Kaletra®
Lopinavir/ritonavir inhibits the CYP3A isoenzyme in vitro and in vivo. Concomitant use of Kaletra® and drugs metabolized by CYP3A isoenzymes (including dihydropyridine calcium antagonists, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to an increase in their plasma concentrations and an increase or prolongation of therapeutic effect and side effects.
A significant increase in AUC (≥3-fold) during treatment with lopinavir/ritonavir is observed with simultaneous use of drugs that are actively metabolized by CYP3A isoenzymes and undergo first-pass metabolism. The “Contraindications” section lists drugs that cannot be combined with lopinavir/ritonavir, given the severity of the interaction and the possibility of developing serious adverse reactions.
Lopinavir/ritonavir is metabolized by CYP3A isoenzymes. Concomitant use of lopinavir/ritonavir with inducers of this isoenzyme may lead to a decrease in lopinavir plasma concentrations and its therapeutic effect, although these changes were not observed with simultaneous use of ketoconazole. Other drugs that inhibit CYP3A isoenzymes may cause an increase in plasma concentrations of lopinavir.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Stavudine and lamivudine
When lopinavir/ritonavir was used in combination with stavudine and lamivudine, no changes in the pharmacokinetics of lopinavir were observed.
Didanosine
Didanosine is recommended to be taken on an empty stomach. Therefore, in combination with didanosine, lopinavir/ritonavir tablets should be taken separately from meals.
Zidovudine and abacavir
Lopinavir/ritonavir induces glucuronidation, so a decrease in the concentration of zidovudine and abacavir is possible when used simultaneously with Kaletra®. The clinical significance of the possible interaction is unknown.
Tenofovir
Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of interaction is unknown. Patients receiving lopinavir/ritonavir concomitantly with tenofovir should be monitored for side effects of the latter.
Other NRTIs
When treated with protease inhibitors, especially in combination with NRTIs, increased CPK activity, myalgia, myositis, and rarely rhabdomyolysis were observed.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
Nevirapine
There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. Results from a study in HIV-positive children showed a decrease in lopinavir concentrations during concomitant use with nevirapine .
It is believed that the effect of nevirapine in HIV-positive adult patients may be similar to that in children, which may result in decreased lopinavir concentrations. The clinical significance of the pharmacokinetic interaction is unknown. Lopinavir/ritonavir in combination with nevirapine should not be used once a day.
Efavirenz
Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg 2 times/day does not affect the concentration of lopinavir in the blood plasma compared to the use of lopinavir/ritonavir 400/100 mg 2 times/day without efavirenz. Increasing the dose of lopinavir/ritonavir tablets to 600/150 mg (6 tablets of 100/25 mg) 2 times/day when administered concomitantly with efavirenz significantly increased plasma concentrations of lopinavir by approximately 36% and ritonavir concentrations by approximately 56% to 92% compared with a dose of lopinavir/ritonavir tablets 400/100 mg (4 tablets 100/25 mg) taken 2 times a day without efavirenz.
Efavirenz
and
nevirapine
induce CYP3A and may therefore reduce plasma concentrations of other HIV protease inhibitors when used in combination with lopinavir/ritonavir. Lopinavir/ritonavir with efavirenz should not be taken once a day.
Delavirdine
Delavirdine may cause increased plasma concentrations of lopinavir.
Protease inhibitors
Amprenavir
Lopinavir/ritonavir may cause increased concentrations of amprenavir. When treated with amprenavir at a dose of 750 mg 2 times / day in combination with lopinavir/ritonavir, an increase in AUC and Cmin is observed compared to those when using amprenavir at a dose of 1200 mg 2 times / day, while Cmax does not change significantly. Concomitant therapy with lopinavir/ritonavir and amprenavir causes a decrease in lopinavir concentrations. Lopinavir/ritonavir should not be used once a day in combination with amprenavir.
Fosamprenavir
A study showed that coadministration of lopinavir/ritonavir with fosamprenavir decreased fosamprenavir and lopinavir concentrations.
Adequate doses of fosamprenavir and lopinavir/ritonavir in combination with respect to safety and efficacy have not been established. Concomitant use of increased doses of fosamprenavir (1400 mg 2 times / day) with lopinavir/ritonavir (533/133 mg 2 times / day) in patients previously taking antiretroviral therapy led to an increased incidence of gastrointestinal side effects and increased triglyceride concentrations in the combination regimen. no increase in antiviral efficacy compared to standard doses of fosamprenavir/ritonavir .
The simultaneous use of these two drugs is not recommended.
