus phenotype in 56 patients with HIV RNA above 1000 copies/mL previously treated with nelfinavir, indinavir, saquinavir or ritonavir (study M98-957). In that study, patients were randomized to receive lopinavir/ritonavir at one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors.

Before therapy, the EC50 (the drug concentration needed to suppress replication of 50% of viruses) of lopinavir against 56 strains of the virus was 0.5-96 times the EC50 for the wild-type virus. Fifty-five percent (31/56) of the virus strains were found to have more than a 4-fold decrease in sensitivity to lopinavir, with an average decrease in sensitivity to lopinavir of 27.9 times among the 31 strains.

Forty-eight weeks after initiation of lopinavir/ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, HIV RNA concentrations ≤400 copies/mL were determined in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with initial lopinavir sensitivity decreases of ≤10 fold, 10-40 fold, and ≥40 fold, respectively. In these groups, HIV RNA concentrations were ≤50 copies/mL in 81% (22/27), 60% (9/15), and 25% (2/8) of patients, respectively.

But additional studies are 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 lopinavir/ritonavir was used at a dose of 400/100 mg twice daily, the average equilibrium plasma concentrations of lopinavir in HIV-infected patients were 15-20 times higher than those of ritonavir, and plasma concentrations of ritonavir were less than 7% of those when ritonavir was taken at a dose of 600 mg twice daily. The in vitro EC50 of lopinavir is about 10 times lower than that of ritonavir. Thus, the antiviral activity of the combination of lopinavir and ritonavir is determined by lopinavir.

Intake

In HIV-positive patients receiving lopinavir/ritonavir at a dose of 400/100 mg twice daily with meals for 3 weeks, the mean maximum plasma concentration of lopinavir (Cmax) was 9.8±3.7 µg/mL and was reached approximately 4 hours after administration. The mean residual concentration (morning before taking the next dose) at equilibrium averaged 7.1±2.9 µg/mL, and the minimum concentration was 5.5±2.7 µg/mL. The AUC of lopinavir over 12 h averaged 92.6±36.7 µg-h/ml. The absolute bioavailability of lopinavir in combination with ritonavir has not been established.

The effect of food on drug absorption

The AUC and Cmax were not significantly altered with food when lopinavir/ritonavir 400/100 mg tablets were taken alone compared to those when the drug was taken on an empty stomach. AUC was increased when taking tablets together with food with moderate fat content (500-682 kcal, 23-25% of calories due to fat) and high fat content (872 kcal, 56% of calories due to fat) by 26.9 and 18.9%, respectively, compared to fasting. Cmax is increased by 17.6% when tablets are taken with a moderately fatty food, high-fat food does not significantly change Cmax. Therefore, lopinavir/ritonavir tablets can be used regardless of meals.

Distribution

In equilibrium, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein and albumin, but it has greater affinity for alpha-1-acid glycoprotein. In equilibrium, lopinavir binding to proteins remains constant across the range of reported concentrations following lopinavir/ritonavir doses of 400/100 mg twice daily and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

Lopinavir primarily undergoes extensive oxidative metabolism involving the hepatocyte cytochrome P450 system almost exclusively by the CYP3A isoenzyme. Ritonavir is a potent inhibitor of CYP3A and interferes with lopinavir metabolism, which provides increased levels of lopinavir in blood plasma. Thirteen oxidative metabolites of lopinavir have been detected in human plasma, the 4-oxo- and 4-hydroxymetabolite isomers being the main metabolites with antiviral activity. After a single 400/100 mg dose of 14C-labeled lopinavir/ritonavir, 89% of plasma radioactivity was associated with the unchanged drug. Concentrations of lopinavir before the next dose decreased over time and stabilized after about 10-16 days.

After a single dose of 400/100 mg lopinavir/ritonavir, after 8 days, approximately 10.4±2.3% of the lopinavir dose taken is detected in the urine and 82.6±2.5% of lopinavir is detected in the feces, with unchanged lopinavir accounting for 2.2% and 19.8%, respectively. After multiple doses, less than 3% of lopinavir dose is excreted unchanged through the kidneys. Clearance of lopinavir during oral administration is 5.98±5.75 l/h.

Once-daily use

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

Particular groups

Gender, race, and age

The pharmacokinetics of lopinavir in the elderly have not been studied. In adults, the pharmacokinetics of lopinavir were independent of gender. There was also no clinically significant dependence of pharmacokinetics on race.

