Diacont test strips for glucometer, 50 pcs

Calidavir, 200 mg+50 mg 60 pcs

Name: Calidavir, 200 mg+50 mg 60 pcs
SKU: 359450
Availability: OutOfStock

€1.00

Out of stock

(E-mail when Stock is available)

EAN: 4605310011232 SKU: 359450 Categories: Antiviral, Medicine

Description

Antiviral [HIV] drug

ATX:

J.05.A.R.10 Lopinavir + Ritonavir

J.05.A.R..A.R Combinations of antiviral drugs active against HIV

Pharmacodynamics:

Calidavir® 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 the drug. Inhibition of HIV proteases prevents the synthesis of viral proteins and prevents the cleavage of the gag-pol polypeptide, which leads to the formation of immature and non-infectious virus.

Ritonavir inhibits CYP3A isoenzyme-mediated metabolism of lopinavir in the liver, which leads to increased plasma concentrations of lopinavir. Ritonavir is also an HIV protease inhibitor.

Resistance

The isolation of resistant strains in vitro

The HIV-1 strain with reduced sensitivity to lopinavir has been isolated in vitro. HIV-1 was passaged in vitro separately with lopinavir and a combination of lopinavir and ritonavir at concentrations equivalent to the plasma concentrations observed during lopinavir/ritonavir treatment. Based on genotypic and phenotypic studies of the virus subtypes isolated during the passage, the presence of ritonavir at these concentration levels does not significantly affect the isolation of lopinavir-resistant virus subtypes.

In summary, an in vitro study of phenotypic cross-resistance characteristics between lopinavir and other protease inhibitors indicates that decreased sensitivity to lopinavir is closely associated with decreased sensitivity to ritonavir and indinavir, but is not associated with decreased sensitivity to amprenavir, saquinavir and nelfinavir.

Resistance studies in patients without a history of antiretroviral therapy

In clinical trials with a limited number of strains studied, no selective resistance to lopinavir was observed in patients without significant resistance to protease inhibitors at baseline.

The study of resistance in patients treated with protease inhibitors

The emergence of lopinavir resistance in patients treated unsuccessfully with basic protease inhibitor treatment has been studied in long-term studies involving 19 patients treated with protease inhibitors in two Phase

Phase II studies and one Phase III study. Patients had incomplete virus suppression or a viral recoil phenomenon resulting from the lopinavir/ritonavir response and showing increasing resistance in vitro between baseline and recoil (defined as the occurrence of new mutations or a two-fold change in phenotypic sensitivity to lopinavir).

Increasing resistance was characterized by patients with initial strains that had undergone multiple mutations during treatment with protease inhibitors, with no more than a 40-fold decrease in initial sensitivity to lopinavir. V82A, I54V, and M46I mutations occurred most frequently. L33F, I50V, and V32I mutations in combination with I47V/A were also observed. Nineteen strains showed a three/four-fold increase in the 50% inhibition concentration (IC50) compared with the original strains (from 6.2 to 43-fold, compared with wild-type viruses).

There is a genotypic correlation of reduced phenotypic sensitivity to lopinavir in viruses isolated after treatment with other protease inhibitors. In vitro antiviral activity of lopinavir was evaluated against 112 strains isolated from patients treated unsuccessfully with one or more protease inhibitors.

Within this group, the following mutations in the HIV protease were associated with decreased in vitro sensitivity to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EU50 of lopinavir against isolates with 0-3, 4-5, 6-7, and 8-10 mutations in the above amino acid positions was 0.8, 2.7, and 13.5, respectively, 44 times the EU50 of wild-type HIV. All 16 virus types that showed 20-fold higher sensitivity had mutations at positions 10, 54, 63, and 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71, and 90.

In addition to the above mutations, V32I and I47A mutations were noted in characterized relapsed strains with reduced sensitivity to lopinavir in patients treated with protease inhibitors and treated with lopinavir/ritonavir.

The I47A and L76V mutations in recurrent strains with reduced sensitivity to lopinavir have been identified in patients treated with lopinavir/ritonavir. The assessment of the importance of individual mutations or sets of mutations is subject to change as additional data become available. It is always recommended to consult the current system for evaluating the results of resistance studies.

The antiviral activity of lopinavir in patients unsuccessfully treated with protease inhibitors

. The clinical significance of reduced sensitivity to lopinavir in vitro was investigated by assessing the virologic response to lopinavir/ritonavir treatment, taking into account baseline viral genotype and phenotype, in 56 patients who failed treatment with various protease inhibitors. The EC50 value of lopinavir based on the 56 initial viral strains exceeded the EC50 value of wild-type HIV in the range of 0.6 to 98-fold.