Indinavir
Lopinavir/ritonavir may increase concentrations of indinavir (when indinavir at a dose of 600 mg 2 times a day is combined with lopinavir/ritonavir, a decrease in Cmax and an increase in Cmin are observed compared with those when using indinavir at a dose of 800 mg 3 times a day, while the AUC is not significantly changes. When using lopinavir/ritonavir at a dose of 400/100 mg 2 times/day, a dose reduction of indinavir may be required. Taking lopinavir/ritonavir in combination with indinavir 1 time/day has not been studied.
Nelfinavir
Lopinavir/ritonavir may cause increased concentrations of nelfinavir and its M8 metabolite. With simultaneous use of nelfinavir at a dose of 1000 mg 2 times / day with lopinavir/ritonavir, an increase in Cmin is observed compared to those when treated with nelfinavir at a dose of 1250 mg 2 times / day, while AUC and Cmax do not change significantly. The combination of lopinavir/ritonavir with nelfinavir leads to a decrease in lopinavir concentrations. Lopinavir/ritonavir should not be used once a day in combination with nelfinavir.
Ritonavir
With simultaneous use of lopinavir/ritonavir with ritonavir at a dose of 100 mg 2 times/day, an increase in lopinavir AUC by 33% and Cmin by 64% was observed compared with those when using only lopinavir/ritonavir at a dose of 400/100 mg 2 times/day.
Saquinavir
Lopinavir/ritonavir may cause increased concentrations of saquinavir. When saquinavir was co-administered at a dose of 800 mg 2 times a day with lopinavir/ritonavir, an increase in AUC, Cmax and Cmin was observed compared with those when saquinavir was used at a dose of 1200 mg 3 times a day. When using lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, a dose reduction of saquinavir may be required. The use of lopinavir/ritonavir in combination with saquinavir once a day has not been studied.
Tipranavir
With simultaneous use of tipranavir at a dose of 500 mg 2 times / day with ritonavir at a dose of 200 mg 2 times / day and lopinavir / ritonavir at a dose of 400/100 mg 2 times / day, AUC and Cmin decrease by 47% and 70%, respectively. Concomitant use of lopinavir/ritonavir and tipranavir with low dose ritonavir is not recommended.
Other drugs
Narcotic analgesics (fentanyl)
Since lopinavir/ritonavir inhibits the CYP3A4 isoenzyme, an increase in the concentration of fentanyl in the blood plasma is possible. If lopinavir/ritonavir and fentanyl are used concomitantly, closely monitor for therapeutic and adverse effects (including respiratory depression).
Antiarrhythmics
(amiodarone, bepridil, lidocaine (systemic) and quinidine)
Concentrations of amiodarone, bepridil, lidocaine and quinidine may be increased when administered concomitantly with lopinavir/ritonavir. Caution should be exercised when combining Kaletra® with the above-mentioned drugs and, if possible, monitor their plasma concentrations.
Digoxin
A review of the literature showed that the simultaneous use of ritonavir (300 mg every 12 hours) and digoxin led to a significant increase in the concentration of digoxin in the blood. Caution is warranted when administering lopinavir/ritonavir concomitantly with digoxin, with adequate monitoring of serum digoxin concentrations.
Antineoplastic drugs (eg, dasatinib, nilotinib, vincristine, vinblastine)
It is possible that the serum concentrations of the above drugs may increase when used concomitantly with lopinavir/ritonavir, which may lead to side effects characteristic of these anticancer drugs.
Anticoagulants
There may be an effect on warfarin concentrations when used concomitantly with lopinavir/ritonavir. It is recommended to monitor the international normalized ratio (INR).
Antidepressants
Bupropion
Concomitant use of bupropion with lopinavir/ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be done under close clinical monitoring for the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.
Trazodone
Concomitant use of ritonavir and trazodone may result in increased trazodone concentrations. Side effects observed include nausea, dizziness, hypotension and syncope. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, with caution and a reduced dose of trazodone.
Anticonvulsants (phenobarbital, phenytoin, and carbamazepine)
It is known that these drugs can induce the CYP3A4 isoenzyme and thus reduce the concentration of lopinavir. Lopinavir/ritonavir should not be used once a day in combination with phenobarbital, phenytoin or carbamazepine.
In addition, concomitant use of phenytoin and lopinavir/ritonavir leads to moderate decreases in steady-state phenytoin concentrations. Phenytoin concentrations should be monitored when the drug is used concomitantly with lopinavir/ritonavir.
Antifungal agents
Ketoconazole, itraconazole
Serum concentrations of itraconazole and ketoconazole may be increased when administered concomitantly with lopinavir/ritonavir. The use of itraconazole and ketoconazole in high doses (>200 mg/day) in combination with lopinavir/ritonavir is not recommended.