Renal failure

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

Hepatic impairment

Lopinavir is metabolized and excreted primarily by the liver. When lopinavir/ritonavir was repeatedly used in dose 400/100 mg 2 times daily in patients infected with HIV and hepatitis C virus with mild to moderate hepatic impairment, AUC and Cmax of lopinavir were increased by 30 and 20% respectively compared to those of HIV-infected patients with normal hepatic function. Binding of lopinavir to plasma proteins in patients with mild and moderate hepatic impairment was slightly lower than in patients in control group (99.09 and 99.31%, respectively). Pharmacokinetics of lopinavir/ritonavir have not been studied in patients with severe hepatic impairment.

Indications

HIV infection

Human acquired immunodeficiency syndrome (HIV infection) in adults and children from 3 years old as part of combination therapy.

Active ingredient

Lopinavir, Ritonavir

Composition

1 coated tablet contains:

acting ingredients:

lopinavir – 100 mg,

ritonavir – 25 mg;

excipients:

copovidone K 28;

sorbitan laurate;

silicon dioxide colloid;

second layer:

sodium stsarylfumarate;

silicon dioxide colloidal

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How to take, the dosage

Orally, regardless of meals. Kaletra tablets should be swallowed whole, without chewing, breaking or crushing.
Adult patients
The recommended oral dose of Kaletra is:

Four tablets of Kaletra 100/25 mg (400/100 mg) twice daily regardless of meals.

Eight Caletra 100/25 mg (800/200 mg) tablets once daily regardless of meals for patients who have fewer than 3 mutations associated with the development of lopinavir resistance. There is insufficient data for once-daily lopinavir/rntonavir use in adult patients with 3 or more lopinavir-resistant mutations.

Companion therapy

The use of Kaletra tablets in combination with omeprazole and rantindine does not require dose adjustments.

In patients with suspected lopinavir hypersensitivity (indicated clinically or laboratory) 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 (5 100/25 mg tablets) twice daily. When concomitant use with these drugs, Kaletra tablets should not be administered once daily.

Children
The once-daily regimen of Kaletra Tablets has not been studied in pediatric patients. 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 a body surface area (BSA) of 1.4 m2 or more. The tables below are recommended for dosage determination for children with a body weight less than 35 kg or with a PPT of 0.6 to 1.4 m2.
For children with a PPT less than 0.6 m or for children younger than 3 years old, there is an oral solution of Kaletra.

Interaction

Lopinavir/ritonavir in vitro and in vivo is an inhibitor of CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs mainly metabolized by CYP3A isoenzyme (e.g. dihydropyridine “slow” calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of these drugs, therapeutic or side effects may be enhanced or prolonged. Drugs that are actively metabolized by CYP3A isoenzyme and have high presystemic metabolism, when taken simultaneously with lopinavir/ritonavir more often have a significant increase in AUC (more than 3-fold). Drugs that are contraindicated specifically because of undesirable interactions and the potential for serious side effects are listed under “Contraindications.

Lopinavir/ritonavir is metabolized by the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs that induce CYP3A isoenzyme may decrease plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes have not been noted with ketoconazole.

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

HIV medications

Nucleoside reverse transcriptase inhibitors (NRTIs)

Stavudine and lamivudine

. No changes in lopinavir pharmacokinetics were observed with concomitant use of lopinavir/ritonavir with stavudine and lamivudine compared with lopinavir/ritonavir monotherapy.

Didanosine

Didanosine is recommended to be taken 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 may decrease plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.

Tenofovir

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

Other NRTIs

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

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine

No changes in lopinavir pharmacokinetics were observed in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. Results from a study involving HIV-positive children showed decreased concentrations of lopinavir during concomitant use with nevirapine. It is believed that the effects of nevirapine on HIV-positive adult patients may be similar to those in children, which may result in decreased lopinavir concentrations. 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 significant desensitization to lopinavir, increased doses of lopinavir/ritonavir to 500/125 mg twice daily may be required if lopinavir/ritonavir is used concomitantly with nevirapine. Lopinavir/ritonavir in combination with nevirapine should not be used once daily.