After 48 weeks of treatment with lopinavir/ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, plasma HIV RNA levels were < 400 copies/mL in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with less than 10-fold. 10-40-fold and greater than 40-fold decreases in sensitivity to lopinavir, respectively, compared with baseline.

Also virologic response was observed in 91% (21/23), 71% (15/21), and 33% (2/6) of patients with 0-5, 6-7, and 8-10 mutations in the above mutations in the HIV protease associated with decreased sensitivity to lopinavir in vitro. Because these patients were not previously taking lopinavir/ritonavir or efavirenz, part of the effect may be attributed to the antiviral activity of efavirenz, especially for patients with a highly resistant virus type. The study does not assume a control group of patients who did not take lopinavir/ritonavir.

Cross-resistance

The efficacy of other protease inhibitors against strains that developed increasing resistance to lopinavir after treatment with lopinavir/ritonavir in patients taking protease inhibitors: The presence of cross-resistance to other protease inhibitors was analyzed in 18 relapsing strains that showed increasing resistance to lopinavir during three Phase II studies and one Phase II study of lopinavir/ritonavir in patients receiving protease inhibitors.

The median IC50 of lopinavir for these 18 strains at baseline and with virologic recoil phenomenon was higher, ranging from 6.9 to 63-fold, respectively, compared with wild-type viruses. Generally, strains with virologic recoil both retained (with cross-resistance at baseline) and developed significant resistance to indinavir, saquinavir, and atazanavir.

Moderate reductions in amprenavir activity were seen at median IC50 multiples of 3.7 to 8 for baseline and relapsed strains, respectively. Strains retained sensitivity to tipranavir with a median IC50 increase at baseline and a virologic recoil phenomenon of 1.9 to 1.8, respectively, compared to wild-type virus. For more information on tipranavir, including genotypic response rates in the treatment of lopinavir-resistant HIV-1 infection, refer to the instructions for use of tipranavir.

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 the CYP3A isoenzyme. Ritonavir inhibits the metabolism of lopinavir and causes increased plasma concentrations.

When lopinavir/ritonavir was administered at a dose of 400/100 mg twice daily, 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 given at 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.

Introduction

. In a pharmacokinetic study involving HIV-positive patients (n=19), when 400/100 mg lopinavir/ritonavir was taken twice daily with food for three weeks, the mean maximum plasma concentration (Cmax) of lopinavir 9.8 ±3.7 µg/mL was determined to be approximately four hours after drug administration.

The mean equilibrium concentration before the morning dose was 7.1 ±2.9 µg/mL and the minimum concentration within the dosing interval was 5.5 ±2.7 µg/mL. The area under the concentration-time curve (AUC) of lopinavir within 12 hours of drug administration averaged 92.6 ± 36.7 µg-h/ml. The absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established.

The effect of food on absorption when taken orally

A single dose of 400/100 mg lopinavir/ritonavir in the dosage form of a tablet after a meal (high fat, 872 kcal, 56% fat) did not result in significant changes in Cmax and AUCinf compared to an empty stomach dose. Therefore, Calidavir* in tablet dosage form can be taken with or without food.

Distribution

In equilibrium, approximately 98-99% of lopinavir is bound to plasma proteins. Lopinavir binds to alpha-1-acid glycoprotein (AKG) and to albumin, but has a higher affinity for AKG. In equilibrium, lopinavir binding to plasma proteins remains constant across the range of reported concentrations produced after administration of 400/100 mg lopinavir/ritonavir twice daily and is comparable in healthy volunteers and HIV-positive patients.

Metabolism

In in vitro studies, lopinavir has been shown to undergo predominantly oxidative metabolism involving the hepatocyte cytochrome P450 system, mainly through the CYP3A isoenzyme. Ritonavir is a potent inhibitor of CYP3A4 isoenzyme that inhibits lopinavir metabolism, which provides increased lopinavir plasma concentrations.

After a single 400/100 mg lopinavir/ritonavir administration (with 14C-labeled lopinavir), 89% radioactivity is provided by the original drug. At least 13 oxidative metabolites of lopinavir have been identified in humans. Ritonavir is capable of inducing cytochrome P450 isoenzymes, which leads to induction of its own metabolism. During long-term use, lopinavir concentrations before the next dose decreased over time, stabilizing after approximately 10-16 days.

Excretion

After 400/100 mg administration of 14C-lopinavir/ritonavir, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the 14C-lopinavir dose taken were detected in the urine and feces, respectively, after eight days. Unchanged lopinavir is 2.2% and 19.8%, respectively. After long-term use, less than 3% of lopinavir doses are excreted unchanged through the kidneys. The clearance (CL/F) of lopinavir when taken orally is 5.98 +/- 5.75 l/h.