Voriconazole
The study showed that co-administration of ritonavir 100 mg every 12 hours reduced the steady-state AUC of voriconazole by an average of 39%; Therefore, concomitant use of lopinavir/ritonavir and voriconazole should be avoided.
Antibacterial drugs
There is a moderate increase in the AUC of clarithromycin when used concomitantly with lopinavir/ritonavir. The dose of clarithromycin should be reduced in patients with renal or hepatic impairment.
Anti-tuberculosis
drugs
Rifabutin
When rifabutin was coadministered with lopinavir/ritonavir for ten days, the Cmax and AUC of rifabutin (unchanged drug and active 25-O-desacetyl metabolite) increased 3.5-fold and 5.7-fold, respectively. Based on these data, a 75% dose reduction of rifabutin (i.e., 150 mg every other day or 3 times a week) is recommended when used with lopinavir/ritonavir. A further reduction in the dose of rifabutin may be necessary.
Rifampicin
Due to the significant decrease in lopinavir concentrations, rifampicin should not be taken in combination with standard dose lopinavir/ritonavir. Use of rifampicin with standard dose lopinavir/ritonavir may result in loss of virologic response and possible development of resistance to lopinavir/ritonavir or to the HIV protease inhibitor class or other concomitantly administered antiretroviral drugs.
Increases in ALT and AST levels have been observed in studies with higher doses of lopinavir/ritonavir when coadministered with rifampicin, and may be dependent on the dosing sequence. If used concomitantly, standard doses of lopinavir/ritonavir should be started for approximately 10 days before rifampicin. The dose of lopinavir/ritonavir should be increased. Careful monitoring of liver function is recommended.
Antiparasitic agents
The therapeutic concentration of atovaquone may be reduced when used concomitantly with lopinavir/ritonavir. It may be necessary to increase the dosage of atovaquone.
GKS
Dexamethasone
may cause an increase in the activity of the CYP3A isoenzyme and a decrease in the concentration of lopinavir.
Fluticasone:
Concomitant use of lopinavir/ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum cortisol concentrations. Should be used with caution.
It is recommended that alternatives to fluticasone be considered, especially for long-term use.
Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported when ritonavir is used concomitantly with inhaled or nasal fluticasone. Similar results were observed with the simultaneous use of lopinavir/ritonavir and other inhaled corticosteroids that are metabolized similarly to fluticasone, such as budesonide .
Particular caution should be exercised with the simultaneous use of lopinavir/ritonavir and any inhaled or nasal corticosteroids.
The possibility of reducing the dose of glucocorticosteroid should be considered with careful monitoring of local and general reactions or switching to GCS that is not a substrate for CYP3A4 (for example, beclomethasone). And also, in case of discontinuation of GCS therapy, a gradual dose reduction should be carried out over a long period.
Dihydropyridine blockers of “slow” calcium channels (for example, felodipine, nifedipine, nicardipine).
There may be an increase in serological concentrations of these drugs when taking lopinavir/ritonavir.
Drugs taken for erectile dysfunction (phosphodiesterase 5 (PDE5) inhibitors
Particular caution should be exercised when using sildenafil, tadalafil for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir. Concomitant use of lopinavir/ritonavir with these drugs may significantly increase their concentrations, which may lead to an increased incidence of side effects such as hypotension and prolonged erection.
Sildenafil:
use sildenafil with caution for the treatment of erectile dysfunction in reduced doses of 25 mg every 48 hours with special monitoring for side effects.
The use of sildenafil concomitantly with lopinavir/ritonavir is contraindicated in pulmonary hypertension.
Tadalafil:
use tadalafil with caution in reduced doses, no more than 10 mg every 72 hours, with careful monitoring of side effects.
Vardenafil:
simultaneous use is contraindicated.
Herbal medicines
In patients receiving treatment with lopinavir/ritonavir, concomitant use of drugs containing St. John's wort is contraindicated, as this combination may reduce plasma concentrations of lopinavir/ritonavir. This effect may occur due to induction of the CYP3A4 isoenzyme and may lead to loss of therapeutic effect and the development of resistance.