Efavirenz

. Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg (two Caletra 200/50 mg tablets + one Caletra 100/25 mg tablet) twice daily has no effect on lopinavir plasma concentrations compared to using lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Increasing the lopinavir/ritonavir tablet dose to 600/150 mg (three (3) 200/50 mg tablets) twice daily when used concomitantly with efavirenz increased plasma lopinavir concentration by approximately 36% and ritonavir concentration by approximately 56%-92% compared to the lopinavir/ritonavir 400/100 mg tablet dose (two (2) 200/50 mg tablets) when taken twice daily without efavirenz (see See “Dosage and administration”).

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

Delavirdine

Delavirdine is able to increase plasma concentrations of lopinavir.

HIV protease inhibitors

Amprenavir

Lopinavir/ritonavir may increase amprenavir concentrations (administration of amprenavir at a dose of 750 mg twice daily plus lopinavir/ritonavir leads to increased AUC, similar Cmax, increased Cmin relative to amprenavir at a dose of 1200 mg twice daily). Concomitant use of lopinavir/ritonavir and amprenavir promotes reduction of lopinavir concentrations (see section “Dosage and administration”). Simultaneous use of lopinavir/ritonavir with amprenavir once daily is contraindicated.

Fosamprenavir

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

Indinavir

Indinavir. Lopinavir/ritonavir may increase indinavir concentrations (when indinavir is combined with lopinavir/ritonavir at a dose of 600 mg twice daily, a decrease in Cmax and an increase in Cmin compared to taking indinavir three times daily at a dose of 800 mg, with similar AUCs). The dose of indinavir may need to be reduced with concomitant administration of lopinavir/ritonavir at a dose of 400/100 mg twice daily. Taking lopinavir/ritonavir in combination with indinavir once daily has not been studied.

Nelfinavir

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

Ritonavir

When lopinavir/ritonavir was coadministered with an additional 100 mg of ritonavir twice daily, lopinavir AUC increased by 33% and Cmin increased by 64% compared to taking lopinavir/ritonavir at 400/100 mg twice daily.

Saquinavir

Lopinavir/ritonavir increases saquinavir concentrations (taking saquinavir 800 mg twice daily plus lopinavir/ritonavir compared to taking saquinavir 1200 mg three times daily results in increased AUC, Cmax and Cmin). The dose of saquinavir when concomitantly used with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. Taking lopinavir/ritonavir in combination with saquinavir once daily has not been studied.

Tipranavir

Concomitant use of tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily) reduces the AUC and Cmin of lopinavir by 55% and 70% respectively. Simultaneous administration of lopinavir/ritonavir and tipranavir with low-dose ritonavir is contraindicated.

Hepatitis C virus protease inhibitors

Telaprevir

The concomitant use of lopinavir/ritonavir with telaprevir leads to a decrease in the equilibrium concentration of telaprevir without changing the equilibrium concentration of lopinavir.

Boceprevir

The concomitant use of lopinavir/ritonavir with boceprevir leads to a decrease in the equilibrium concentrations of boceprevir and lopinavir. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.

Antiviral drugs – CCR5 chemokine receptor inhibitors

Maraviroc

The concomitant use of maraviroc with lopinavir/ritonavir leads to increased concentrations of maraviroc. When concomitant use with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced. The dose of maraviroc should be adjusted according to its instructions for use.

Other drugs

The narcotic analgesics

Fentanyl

Because lopinavir/ritonavir inhibits the CYP3A4 isoenzyme, plasma fentanyl concentrations may increase.

When lopinavir/ritonavir and fentanyl are used concomitantly, therapeutic and side effects (including respiratory depression) should be monitored closely.

Antirhythmic agents (bepridil, lidocaine and quinidine)

Concomitant use with lopinavir/ritonavir may increase concentrations of these drugs. Caution is necessary when using these drugs and monitoring therapeutic concentrations if possible.

Digoxin

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

Drugs that prolong the QT interval

Pheniramine, quinidine, erythromycin, clarithromycin concentrations may increase under the influence of lopinavir/ritonavir with subsequent prolongation of the QT interval and development of cardiac adverse events. Particular caution should be used with lopinavir/ritonavir concomitantly with drugs that prolong the QT interval.

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

Their serum concentrations may increase with lopinavir/ritonavir, which may lead to side effects usually associated with these antitumor drugs.