Daily administration

The pharmacokinetics of lopinavir/ritonavir with once-daily administration have been evaluated in HIV-infected patients who have not previously received antiretroviral therapy. Lopinavir/ritonavir 800/200 mg was used in combination with emtricitabine 200 mg and tenofovir 300 mg once daily.

On long-term administration of 800/200 mg lopinavir/ritonavir once daily for 4 weeks with meals, the mean maximum plasma lopinavir concentration (Cmax) was 11.8 ± 3.7 µg/mL and was reached approximately 6 hours after administration. The mean equilibrium concentration of lopinavir before the morning dose was 3.2 ± 2.1 µg/mL, and the minimum concentration within the dosing interval was 1.7 ± 1.6 µg/mL. The AUC of lopinavir at the 24-hour dosing interval averaged 154.1 ± 61.4 µg/h/ml.

Particular patient groups

Gender, race and age

The pharmacokinetics of lopinavir have not been studied in elderly patients. No sex-dependent pharmacokinetic differences were observed in adult patients. No clinically significant race-dependent pharmacokinetic differences were found.

Children

The pharmacokinetics of lopinavir/ritonavir with 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 patients under 12 years of age. The dosing regimen of 230/57.5 mg/m2 twice daily without nevirapine and 300/75 mg/m2 twice daily with nevirapine provided plasma lopinavir concentrations similar to those obtained in adult patients taking 400/100 mg twice daily (without nevirapine). Once-daily lopinavir/ritonavir administration in children has not been studied.

The mean equilibrium AUC, Cmax, and Cmin of lopinavir after lopinavir/ritonavir 230/57.5 mg/m2 twice daily without nevirapine (n=12) were 72.6 ± 31.1 µg/h/mL; 8.2 ± 2.9 and 3.4 ± 2.1 µg/mL, respectively; and 85.8 ± 36.9 µg/h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after receiving 300/75 mg/m2 twice daily with nevirapine (n=12). The nevirapine regimen was 7 mg/kg twice daily (in patients six months to eight years) or 4 mg/kg twice daily (in patients older than eight years).

Renal Impairment

The pharmacokinetics of lopinavir have not been studied in patients with renal impairment; however, because the renal clearance of lopinavir is negligible, a decrease in total clearance in patients with renal impairment is not expected.

Hepatic impairment

Lopinavir is predominantly metabolized and excreted by the liver. Combined lopinavir/ritonavir dosing of 400/100 mg twice daily in patients co-infected with HIV and hepatitis C virus with moderate to mild hepatic impairment resulted in a 30% increase in lopinavir AUC and a 20% increase in Cmax compared to HIV-infected patients with normal liver function.

The binding of lopinavir to plasma proteins was lower in mild and moderate hepatic failure compared to control groups (99.09% versus 99.31%, respectively). Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment.

Pregnancy and Postpartum

Pharmacokinetic data show that there is a slight decrease in AUC and Cmax of lopinavir in pregnant women in the third trimester of pregnancy compared to the second trimester of pregnancy.

Indications

Active ingredient

Composition

Active ingredient:

Lopinavir 200 mg,

Ritonavir 50 mg,

Auxiliary substances:

Each film-coated tablet contains:

The core: Hyprolose (hydroxypropyl cellulose), 40.0 mg;

sodium carboxymethyl starch (primogel), 30.0 mg;

copovidone (collidon VA 64) -11.0 mg;

colloidal silicon dioxide (aerosil brand A-300) – 14.0 mg;

croscarmellose sodium – 20.0 mg;

lactose monohydrate – 140.0 mg;

Macrogol 6000 (polyethylene glycol 6000) – 5.0 mg;

Sodium stearyl fumarate – 5.0 mg;

Polysorbate 80 (tween-80) – 5.0 mg.

Film jacket:

Ready water-soluble film jacket -14.0 mg (Shell composition: Hypromellose (hydroxypropyl methylcellulose) – 74.2%, macrogol 6000 (polyethylene glycol 6000) – 14.3%, titanium dioxide – 3.5%, talc – 2.3%, iron oxide red dye – 1.4%, iron oxide yellow dye – 4.3%).

How to take, the dosage

Orally, regardless of meals. CalidavirÂ® tablets should be swallowed whole without chewing, breaking or crushing.

Adults

The recommended oral dose of KalidavirÂ® is:

Take 400/100 mg (four tablets of CalidavirÂ® 100/25 mg or two tablets of CalidavirÂ® 200/50 mg) twice daily regardless of meals.