HMG-CoA reductase inhibitors
Plasma concentrations of HMG-CoA reductase inhibitors that are highly dependent on the metabolism of the CYP3A4 isoenzyme, such as lovastatin and simvastatin, may increase significantly when used simultaneously with lopinavir/ritonavir. Since increased concentrations of HMG-CoA reductase inhibitors may contribute to the occurrence of myopathy, including rhabdomyolysis, simultaneous use with lopinavir/ritonavir is not recommended. Concomitant use of lopinavir/ritonavir with lovastatin and simvastatin is contraindicated. The metabolism of atorvastatin and rosuvastatin is less dependent on the CYP3A isoenzyme. When atorvastatin was used simultaneously with lopinavir/ritonavir, an average of 4.7-fold increase in Cmax and 5.9-fold increase in atorvastatin AUC was observed, and when rosuvastatin was used simultaneously with lopinavir/ritonavir, a 2-fold increase in AUC and a 5-fold increase in Cmax was observed, therefore in combination with lopinavir /ritonavir, the lowest doses of atorvastatin and rosuvostatin should be used. The results of a drug interaction study between lopinavir/ritonavir and pravastatin did not show a clinically significant interaction. The metabolism of pravastatin and fluvastatin does not depend on the CYP3A4 isoenzyme, therefore these drugs do not interact with lopinavir/ritonavir. If treatment with an HMG-CoA reductase inhibitor is indicated, the use of pravastatin or fluvastatin is recommended.
Immunosuppressants
Concentrations of these drugs (eg, cyclosporine, tacrolimus, and sirolimus) may increase when administered concomitantly with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until blood concentrations of these drugs are stabilized.
Methadone
Lopinavir/ritonavir has been shown to reduce plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended.
Buprenorphine
Buprenophrine at a dose of 16 mg 1 time/day does not require dose changes.
Oral contraceptives or patch-type contraceptives
Because ethinyl estradiol concentrations may be decreased when lopinavir/ritonavir is coadministered with estrogen-based oral contraceptives or patch contraceptives, alternative or additional contraception should be used.
Drugs with which clinically significant interactions are not expected.
Drug interaction studies do not show clinically significant interactions with desipramine, omeprazole and ranitidine.
Based on known metabolic profiles, there are no clinically significant drug interactions between Kaletra® and fluvastatin, dapsone, trimethoprim/sulfamethoxazone, azithromycin, or fluconazole in patients with normal hepatic and renal function.
Kaletra, 80 mg+20 mg/ml, oral solution, 60 ml, 5 pcs.
Lopinavir/ritonavir in vitro
and
in vivo
is an inhibitor of the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs primarily metabolized by the CYP3A isoenzyme (for example, dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of these drugs , the therapeutic or side effects of which may be enhanced or prolonged.For drugs that are extensively metabolized by the CYP3A isoenzyme and have a high first-pass metabolism, when taken concomitantly with lopinavir/ritonavir, a significant increase in AUC (more than 3-fold) is more often observed.Drugs that are contraindicated precisely because of undesirable interactions and the possibility of developing serious side effects, are listed in the “Contraindications” section.
Lopinavir/ritonavir is metabolized by the CYP3A isoenzyme. Concomitant use of lopinavir/ritonavir and drugs that induce CYP3A may reduce plasma concentrations of lopinavir and reduce its therapeutic effect, although these changes were not observed with simultaneous use with ketoconazole.
Concomitant use of lopinavir/ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir.
HIV drugs
Nucleoside reverse transcriptase inhibitors (NRTIs)
Stavudine and lamivudine
There were no changes in the pharmacokinetics of lopinavir with simultaneous use of lopinavir/ritonavir with stavudine and lamivudine compared with lopinavir/ritonavir monotherapy.
Didanosine
It is recommended to take didanosine on an empty stomach; therefore, didanosine should be taken one hour before or two hours after taking Kaletra® solution with meals.
Zidovudine and abacavir
Lopinavir/ritonavir induces glucuronidation, so the drug may reduce plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.
Tenofovir
The study showed that lopinavir/ritonavir increases tenofovir plasma concentrations. The mechanism of this interaction is unknown. Patients taking lopinavir/ritonavir and tenofovir should be monitored for tenofovir-related side effects.
Other NRTIs
Increased creatine phosphokinase (CPK) activity, myalgia, myositis, and rarely rhabdomyolysis have been reported with HIV protease inhibitors, especially in combination with NRTIs.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
Nevirapine
There were no changes in the pharmacokinetics of lopinavir in healthy adult patients during concomitant use of nevirapine and lopinavir/ritonavir. Results from a study in HIV-positive children showed decreased concentrations of lopinavir during co-administration with nevirapine. It is believed that the effect of nevirapine in HIV-positive adult patients may be similar to that in children, which may result in decreased lopinavir concentrations. The clinical significance of the pharmacokinetic interaction is unknown. Concomitant use of lopinavir/ritonavir with nevirapine once daily is contraindicated.
In patients who have previously received antiretroviral therapy or who have phenotypic or genotypic evidence of significantly reduced sensitivity to lopinavir, the dose of lopinavir/ritonavir may need to be increased to 533/133 mg twice daily when lopinavir/ritonavir is coadministered with nevirapine.