The dose of nilotinib and dasatinib should be adjusted according to the instructions for use of these drugs.

Anticoagulants

Possible effect on warfarin concentrations when used concomitantly with lopinavir/ritonavir. Monitoring of INR (international normalized ratio) is recommended.

Rivaroxaban

The concomitant use of rivaroxaban with lopinavir/ritonavir may cause increased concentrations of rivaroxaban, which may increase the risk of bleeding.

Antidepressants

Bupropion

Simultaneous use of bupropion with lopinavir/ritonavir decreases plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be done under close clinical monitoring of bupropion efficacy without exceeding the recommended dose, despite the observed increase in metabolism.

Trazodone

The concomitant use of ritonavir and trazodone may increase trazodone concentrations. Side effects have been observed: nausea, dizziness, arterial hypotension, and fainting. Use trazodone with a CYP3A4 isoenzyme inhibitor such as lopinavir/ritonavir with caution and reducing the dose of trazodone.

Anticonvulsants (phenobarbital, phenytoin, carbamazepine)

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

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

Lamotrigine and valproic acid

Lamotrigine and valproic acid concentrations were decreased when these drugs were used concomitantly with lopinavir/ritonavir. The decrease in lamotrigine concentrations was up to 50%. These drug combinations should be used with caution. If these drugs are used concomitantly with lopinavir/ritonavir, especially during dose selection, it may be necessary to increase the dose of lamotrigine or valproic acid and monitor their plasma concentrations.

Antifungal agents

The serum concentrations of ketoconazole and itraconazole may be increased by lopinavir/ritonavir. It is not recommended to use ketoconazole and itraconazole in high doses (more than 200 mg/day) together with lopinavir/ritonavir.

Voriconazole

A study showed that concomitant use of ritonavir at a dose of 100 mg every 12 hours reduced the equilibrium AUC of voriconazole by an average of 39%; concomitant use of lopinavir/ritonavir and voriconazole is contraindicated.

Gout medications

Concomitant use of colchicine with lopinavir/ritonavir may increase colchicine concentrations. Prescribing and dose selection of colchicine should be done according to its instructions for use.

Antibacterials

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

Antituberculosis drugs

Rifabutin

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

Rifampicin

The concomitant use of rifampicin with lopinavir/ritonavir is accompanied by a dose-dependent decrease in lopinavir plasma concentrations compared to lopinavir/ritonavir at the standard dose of 400/100 mg without rifampicin. Use of rifampicin with standard dose lopinavir/ritonavir may lead to loss of virologic response and possible development of resistance to lopinavir/ritonavir or to a class of HIV protease inhibitors or other concomitant antiretrovirals.

Concomitant use of rifampicin with lopinavir/ritonavir (800/200 mg twice daily) reduced plasma concentrations of lopinavir by up to 57% compared to taking lopinavir/ritonavir at a dose of 400/100 mg twice daily without concomitant administration of rifampicin. When rifampicin was used concomitantly with lopinavir/ritonavir at a dose of 400/400 mg twice daily, the corresponding decrease in plasma concentrations of lopinavir was up to 7%.

In studies with higher doses of lopinavir/ritonavir, an increase in ALT and AST activity has been noted with concomitant use of rifampicin; this phenomenon may depend on the sequence of dosing.

If 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 starting rifampicin, with the lopinavir/ritonavir dose gradually increased. Close monitoring of liver function is necessary.

Antiparasitic agents

Therapeutic concentrations of atovaquone may be reduced when used concomitantly with lopinavir/ritonavir. Increased doses of atovaquone may be necessary.

Glucocorticosteroids (GCS)

Dexamethasone may increase CYP3A4 activity and decrease lopinavir concentrations.

Fluticasone: Concomitant use of lopinavir/ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum concentrations of cortisol. Use should be used with caution. It is recommended that alternatives to fluticasone be considered, especially with long-term use.

Systemic effects of glucocorticosteroids, including Icenko-Cushing’s syndrome and suppression of the adrenal cortex, have been reported when ritonavir is used simultaneously with intranasal and inhaled forms of fluticasone and budesonide.

The concomitant use of lopinavir/ritonavir and fluticasone and other GKS 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 inhibition of adrenal cortical function.

Particular caution should be exercised when using lopinavir/ritonavir and any of the inhaled or nasally administered glucocorticosteroids concomitantly.