The 800/200 mg (eight CalidavirÂ® 100/25 mg tablets or four CalidavirÂ® 200/50 mg tablets) once daily regardless of meals for patients with fewer than 3 mutations associated with the development of lopinavir resistance. There is insufficient data for once-daily lopinavir/ritonavir use in adult patients with 3 or more mutations associated with the development of lopinavir resistance.

Companion therapy

The use of KalidavirÂ® tablets in combination with omeprazole and ranitidine does not require dose adjustments.

In patients with suspected lopinavir hypersensitivity (demonstrated clinically or laboratory) who have previously received antiretroviral therapy in combination with efavirenz, nevirapine, amprenavir or nelfinavir, the dose of KalidavirÂ® tablets should be increased to 500/125 mg (5 100/25 mg tablets) twice daily. It is contraindicated to prescribe KalidavirÂ® tablets once daily if used concomitantly with these drugs.

In children

The use of KalidavirÂ® once daily in pediatric patients is contraindicated. An adult dose of KalidavirÂ® tablets (400/100 mg twice daily) without concomitant use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children who weigh 35 kg or more or have 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 of less than 35 kg or a BMD of 0.6 to 1.4 m2.

Lopinavir/ritonavir in the oral dosage form should be used for children with a PPT of less than 0.6 m2 or for children younger than 3 years of age.

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. In drugs that are actively metabolized by CYP3A isoenzyme and have high presystemic metabolism, a significant increase in AUC (more than 3-fold) is more often observed when taken simultaneously with lopinavir/ritonavir.

Lopinavir/ritonavir does not inhibit the CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 isoenzymes at clinically significant concentrations.

In vivo, lopinavir/ritonavir has been shown to induce its own metabolism and enhance the biotransformation of some other drugs that undergo glucuronidation and are metabolized with cytochrome P450 isoenzymes (including CYP2C9 and CYP2C19 isoenzymes). This may lead to decreased plasma concentrations and reduced efficacy of co-administered drugs. Drugs that are contraindicated specifically because of undesirable interactions and the possibility of 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

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 this 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 once daily is contraindicated.

Efavirenz

Increasing the lopinavir/ritonavir tablet dose to 500/125 mg (two 200/50 mg tablets + one 100/25 mg tablet) twice daily has no effect on plasma lopinavir 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 section “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.

The simultaneous use of lopinavir/ritonavir with both efavirenz and nevirapine once daily is contraindicated.

Delavirdine

Delavirdine is able to increase plasma concentrations of lopinavir.

Rilpivirine

Simultaneous use of rilpivirine with lopinavir/ritonavir may increase concentrations of rilpivirine, but no change in lopinavir/ritonavir dosage is required. Prescribing and dose selection of rilpivirine should be done according to its instructions for use.

Etravirine

The concomitant use of etravirine with lopinavir/ritonavir may increase etravirine concentrations, but no change in lopinavir/ritonavir dosage is required. The prescribing and dose selection of etravirine should be done according to its instructions for use.

HIV protease inhibitors

Amprenavir

Lopinavir/ritonavir may increase plasma concentrations of amprenavir (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.

. Co-administration of an increased dose of fosamprenavir (1400 mg twice daily) with lopinavir/ritonavir (533/133 mg twice daily) in patients who were previously taking HIV protease inhibitors resulted in an increased frequency of gastrointestinal (GI) side effects and increased blood triglyceride concentration without enhancing antiviral activity, compared with the standard fosamprenavir/ritonavir dose.

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, an increase in Cmin compared to taking indinavir three times daily in a dose of 800 mg is observed, with a similar AUC). 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 can increase concentrations of nelfinavir and the nelfinavir metabolite M8 (similar AUC, similar Cmax and increased Cmin are observed when taking nelfinavir at a dose of 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”).

The simultaneous use of lopinavir/ritonavir with nelfinavir once daily is contraindicated.

Ritonavir

The co-administration of lopinavir/ritonavir with an additional 100 mg of ritonavir twice daily increased the AUC of lopinavir by 33% and the Cmin increased by 64% compared to taking lopinavir/ritonavir at a dose of 400/100 mg twice daily.

Saquinavir

Lopinavir/ritonavir increases saquinavir concentrations (taking saquinavir 800 mg twice daily in combination with lopinavir/ritonavir leads to increased AUC, Cmax and Cmin compared to taking saquinavir 1200 mg three times daily). 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. Simultaneous use of telaprevir and lopinavir/ritonavir is not recommended.

Boceprevir

Concomitant use of lopinavir/ritonavir with boceprevir decreases the equilibrium concentrations of boceprevir and lopinavir. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.

Simeprevir

Concomitant use of simeprevir with lopinavir/ritonavir may increase concentrations of simeprevir. Simultaneous use of lopinavir/ritonavir and simeprevir is contraindicated.