Efavirenz
In patients previously treated with various protease inhibitors, when the dose of lopinavir/ritonavir was increased by 33.3% from 400/100 mg twice daily to 533/133 mg twice daily during therapy with efavirenz and two nucleoside reverse transcriptase inhibitors, the concentration of lopinavir in plasma was comparable to that when using lopinavir/ritonavir at a dose of 400/100 mg twice without efavirenz.
In patients who have received various protease inhibitors or have phenotypic or genotypic signs of decreased sensitivity to lopinavir, the dose of Kaletra® may need to be increased to 533/133 mg twice daily while being treated with efavirenz.
Increasing the lopinavir/ritonavir dose to 600/150 mg twice daily when coadministered with efavirenz increased lopinavir plasma concentrations by approximately 36% and ritonavir concentrations by approximately 56% to 92% compared with the 400/100 mg lopinavir/ritonavir dose when administered twice a day without efavirenz (see section "Dosage and Administration").
Efavirenz
and
nevirapine
induce CYP3A and may therefore reduce plasma concentrations of other viral protease inhibitors when used in combination with lopinavir/ritonavir. Concomitant use of lopinavir/ritonavir with either efavirenz or 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 (amprenavir 750 mg twice daily plus lopinavir/ritonavir results in an increase in AUC similar to Cmax and an increase in Cmin relative to amprenavir 1200 mg twice daily). The simultaneous use of lopinavir/ritonavir and amprenavir helps to reduce the concentration of lopinavir (see section "Dosage and Administration"). Concomitant use of lopinavir/ritonavir with amprenavir once daily is contraindicated.
Fosamprenavir
A study showed that coadministration of lopinavir/ritonavir with fosamprenavir decreased fosamprenavir and lopinavir concentrations. Adequate doses of fosamprenavir and lopinavir/ritonavir in combination with respect to safety and efficacy have not been established.
Indinavir.
Lopinavir/ritonavir may increase indinavir concentrations (when combining indinavir at a dose of 600 mg twice a day with simultaneous use of lopinavir/ritonavir, a decrease in Cmax is observed, an increase in Cmin compared with taking indinavir three times a day at a dose of 800 mg, while the AUC is similar ). The dose of indinavir may need to be reduced when co-administering lopinavir/ritonavir 400/100 mg twice daily. Lopinavir/ritonavir in combination with indinavir once daily has not been studied.
Nelfinavir
Lopinavir/ritonavir may increase concentrations of nelfinavir and nelfinavir metabolite M8 (with nelfinavir 1000 mg twice daily and lopinavir/ritonavir compared with nelfinavir 1250 mg twice daily, similar AUC, similar Cmax, increased Cmin are observed). The simultaneous use of lopinavir/ritonavir and nelfinavir leads to a decrease in lopinavir concentrations (see section "Dosage and Administration"). Concomitant 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 with lopinavir/ritonavir 400/100 mg twice daily.
Saquinavir
Lopinavir/ritonavir increases saquinavir concentrations (saquinavir 800 mg twice daily plus lopinavir/ritonavir compared with saquinavir 1200 mg three times daily results in increased AUC, Cmax, and Cmin). The dose of saquinavir when co-administered with lopinavir/ritonavir 400/100 mg twice daily may need to be reduced. Lopinavir/ritonavir in combination with saquinavir once daily has not been studied.
Tipranavir
When tipranavir (500 mg twice daily) was coadministered with ritonavir (200 mg twice daily) and lopinavir/ritonavir (400/100 mg twice daily), the AUC and Cmin of lopinavir decreased by 55% and 70%, respectively. Concomitant use of lopinavir/ritonavir and tipranavir with low dose ritonavir is contraindicated.
Hepatitis C virus protease inhibitors
Telaprevir
Concomitant use of lopinavir/ritonavir with telaprevir results in a decrease in the steady-state concentration of telaprevir without changing the steady-state concentration of lopinavir.
Boceprevir
Concomitant use of lopinavir/ritonavir with boceprevir leads to a decrease in the steady-state concentrations of boceprevir and lopinavir. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.
Antiviral drugs - CCR5 chemokine receptor inhibitors
Maraviroc
Concomitant use of maraviroc with lopinavir/ritonavir leads to increased concentrations of maraviroc. When used concomitantly with lopinavir/ritonavir at a dose of 400/100 mg twice daily, the dose of maraviroc should be reduced. The dose of maraviroc should be selected in accordance with its instructions for use.
Other drugs
Narcotic analgesics
Fentanyl
Since lopinavir/ritonavir inhibits the CYP3A4 isoenzyme, an increase in the concentration of fentanyl in the blood plasma is possible.
If lopinavir/ritonavir and fentanyl are used concomitantly, closely monitor for therapeutic and adverse effects (including respiratory depression).