Dose reduction of glucocorticosteroid should be considered with careful monitoring of local and general reactions or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (e.g., beclomethasone). Also, if glucocorticosteroid therapy is discontinued, the dose should be gradually reduced over an extended period of time.

Slow calcium channel blockers (e.g., felodipine, nifedipine, nicardipine).

Inhibitors with lopinavir/ritonavir may increase serum concentrations.

FDE-5 inhibitors

. Particular caution should be exercised when using sildenafil and tadalafil to treat erectile dysfunction in patients taking lopinavir/ritonavir, as a significant increase in their concentrations and the development of side effects such as hypotension and prolonged erections can be expected when these drugs are taken concurrently.

Sildenafil

The use of sildenafil to treat erectile dysfunction should be cautious at lower doses (25 mg every 48 hours) and side effects should be monitored more frequently.

The use of sildenafil to treat pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.

Tadalafil

Tadalafil should be used cautiously at lower doses (no more than 10 mg every 72 hours) and side effects should be monitored more frequently.

The use of tadalafil to treat pulmonary arterial hypertension while taking lopinavir/ritonavir is not recommended.

Vardenafil

The concomitant use of vardenafil with lopinavir/ritonavir is contraindicated.

Pharmaceuticals of herbal origin

Patients treated with lopinavir/ritonavir should not take preparations containing St. John’s wort at the same time, since this combination may reduce plasma concentrations of lopinavir/ritonavir. This effect may occur due to induction of CYP3A4 isoenzyme and may lead to loss of therapeutic effect and development of resistance.

HMG-CoA reductase inhibitors

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

There is no evidence of clinically significant interaction of lopinavir/ritonavir with pravastatin. Pravastatin and fluvastatin metabolism is independent of CYP3A4, so they should not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated while lopinavir/ritonavir is in use, pravastatin or fluvastatin are recommended.

The concentrations of these drugs (e.g., cyclosporine, tacrolimus, and sirolimus) may be elevated when used concomitantly with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until blood concentrations of these drugs have stabilized.

Methadone

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

Buprenorphine

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

The oral contraceptive or patch-form contraceptive

Because concentrations of ethinylestradiol may be decreased with concomitant use of lopinavir/ritonavir and estrogen-containing oral contraceptives or patch-form contraceptives, alternative or additional contraceptive measures should be used.

Vasodilators

Concomitant use of bosentan in combination with lopinavir/ritonavir resulted in a 6-fold and 5-fold increase in Cmax and AUC of bosentan, respectively. Prescribing and dose selection of bozentan should be done according to its instructions for use.

There are no expected clinically significant interactions between lopinavir/ritonavir and desipramine, raltegravir, omeprazole and ranitidine. Given the metabolism data, no clinically significant interaction of lopinavir/ritonavir with fluvastatin, dapsone, trimethoprim sulfamethoxazole, azithromycin or fluconazole in patients with normal renal and hepatic function is expected.

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Special Instructions

Hepatic impairment

Lopinavir/ritonavir is mainly metabolized in the liver. Therefore, caution should be exercised when prescribing this drug in patients with mild to moderate hepatic impairment. The use of lopinavir/ritonavir has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggest that in HIV-infected patients with HCV infection and mild to moderate hepatic impairment, lopinavir plasma concentrations may be increased by about 30%, and its binding to plasma proteins may be decreased.

In the presence of hepatitis B or C or significant increase in aminotransferase activity before the start of treatment there is an increased risk of further increase. Cases of liver dysfunction, including lethal outcome, have been reported in clinical practice. They were usually observed in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis who received excessive drug therapy. The association of these cases with lopinavir/ritonavir therapy has not been established.

There have been reported cases of increased transaminase activity 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 abnormalities have been serious, but a causal relationship of these cases to lopinavir/ritonavir therapy has not been established.

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

Diabetes mellitus/hyperglycemia

In post-marketing surveillance in HIV-infected patients receiving protease inhibitors, cases of development and decompensation of diabetes mellitus and hyperglycemia have been reported. In some cases, insulin or oral antidiabetic agents had to be prescribed or their doses increased. Sometimes diabetic ketoacidosis developed. In some patients, hyperglycemia persisted after withdrawal of the protease inhibitor. These cases were reported voluntarily, so it was not possible to assess their frequency and relationship to protease inhibitor therapy.