Antiviral drugs – CCR5 chemokine receptor inhibitors

Maraviroc

The concomitant use of maraviroc with lopinavir/ritonavir leads to an increase in plasma concentration 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.

Integrase inhibitors

Raltegravir

The concomitant use of lopinavir/ritonavir with raltegravir did not change the AUC and Cmax of raltegravir. A 30% decrease in C12 of raltegravir was observed. Pharmacokinetic parameters of lopinavir did not change. If lopinavir/ritonavir is used concomitantly with raltegravir, no change in lopinavir/ritonavir dose is required.

Other drugs

The narcotic analgesics

Fentanyl

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

In concomitant use of lopinavir/ritonavir and fentanyl, therapeutic and side effects (including respiratory depression) should be closely monitored.

Antirhythmic agents

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

Dronedarone

Concomitant use with lopinavir/ritonavir may increase concentrations of dronedarone. Concomitant use with lopinavir/ritonavir is contraindicated.

Digoxin

In those patients who started digoxin therapy during therapy with lopinavir/ritonavir, a less significant increase in digoxin concentrations should be expected.

Drugs that prolong the QT interval

The serum concentrations of these drugs may increase when used concomitantly with lopinavir/ritonavir, which may lead to increased side effects usually associated with these antineoplastic agents.

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. Concomitant use of rivaroxaban with lopinavir/ritonavir is not recommended.

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

Antipsychotics

Quetiapine, blonserine and pimozide

It is known that these drugs can induce CYP3A4 isoenzyme and, thus, reduce lopinavir concentration. 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.

Phenobarbital, phenytoin, carbamazepine concentrations should be monitored when used 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, an increase in the dose of lamotrigine or valproic acid may be required, as well as monitoring of their plasma concentrations.

For patients who begin or discontinue KalidavirÂ® during therapy with lamotrigine, plasma lamotrigine concentrations should be monitored before starting coadministration with KalidavirÂ®, during the first 2 weeks of coadministration or within 2 weeks of withdrawal of KalidavirÂ® to determine whether the lamotrigine dose should be changed.

Sleeping drugs

Midazolam for oral administration and triazolam

As lopinavir/ritonavir inhibits the CYP3A isoenzyme, plasma concentrations of midazolam and triazolam may increase, with an increased risk of significant sedation and respiratory depression. Concomitant use of lopinavir/ritonavir and triazolam is contraindicated.

Ergot alkaloids

Dihydroergotamine, ergonovine, ergotamine, and methyl ergonovine

The increased plasma concentration of ergot derivatives leads to increased toxicity, including vasospasm and ischemia. Co-administration with lopinavir/ritonavir is contraindicated.

Drugs that regulate gastrointestinal motility

Cyzapride

Augmentation of the plasma concentration of cisapride increases the risk of severe arrhythmia. Co-administration with lopinavir/ritonavir is contraindicated.

Antihistamines

Astemizole and terfenadine

An increase in the plasma concentration of astemizole and terfenadine increases the risk of severe arrhythmia. Co-administration with lopinavir/ritonavir is contraindicated.

Beta-2-adrenomimetics

Salmeterol

Because lopinavir/ritonavir inhibits the CYP3A isoenzyme, plasma concentrations of salmeterol may increase. Concomitant use of lopinavir/ritonavir and salmeterol may increase the risk of cardiovascular side effects associated with salmeterol use, including QT interval prolongation, palpitations and sinus tachycardia.

The concomitant use of lopinavir/ritonavir and salmeterol is contraindicated.

Alpha 1-adrenoblockers

Alfuzosin

As lopinavir/ritonavir inhibits the CYP3A isoenzyme, plasma concentrations of alfuzosin may increase, increasing the risk of severe arterial hypotension. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated.

Antirhythmic agents

Amiodarone

. Because lopinavir/ritonavir inhibits the CYP3A isoenzyme, plasma concentrations of amiodarone may increase, while increasing the risk of arrhythmias and other adverse reactions associated with amiodarone use. Concomitant use of lopinavir/ritonavir and amiodarone is contraindicated.

Antifungal agents

The serum concentrations of ketoconazole and itraconazole may be increased by lopinavir/ritonavir. The use of ketoconazole and itraconazole in high doses (more than 200 mg/day) together with lopinavir/ritonavir is contraindicated.

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

Antibacterials

Lopinavir/ritonavir may cause a moderate increase in the AUC of clarithromycin. In patients with impaired liver function, the dose of clarithromycin should be reduced when used concomitantly with lopinavir/ritonavir. In patients with renal impairment (with creatinine clearance < 30 ml/min) the dose of clarithromycin should be reduced when used concomitantly with lopinavir/ritonavir. Thus, caution should be exercised when using clarithromycin and lopinavir/ritonavir concomitantly in patients with hepatic and renal impairment.