Antiarrhythmic drugs
(bepridil, lidocaine and quinidine)
When used simultaneously with lopinavir/ritonavir, the concentrations of these drugs may increase. Caution is required when using these drugs and monitoring of therapeutic concentrations, if possible.
Digoxin
An analysis of the literature showed that the simultaneous use of ritonavir (300 mg every 12 hours) and digoxin led to a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin and monitoring digoxin serum concentrations.
Drugs that prolong the QT interval
Under the influence of lopinavir/ritonavir, the concentrations of pheniramine, quinidine, erythromycin, clarithromycin may increase with subsequent prolongation of the QT interval and the development of cardiac side effects. Particular caution should be exercised when coadministering lopinavir/ritonavir with drugs that prolong the QT interval.
Antineoplastic agents
(eg, dasatinib, nilotinib, vincristine, vinblastine)
Increased serum concentrations may occur when administered concomitantly with lopinavir/ritonavir, which may result in side effects commonly associated with these antineoplastic agents.
The dose of nilotinib and dasatinib should be adjusted in accordance with the instructions for use of these drugs.
Anticoagulants
There may be an effect on warfarin concentrations when used concomitantly with lopinavir/ritonavir. It is recommended to monitor the INR (international normalized ratio).
Rivaroxaban
Concomitant use of rivaroxaban with lopinavir/ritonavir may cause increased concentrations of rivaroxaban, which may lead to an increased risk of bleeding.
Antidepressants
Bupropion
Concomitant use of bupropion with lopinavir/ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be done under close clinical monitoring for the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.
Trazodone
Concomitant use of ritonavir and trazodone may result in increased trazodone concentrations. Side effects observed: nausea, dizziness, hypotension and fainting. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, with caution and a reduced dose of trazodone.
Anticonvulsants
(phenobarbital, phenytoin, carbamazepine)
These drugs are known to induce CYP3A4 and thus reduce lopinavir concentrations. Concomitant 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 steady-state phenytoin concentrations. Phenytoin concentrations should be monitored when the drug is used concomitantly with lopinavir/ritonavir.
Lamotrigine and valproic acid
When these drugs were used concomitantly with lopinavir/ritonavir, a decrease in the concentrations of lamotrigine and valproic acid was observed. The reduction in lamotrigine concentrations reached 50%. These drug combinations should be used with caution. When 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, as well as monitor their plasma concentrations.
Antifungal agents
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 not recommended.
Voriconazole
The study showed that coadministration of ritonavir 100 mg every 12 hours reduced the steady-state AUC of voriconazole by an average of 39%; simultaneous use of lopinavir/ritonavir and voriconazole is contraindicated.
Drugs for the treatment of gout
With simultaneous use of colchicine with lopinavir/ritonavir, an increase in the concentration of colchicine is possible. The prescription and dose selection of colchicine should be made in accordance with its instructions for use.
Antibacterial agents
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.
Anti-tuberculosis drugs
Rifabutin
When coadministered with rifabutin and lopinavir/ritonavir for ten days, the Cmax and AUC of rifabutin (unchanged drug and active 25-O-desacetyl metabolite) increased by 3.5-fold and 5.7-fold, respectively. Based on these data, a 75% dose reduction of rifabutin (i.e., 150 mg every other day or three times a week) is recommended when used with lopinavir/ritonavir. A further reduction in the dose of rifabutin may be necessary.
Rifampicin
Concomitant use of rifampicin with lopinavir/ritonavir is accompanied by a dose-dependent decrease in plasma concentrations of lopinavir compared to the use of lopinavir/ritonavir at a standard dose of 400/100 mg without rifampicin.
Use of rifampicin with standard dose lopinavir/ritonavir may result in loss of virologic response and possible development of resistance to lopinavir/ritonavir or to the HIV protease inhibitor class or other concomitantly administered antiretroviral drugs.
When rifampicin was coadministered with lopinavir/ritonavir (800/200 mg twice daily), the reduction in lopinavir plasma concentrations reached 57% compared with lopinavir/ritonavir 400/100 mg twice daily without concomitant rifampicin. When rifampicin was co-administered with lopinavir/ritonavir at a dose of 400/400 mg twice daily, the corresponding decrease in plasma lopinavir concentrations reached 7%.
In studies with higher doses of lopinavir/ritonavir, increased ALT and AST levels were observed when co-administered with rifampicin, which may depend on the dosing sequence.
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, and the dose of lopinavir/ritonavir should be gradually increased. Careful monitoring of liver function is necessary.
Antiparasitic agents
The therapeutic concentration of atovaquone may be reduced when used concomitantly with lopinavir/ritonavir. It may be necessary to increase the dosage of atovaquone.
Glucocorticosteroids (GCS)
Dexamethasone may cause an increase in CYP3A4 activity and a decrease in lopinavir concentrations.