Pancreatitis

The development of pancreatitis has been observed in patients receiving lopinavir/ritonavir, including the occurrence of marked hypertriglyceridemia. Fatal cases have been reported. Although no association of this side effect with lopinavir/ritonavir has been established, a significant increase in triglyceride concentration is a risk factor for pancreatitis. Patients with advanced HIV infection have an increased risk of hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis have an increased risk of exacerbation during treatment with lopinavir/ritonavir.

Resistance/cross-resistance

Cross-resistance of varying severity has been observed in studies of protease inhibitors. The effect of lopinavir/ritonavir on the efficacy of subsequent therapy with other protease inhibitors is currently being studied.

Hemophilia

In patients with type A and type B hemophilia, cases of bleeding, including spontaneous formation of subcutaneous hematomas and development of hemarthrosis, have been described when treated with protease inhibitors. Additional doses of factor VIII have been administered to some patients. In more than half of the cases described, treatment with protease inhibitors could be continued or resumed. The cause and effect or mechanism of these adverse events during treatment with protease inhibitors has not been established.

Pr interval prolongation

Moderate asymptomatic PR interval prolongation has been reported in some patients while taking lopinavir/ritonavir. Rare cases of grade II and III atrioventricular block have been reported while taking lopinavir/ritonavir in patients with organic heart disease and pre-existing conduction system disorders or in patients taking drugs that prolong PR interval (such as verapamil or atazanavir). In these patients, lopinavir/ritonavir should be used with caution.

The electrocardiogram

The QTcF interval (corrected by Fridericia) was evaluated in a randomized, placebo-controlled crossover study with an active control (moxifloxacin 400 mg once daily) involving 39 healthy adult volunteers. Ten measurements were taken over 12 hours on day 3 of the study. The mean maximum difference in QTcF compared with placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for the 400/100 mg twice daily and 800/200 mg twice daily doses of lopinavir/ritonavir, respectively. The changes observed with the above two dosing regimens were approximately 1.5 and 3 times higher than those observed with the recommended once-daily or twice-daily lopinavir/ritonavir doses in equilibrium. No patients reported an increase in the QTcF >60 ms interval from baseline; the QTcF interval did not exceed a potentially clinically meaningful threshold of 500 ms.

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

The redistribution of fat

With antiretroviral therapy, redistribution/accumulation of fat with deposition in the central parts of the body, back, neck, appearance of “buffalo hump”, reduction of fat deposits in the face and extremities, increase in mammary glands and cushingoid was observed. The mechanism and long-term effects of these adverse events are not known. Their relationship to therapy has not been established.

Elevated lipid concentrations

Lopinavir/ritonavir treatment resulted in increased concentrations of total cholesterol and triglycerides. Triglyceride and cholesterol concentrations should be monitored before starting lopinavir/ritonavir treatment and regularly during therapy. If lipid abnormalities are present, appropriate therapy is indicated.

In patients who received combined antiretroviral therapy, including lopinavir/ritonavir, the development of immune reconstitution syndrome was observed. Against the background of recovery of immune function 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 evaluation and treatment.

The development of autoimmune diseases, such as Graves’ disease, polymyositis and Guillain-Barré syndrome, has been seen in the immune reconstitution syndrome, but the time course of these phenomena can vary greatly and may be several months from the start of therapy.

Osteonecrosis

Many factors are known to play a role in the etiology of osteonecrosis (GCS use, 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 seek medical attention if pain, stiffness in the joints and impaired motor function occur.

The use in the elderly

The number of patients aged 65 years and older was insufficient to evaluate whether their response to lopinavir/ritonavir treatment was different from that in younger patients. Caution should be exercised when using lopinavir/ritonavir in the elderly, given the increased incidence of reduced liver, renal or cardiac function, comorbidities and concomitant therapy.

Periatric use

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 adverse effect profile in the clinical trial was similar to that of adults.

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

Impact on driving, operating machinery

At the time of treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and rapid psychomotor reactions. In case of development of side effects that may affect the mentioned abilities, such as dizziness, it is recommended to refrain from driving motor transport and operating mechanisms. Studies of the ability to drive vehicles and operate mechanisms have not been conducted.