Fusidic acid

Concomitant use of lopinavir/ritonavir with fusidic acid leads to increased plasma concentrations of fusidic acid. The use of fusidic acid for the treatment of skin infections is contraindicated when lopinavir/ritonavir is taken concomitantly.

When using fusidic acid to treat bone and joint infections, where co-administration with KalidavirÂ® is unavoidable, it is recommended to control musculoskeletal and connective tissue side effects.

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, a 75% dose reduction of rifabutin (i.e., taking 150 mg every other day or three times a week) is recommended when used with lopinavir/ritonavir. Further reductions in rifabutin dosage may be necessary. Rifabutin side effects (including neutropenia and uveitis) should be closely monitored due to possible increase in the effects of rifabutin. Further dose reduction of rifabutin may be required. Reducing the rifabutin dose to 150 mg twice weekly is recommended for patients who cannot tolerate the 150 mg dose three times weekly. Note that the 150 mg twice weekly dosing regimen may not provide optimal therapeutic effects of rifabutin, which may lead to the development of resistance and treatment failure. No dose changes are required for KalidavirÂ®.

Rifampicin

The co-administration of KalidavirÂ® at the standard dose with rifampicin is contraindicated because decreased lopinavir concentrations may lead to a significant reduction in its therapeutic effect.

Bedaquiline

Delamanid

There have been no studies on the interaction of delamanid with ritonavir alone. Studies in healthy volunteers used delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days, and showed slight increases in concentrations of delamanid and the metabolite delamanid (DM-6705). If the use of delamanid and ritonavir is indeed necessary, ECG should be monitored more frequently throughout the duration of delamanid treatment due to the risk of QTc interval prolongation associated with the metabolite DM-6705. Blood transaminase activity should be monitored.

Antiparasitic agents

Therapeutic concentration of atovaquone may decrease with lopinavir/ritonavir. It may be necessary to increase the dose of atovaquone.

Glucocorticosteroids (GCS)

Dexamethasone may increase CYP3A4 isoenzyme activity and decrease lopinavir concentrations. Antiviral activity should be monitored while using dexamethasone and lopinavir/ritonavir.

Fluticasone

The concomitant use of lopinavir/ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum concentrations of cortisol. 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 coadministered with intranasal and inhaled forms of fluticasone and budesonide.

An increase in serum concentrations of these drugs may be observed when used simultaneously with lopinavir/ritonavir. It is recommended that therapeutic effects and adverse reactions be monitored when lopinavir/ritonavir is used concomitantly with the drugs in this group.

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

Tadalafil

Vardenafil

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

Avanafil

The co-administration of avanafil and lopinavir/ritonavir can significantly increase avanafil concentrations. Simultaneous use of avanafil and lopinavir/ritonavir is contraindicated.

Pharmaceuticals based on medicinal plants

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.

If a patient is already taking St. John’s wort preparations and is prescribed lopinavir/ritonavir, the St. John’s wort preparations should be stopped and the viral load level checked. Plasma concentrations of lopinavir/ritonavir may increase if drugs containing St. John’s wort are withdrawn. A change in lopinavir/ritonavir dose may be required. The inducing effect may persist for at least 2 weeks after discontinuation of treatment with St. John’s wort. Lopinavir/ritonavir is recommended 2 weeks after discontinuation of St. John’s wort.

HMG-CoA reductase inhibitors

Lopinavir/ritonavir may cause significant increases in plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 isoenzyme, such as lovastatin and simvastatin. Increased concentrations of these drugs may lead to myopathy, including rhabdomyolysis, so their combination with lopinavir/ritonavir is contraindicated.

Rosuvastatin, whose metabolism is less dependent on CYP3A4 isoenzyme, should be used with ritonavir/lopinavir with caution in minimal doses. Co-administration of atorvastatin with lopinavir/ritonavir is contraindicated. There are no signs of clinically significant interaction of lopinavir/ritonavir with pravastatin. Pravastatin and fluvastatin metabolism is independent of CYP3A4 isoenzyme, so they should not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated while lopinavir/ritonavir is in use, it is recommended to use pravastatin or fluvastatin.

Immunosuppressants

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

Vasodilator

Special Instructions

Hepatic impairment

Lopinavir/ritonavir is mainly metabolized in the liver. Therefore, caution should be exercised when prescribing KalidavirÂ® to patients with mild to moderate hepatic impairment. Lopinavir/ritonavir is contraindicated in patients with severe hepatic impairment. Pharmacokinetic data suggest that in HIV-positive patients with hepatitis C and mild to moderate liver dysfunction, lopinavir plasma concentrations may increase by about 30%, and its binding to plasma proteins may decrease. If a patient has hepatitis B or C or a significant increase in aminotransferase activity before starting treatment, there is an increased risk of further increase.