Fluticasone:
Concomitant use of lopinavir/ritonavir and fluticasone may significantly increase plasma concentrations of fluticasone and decrease serum cortisol concentrations. Should be used with caution. It is recommended that alternatives to fluticasone be considered, especially for long-term use.
Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported during concomitant use of ritonavir with intranasal and inhaled forms of fluticasone and budesonide.
Concomitant use of lopinavir/ritonavir and fluticasone, as well as other corticosteroids that are metabolized by CYP3A4, such as budesonide, is not recommended unless the potential benefit of such therapy outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Particular caution should be exercised when lopinavir/ritonavir and any inhaled or nasal corticosteroids are used concomitantly.
Consideration should be given to reducing the dose of the glucocorticosteroid with careful monitoring of local and general reactions or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (eg, beclomethasone). And also, in case of discontinuation of glucocorticosteroid therapy, a gradual dose reduction should be carried out over a long period.
Disulfiram/metronidazole
Lopinavir/ritonavir oral solution contains ethanol, which may cause an antabuse reaction when disulfiram is used concomitantly with other drugs that cause this reaction, such as metronidazole.
Blockers of “slow” calcium channels
(for example, felodipine, nifedipine, nicardipine).
Increased serum concentrations of these drugs may be observed when used concomitantly with lopinavir/ritonavir.
PDE-5 inhibitors
Particular caution should be exercised when using sildenafil and tadalafil for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir, since a significant increase in their concentrations and the development of side effects such as arterial hypotension and prolonged erection can be expected when taking these drugs simultaneously.
Sildenafil
Sildenafil should be used cautiously for the treatment of erectile dysfunction at reduced doses (25 mg every 48 hours) and frequently monitored for side effects.
The use of sildenafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is contraindicated.
Tadalafil
Tadalafil should be used cautiously, in reduced doses (no more than 10 mg every 72 hours) and monitor side effects more often.
The use of tadalafil for the treatment of pulmonary arterial hypertension while taking lopinavir/ritonavir is not recommended.
Vardenafil
Concomitant use of vardenafil with lopinavir/ritonavir is contraindicated.
Herbal medicines
In patients receiving treatment with lopinavir/ritonavir, concomitant use of drugs containing St. John's wort is contraindicated, as this combination may reduce plasma concentrations of lopinavir/ritonavir. This effect may occur due to induction of the CYP3A4 isoenzyme and may lead to loss of therapeutic effect and the development of resistance.
HMG-CoA reductase inhibitors
Lopinavir/ritonavir may cause a significant increase in plasma concentrations of HMG-CoA reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin. Increasing concentrations of these statins can lead to the development of myopathy, including rhabdomyolysis, so their combination with lopinavir/ritonavir is contraindicated. Rosuvastatin and atorvastatin, whose metabolism is less dependent on the CYP3A4 enzyme, should be used with caution in minimal doses together with ritonavir/lopinavir. When taken in combination with lopinavir/ritonavir, an increase in the Cmax and AUC of atorvastatin was observed by 4.7 and 5.9 times, respectively, which increases the risk of serious adverse reactions of myopathy and rhabdomyolysis.
There were no signs of clinically significant interaction between lopinavir/ritonavir and pravastatin. The metabolism of pravastatin and fluvastatin is independent of CYP3A4 and should therefore not interact with lopinavir/ritonavir. If treatment with HMG-CoA reductase inhibitors is indicated during the use of lopinavir/ritonavir, it is recommended to use pravastatin or fluvastatin.
Immunosuppressants
Concentrations of these drugs (eg, cyclosporine, tacrolimus, and sirolimus) may increase when administered concomitantly with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until blood concentrations of these drugs are stabilized.
Methadone
Lopinavir/ritonavir has been shown to reduce plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended.
Buprenorphine
Buprenorphine 16 mg once daily does not require dose adjustment.
Oral contraceptives or patch-type contraceptives
Because ethinyl estradiol concentrations may be decreased when lopinavir/ritonavir is coadministered with estrogen-containing oral contraceptives or patch contraceptives, alternative or additional contraception should be used.
Vasodilators
When bosentan was co-administered in combination with lopinavir/ritonavir, an increase in the Cmax and AUC of bosentan was observed by 6 and 5 times, respectively. The prescription and dose selection of bosentan should be made in accordance with its instructions for use.
No clinically significant interaction expected
Studies have not revealed clinically significant interactions between lopinavir/ritonavir and desipramine, raltegravir, omeprazole and ranitidine.
Based on the metabolic data, no clinically significant interaction is expected between lopinavir/ritonavir and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole in patients with normal renal and hepatic function.