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Contraindications

• High sensitivity to lopinavir, ritonavir or auxiliary components of the drug Kaletra.
• Severe hepatic failure.
• Simultaneous use of drugs whose clearance is significantly dependent on metabolism by CYP3A isoenzyme. Such drugs include: astemizole, blonanserin, terfenadine, midazolam, triazolam, cisapride, pimozide, salmeterol, sildenafil (only when treating pulmonary hypertension), vardenafil, voriconazole, ergot alkaloids (e.g, ergotamine and dihydroergotamine, ergometrine and methylergometrine), HMG-CoA reductase inhibitors (lovastatin, simvastatin), fosamprenavir, alfuzosin, fusidic acid, amiodarone.
• Simultaneous use with St. John’s wort, boceprevir.
• Simultaneous use of a standard dose of Kaletra with rifampicin.
• Simultaneous use of Kaletra and tipranavir with low-dose ritonavir.
• Children under 3 years of age (children 6 months to 3 years of age should take the drug in the oral dosage form.)
• Caletra once daily in combination with carbamazepine, phenobarbital or phenytoin.
• Caletra once daily in combination with efavirenz, nevirapine, amprenavir, or nelfinavir.

Cautions

• Viral hepatitis B and C.
• Hepatic cirrhosis.
• Mild to moderate hepatic failure.
• Elevated activity of “liver” enzymes.
• Pancreatitis.
• Hemophilia A and B.
• Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).
• Elderly age (>65 years).
• Patients with organic heart disease, patients with a history of cardiac conduction disorders, or patients taking drugs that prolong PR interval (such as verapamil or atazanavir).
• Simultaneous use with erectile dysfunction drugs, namely sildenafil, tadalafil.
• Combined use with fentanyl.Concomitant use with fentanyl, rosuvastatin, atorvastatin, bupropion, inhaled or nasally administered glucocorticosteroids (e.g., fluticasone, budesonide), antiarrhythmic drugs (e.g., bepridil, lidocaine, quinidine), digoxin, rifampicin, lamotrigine, valproic acid.
• Simultaneous use with drugs that prolong the QT interval.
  

Side effects

Adults

The most common side effects associated with lopinavir/ritonavir administration were diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. Diarrhea, nausea, and vomiting may occur early in therapy, whereas hypertriglyceridemia and hypercholesterolemia may develop later.

Immune system disorders

Often: hypersensitivity reactions, including urticaria and angioedema; infrequent: immune reconstitution syndrome.

Digestive system disorders

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

Nervous system disorders

Frequently: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety; infrequently: aguevnia, seizures, tremors, cerebrovascular disorders, sleep disorders, decreased libido.

Systemic diseases

Often: arterial hypertension; infrequent: atherosclerosis, myocardial infarction, atrioventricular block, tricuspid valve failure, deep vein thrombosis.

Skin and subcutaneous fat disorders

Often: rash, including maculopapular, lipodystrophy, including facial subcutaneous fat depletion, dermatitis, eczema, seborrhea, increased night sweats, itching; infrequent: alopecia, capillaritis, vasculitis.

Musculoskeletal system disorders

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

Metabolic and endocrine disorders

Often: hypercholesterolemia, hypertriglyceridemia, weight loss, decreased appetite, diabetes; infrequent: weight gain, lactacidosis, increased appetite, male hypogonadism.

Renal and urinary tract disorders

Often: renal failure; infrequent: hematuria, nephritis.

Reproductive system disorders

Often: erectile dysfunction, amenorrhea, menorrhagia.

Blood and hematopoietic system disorders

Often: anemia, leukopenia, neutropenia, lymphadenopathy.

Sensory organs

Infrequent: vestibular dizziness, tinnitus, visual impairment.

Infections

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

General

Often: weakness, asthenia.

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

Children

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

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

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Overdose

There is currently limited clinical experience with acute lopinavir/ritonavir overdose in humans. There is no specific antidote.

The treatment consists of measures aimed at maintaining the body’s life support, including control of vital systems and monitoring the clinical condition of the patient.

If necessary, unabsorbed medications are removed by gastric lavage, for which administration of activated charcoal may be helpful. Since lopinavir/ritonavir is highly bound to plasma proteins, the use of dialysis is not appropriate.

Pregnancy use

During pregnancy, the potential benefit of taking the drug should be analyzed in relation to the possible risk to the mother and the baby.

Women should stop breastfeeding.