In patients with pre-existing liver disorders, including chronic hepatitis, there is an increased incidence of liver function impairment during combination antiretroviral therapy. Therefore, close monitoring should be done according to standard clinical practice. If patients deteriorate, lopinavir/ritonavir therapy should be withdrawn.

HIV-infected patients with chronic hepatitis B or C receiving combination antiretroviral therapy are at increased risk of serious and potentially fatal side effects. They were commonly seen in patients with advanced HIV infection and concomitant chronic hepatitis or cirrhosis who received excessive drug therapy. A causal relationship of such cases to 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 the causal relationship of these cases to lopinavir/ritonavir therapy has not been established.

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

Renal dysfunction

Diabetes mellitus/hyperglycemia

In post-marketing studies in HIV-infected patients receiving protease inhibitors, cases of development and decompensation of diabetes mellitus and hyperglycemia have been reported. To treat these conditions, in some cases insulin or oral hypoglycemic drugs had to be prescribed or their doses increased. In some cases, diabetic ketoacidosis has developed. In some patients, hyperglycemia persisted after withdrawal of the protease inhibitor. These cases have been reported voluntarily, so it is not possible to assess their frequency and relationship to protease inhibitor therapy. Blood glucose concentrations should be monitored when using lopinavir/ritonavir in patients with diabetes mellitus.

Pancreatitis

The development of pancreatitis has been observed in patients receiving lopinavir/ritonavir, including patients with severe hypertriglyceridemia. Fatal cases have been reported. Although the association of this side effect with lopinavir/ritonavir has not been established, a significant increase in triglyceride concentration is a risk factor for pancreatitis. Patients with advanced HIV infection are at increased risk of developing hypertriglyceridemia and pancreatitis, and patients with a history of pancreatitis are at increased risk of recurrence during treatment with lopinavir/ritonavir.

Patients who have the following symptoms: nausea, vomiting, abdominal pain, or abnormal laboratory values (e.g., increased lipase or amylase activity) should be evaluated, and treatment with KalidavirÂ® should be stopped if the diagnosis of pancreatitis is confirmed.

Resistance/cross-resistance

Cross-resistance of varying degrees 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

Electrocardiogram

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

Fat redistribution

With antiretroviral therapy, redistribution/accumulation of fat with deposition in the central parts of the body, back, neck, appearance of a “buffalo hump”, reduction of fat deposition 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 association with lopinavir/ritonavir therapy has not been established.

High risk of lipodystrophy is associated with individual characteristics such as advanced age, concomitant therapy (long-term antiretroviral therapy and associated metabolic disorders). The clinical examination should include evaluation of both physical signs of fat redistribution and laboratory parameters (fasting serum lipid and blood glucose concentration measurements). Treatment of lipid metabolism disorders should be performed in accordance with standard clinical practice.

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. In the presence of lipid disorders, appropriate therapy is indicated. Particular caution should be exercised when prescribing lopinavir/ritonavir to patients with high baseline blood lipid concentrations and a history of lipid metabolism disorders. Treatment of lipid metabolism disorders should be performed in accordance with standard clinical practice (see section “Interaction with other medicinal products. HMG-CoA reductase inhibitors”).

Synopsis

Filmed film-coated tablets are oval, biconvex, light brown to brown in color.

The core is white or white with a yellowish tint on the break.

Contraindications

– Hypersensitivity to lopinavir, ritonavir or excipients of the drug.

– Severe hepatic insufficiency.

– Simultaneous use with preparations of St. John’s wort, boceprevir, simeprevir.

– Concomitant use of the standard dose of KalidavirÂ® with rifampicin.

– Concomitant use of KalidavirÂ® and tipranavir with low-dose ritonavir.

– Children under 3 years of age (for this dosage form).

– Use KalidavirÂ® once daily in combination with carbamazepine, phenobarbital or phenytoin.

– Use KalidavirÂ® once daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

– Use KalidavirÂ® once daily in children (under 18 years of age).

– Concomitant use with ketoconazole and itraconazole in high doses (more than 200 mg/day).

– Concomitant use with dronedarone.

– Concomitant use with colchicine in patients with renal and/or hepatic impairment.

– Use of lopinavir/ritonavir once daily in pregnant women.

– Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

– Viral hepatitis B and C.

– Liver cirrhosis.

– Mild to moderate hepatic insufficiency.