Kaletra
St. John's wort (Hypericum perforatum), rifampicin reduces the concentration of the drug in plasma, which can lead to a decrease in the therapeutic effect and the development of resistance.
Lopinavir and ritonavir inhibit the CYP3A isoenzyme in vitro. The simultaneous administration of the drug and drugs that are primarily metabolized by the CYP3A system can increase or prolong their therapeutic effect and side effects: astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, amiodarone, ergot alkaloids - ergotamine and dihydroergotamine, ergometrine and methylergometrine.
The drug also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. The clinical significance of this phenomenon is unknown. Until more detailed information is available, it should not be used concomitantly with drugs whose metabolism depends on the activity of CYP2D6 (for example, propafenone), and an increase in plasma concentrations of which can lead to serious or life-threatening side effects.
At concentrations used in clinical settings, does not inhibit CYP2C9, CYP2C19, CYP2E1, CYP2B6, or CYP1A2.
Didanosine should be taken 1 hour before or 2 hours after taking Kaletra (gastric juice-resistant dosage forms of didanosine should be taken 2 hours after meals).
Kaletra reduces plasma concentrations of zidovudine and abacavir.
The results of a study in HIV-positive children revealed a decrease in the concentration of lopinavir when administered simultaneously with nevirapine. The effects of nevirapine in HIV-positive adults are likely to be similar to those in HIV-infected children (resulting in decreased lopinavir concentrations).
Kaletra increases plasma concentrations of the HIV protease inhibitors indinavir, nelfinavir and saquinavir. When taken simultaneously with the drug at a dose of 400 mg + 100 mg 2 times a day, indinavir at a dose of 600 mg 2 times a day and saquinavir 800 mg 2 times a day, there are no changes in AUC and the Cmin of indinavir and saquinavir increases compared to traditional treatment regimens . When taken simultaneously with an additional 100 mg of ritonavir 2 times a day, the AUC of lopinavir increased by 33% and Cmin by 64% compared with taking the drug at a dose of 400/100 mg (3 capsules) 2 times a day. The optimal doses of HIV protease inhibitors when prescribed in combination with Kaletra have not yet been established in terms of efficacy and safety.
Antiarrhythmic drugs (bepridil, lidocaine and quinidine): the concentrations of these drugs may increase when administered simultaneously with Kaletra (care should be taken and, if possible, their plasma concentrations should be monitored).
Warfarin concentrations may change when administered concomitantly (monitoring of blood coagulation parameters is recommended).
Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine) reduce the concentration of lopinavir.
Increases concentrations of BMCC (felodipine, nifedipine, nicardipine) in plasma.
HMG-CoA reductase inhibitors (lovastatin and simvastatin) are significantly metabolized by CYP3A4, and when administered concomitantly, their plasma concentrations may increase significantly (risk of myopathy and rhabdomyolysis). The combined use of these drugs is not recommended. Atorvastatin and cerivastatin are metabolized to a lesser extent by CYP3A4. When co-administered with atorvastatin, an increase in Cmax and AUC was observed by an average of 4.7 and 5.9%. When administered concomitantly, the lowest effective doses of atorvastatin and cerivastatin should be used. In cases where treatment with HMG-CoA reductase inhibitors is indicated, it is recommended to use pravastatin or fluvastatin (their metabolism does not depend on CYP3A4).
Dexamethasone may induce CYP3A4 and reduce lopinavir blood concentrations.
The AUC of sildenafil after a single dose of 100 mg against the background of regular administration of ritonavir at a dose of 500 mg 2 times a day is 1000% greater than without ritonavir (simultaneous use of the drug with sildenafil is not recommended, and the dose of sildenafil should not exceed 25 mg per 48 h).
May increase the concentration of cyclosporine and tacrolimus in the blood (more frequent determination of the therapeutic concentration of these drugs is recommended until a stable state is established).
Plasma concentrations of ketoconazole and itraconazole may increase (doses greater than 200 mg/day are not recommended).
Moderately increases the AUC of clarithromycin, therefore, in patients with renal/hepatic insufficiency, a reduction in the dose of clarithromycin is necessary.
Oral contraceptives: Because ethinyl estradiol concentrations may decrease, alternative or additional methods of contraception should be used.
When co-administered with rifabutin for 10 days, the Cmax and AUC of rifabutin increased by 3.5 and 5.7 times, respectively (parent drug and active 25-O-desacetyl metabolite), a 75% dose reduction of rifabutin is recommended (further dose reduction of rifabutin may be necessary).
It is possible to increase the concentration of drugs that cause prolongation of the QT interval (chlorphenamine, quinidine, erythromycin, clarithromycin), which increases the risk of developing rhythm disturbances.