– Increased activity of “liver” enzymes.

– Pancreatitis.

– Hemophilia A and B.

– Dyslipidemia (hypercholesterolemia, hypertriglyceridemia).

– Older age (over 65 years).

– Simultaneous use with drugs for the treatment of erectile dysfunction, namely sildenafil, tadalafil.

– Concomitant use with fentanyl, rosuvastatin, bupropion, inhaled or nasally administered glucocorticosteroids such as fluticasone, budesonide.

– Concomitant use with digoxin.

– Concomitant use with lamotrigine and valproic acid.

– Concomitant use with bedaquiline.

– Concurrent use with trazodone.

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, while hypertriglyceridemia and hypercholesterolemia may develop later. Moderate to serious side effects are listed below by frequency (very often >1/10; often >1/100, but <1/10; infrequent >1/1000, but <1/100).

Immune system disorders

Often: hypersensitivity reactions, including urticaria and angioedema.

Infrequent: immune reconstitution syndrome.

Digestive system disorders

Very common: diarrhea, nausea.

Often: vomiting, abdominal pain (upper and lower), gastroenteritis, colitis, dyspepsia, pancreatitis, gastroesophageal reflux, hemorrhoids, flatulence, bloating, hepatitis, hepatomegaly, cholangitis, hepatic steatosis.

Infrequent: constipation, stomatitis, oral mucous membrane ulcers, duodenitis, gastritis, gastrointestinal bleeding, including rectal bleeding, dry mouth, gastric and intestinal ulcers, fecal incontinence.

Prevalence unknown: jaundice.

Nervous system disorders

Often: headache, migraine, insomnia, neuropathy, peripheral neuropathy, dizziness, anxiety.

Infrequent: agueusia, dysgeusia, seizures, tremor, cerebrovascular disorders, sleep disturbance, decreased libido.

Cardiovascular system disorders

Often: arterial hypertension.

Infrequent: atherosclerosis, myocardial infarction, atrioventricular block, tricuspid valve failure, deep vein thrombosis.

Frequency unknown: increased PR interval.

Skin and subcutaneous fatty tissue disorders

Often: rash, including maculopapular, dermatitis, eczema, seborrhea, increased sweating at night, itching.

Infrequent: alopecia, capillaritis, vasculitis.

Infrequent unknown: lipodystrophy and redistribution of subcutaneous fat.

Musculoskeletal 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.

Prevalence unknown: insulin resistance.

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: infections of the upper respiratory tract.

Often: 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 (ACT), alanine aminotransferase (ALT), gammaglutamyltranspeptidase (GGTP), lipase, amylase, creatine phosphokinase, decreased inorganic phosphorus concentration, hemoglobin, reduced 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.

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

In individual cases of hepatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme exudative and bradyarrhythmia have also been reported with lopinavir/ritonavir.

Description of individual side effects

Cushing’s syndrome has been noted in patients receiving ritonavir and taking fluticasone propionate intranasally or inhaled. This effect may also potentially occur with other corticosteroids metabolized by cytochrome P450, such as budesonide.

Elevated creatine phosphokinase activity, myalgia, myositis, and in rare cases rhabdomyolysis have been reported with treatment with protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors.

HIV-infected patients with severe immune deficiencies may experience asymptomatic or residual opportunistic infections during initiation of combination antiretroviral therapy (cART). Autoimmune disorders (such as diffuse toxic goiter) have also been reported, but the timing of onset is more variable – the disease may begin long after treatment initiation.

Cases of osteonecrosis have been reported, particularly in patients with a history of risk factors, advanced HIV infection, or after prolonged use of antiretroviral therapy. The frequency of their occurrence is unknown. For information on redistribution of subcutaneous fat, see “Special Precautions”.

Metabolic parameters

The weight and plasma lipid and glucose concentrations may increase during antiretroviral therapy.

Overdose

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

Pregnancy use

Pregnancy

The effects of lopinavir/ritonavir have been evaluated in 3,366 women during pregnancy. Available data show that lopinavir/ritonavir does not increase the risk of common serious birth defects compared to the baseline incidence of birth defects. If necessary, lopinavir/ritonavir can be used during pregnancy.

Breastfeeding period

Rat studies have shown that lopinavir is excreted with the mother’s milk. It is not known whether the drug is excreted in human milk. Women should stop breastfeeding.

Additional information

Weight	0.200 kg
Shelf life	2 years. Do not use after the expiry date printed on the package.
Conditions of storage	In the original manufacturer's package at a temperature not exceeding 25 ° C. Store out of the reach of children.
Manufacturer	Pharmasintez JSC, Russia
Medication form	pills
Brand	Pharmasintez JSC