Kaletra® is a combination drug that contains lopinavir and ritonavir.
Lopinavir is an inhibitor of HIV-1 and HIV-2 proteases of human immunodeficiency virus (HIV) and provides antiviral activity of the drug.
Inhibition of HIV proteases prevents synthesis of virus proteins and prevents cleavage of gag-pol polypeptide, which leads to formation of immature and unable to infect 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.
HIV-1 isolates with reduced sensitivity to lopinavir have been selected in vitro. The presence of ritonavir did not affect the isolation of lopinavir-resistant viruses in vitro.
In the phase III study, antiretroviral (ARV) treatment of previously untreated patients was analyzed with viral isolates from each patient with plasma HIV RNA concentrations greater than 400 copies/mL at weeks 24, 32, 40, and/or 48. All 37 evaluable patients treated with lopinavir/ritonavir showed no evidence of genotypic or phenotypic resistance to lopinavir/ritonavir. No lopinavir/ritonavir resistance was found in children who had not previously received antiretroviral therapy.
In phase II clinical trials of Kaletra® among 227 HIV-infected patients receiving and not receiving prior antiretroviral therapy, 4 of 23 patients with virologic ineffectiveness of therapy (HIV RNA >400 copies/mL) was found to decrease sensitivity to lopinavir after 12-100 weeks of therapy with Kaletra®; 3 of 4 patients had previously received one of the HIV protease inhibitors (nelfinavir, saquinavir or indinavir) and 1 of 4 patients had received combined therapy with HIV protease inhibitors (indinavir, saquinavir and ritonavir).
All 4 patients had at least 4 mutations associated with resistance to HIV protease inhibitors before starting therapy with Kaletra®. A further increase in viral load was associated with the emergence of additional mutations associated with the development of resistance to HIV protease inhibitors.
However, these data are insufficient to identify the mutations responsible for the development of lopinavir resistance.
There is insufficient data to date on the development of cross-resistance with lopinavir/ritonavir therapy.
The virologic response to lopinavir/ritonavir therapy was altered in the presence of three or more of the following amino acid substitutions in the HIV protease gene: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, I84V.
The clinical significance of reduced sensitivity to lopinavir was studied in vitro based on virologic response to lopinavir/ritonavir therapy depending on baseline genotype and virus phenotype in 56 patients with HIV RNA above 1000 copies/mL previously treated with nelfinavir, indinavir, saquinavir or ritonavir (study M98-957).
In this study, patients were treated with lopinavir/ritonavir at one of two doses in combination with efavirenz and nucleoside reverse transcriptase inhibitors. Prior to therapy, the EC50 (the drug concentration needed to suppress replication of 50% of viruses) of lopinavir against 56 strains of the virus was 0.5-96 times the EC50 for the “wild-type” virus. Fifty-five percent (31/56) of the virus strains exhibited more than a 4-fold decrease in sensitivity to lopinavir, with an average decrease in sensitivity to lopinavir of 27.9 times among the 31 strains.
Forty-eight weeks after initiation of lopinavir/ritonavir, efavirenz, and nucleoside reverse transcriptase inhibitors, HIV RNA concentrations ≤400 copies/mL were determined in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with initial sensitivity to lopinavir reduced by a factor ≤10, 10-40, and ≥40 times, respectively. In these groups, HIV RNA concentrations were ≤50 copies/mL in 81% (22/27), 60% (9/15), and 25% (2/8) of patients, respectively.
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.
On ingestion, plasma concentrations of lopinavir and ritonavir after two 200/50 mg tablets are equivalent to three 133/33 mg capsules with minimal variability in pharmacokinetics.
. 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 taking the drug. 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 averaged 92.6 ± 36.7 µg⋅h/mL within 12 hours of drug administration. Absolute bioavailability of lopinavir in combination with ritonavir in humans has not been established.
In equilibrium, approximately 98 – 99% of lopinavir is bound to plasma proteins. Lopinavir binds to alpha1-acid glycoprotein (ACG) and albumin, but lopinavir has a higher affinity for ACG. In equilibrium, the binding of lopinavir to plasma proteins remains constant across the range of reported concentrations produced after administration of 400/100 mg lopinavir/rntonavir twice daily and is comparable in healthy volunteers and HIV-positive patients.
Lopinavir has been shown in in vitro studies to undergo predominantly oxidative metabolism involving the hepatocyte cytochrome P450 system, mainly through the CYP3A isoenzyme. Ritonavir is a potent inhibitor of CYP3A isoenzyme that inhibits lopinavir metabolism, which provides increased concentrations of lopinavir in blood plasma. After a single 400/100 mg dose of lopinavir/ritonavir (with 14C-labeled lopinavir), 89% of the radioactivity is provided by the original drug. At least 13 oxidative metabolites of lopinavir have been identified in humans.
Ritonavir is able to induce cytochrome P450 isoenzymes, leading to induction of its own metabolism. During long-term use, lopinovir concentrations before the next dose decreased over time, stabilizing after approximately 10-16 days.
After 400/100 mg administration of 14C-lopinavir/ritonavir after eight days, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of the 14C-lopinavir dose taken were detected in the urine and feces, respectively. And 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.
Treatment of HIV infection in adults and children from 3 years old as part of combination therapy.
Each tablet contains:
Lopinavir – 200 mg, ritonavir – 50 mg;
Excipients: copovidone K 28 – 426.9 mg; sorbitan laurate – 41.95 mg; colloidal silica – 6.0 mg; second layer: sodium stsaryl fumarate – 6.15 mg; colloidal silicon dioxide – 4.0 mg;
Film coating: Opadray® II pink 85 F 14399 – 15.0 mg (polyvinyl alcohol – 40.00%, titanium dioxide – 24.85%, talc – 14.80%, macrogol 3350 – 20.20%, iron oxide red dye E172 – 0.15%.
How to take, the dosage
The recommended oral dose of Kaletra® is:
- Four tablets of Kaletra® 100/25 mg (400/100 mg) twice daily regardless of meals.
- Eight Caletra® 100/25 mg (800/200 mg) tablets once daily regardless of meals for patients with fewer than 3 mutations associated with the development of lopinavir resistance. There is insufficient data for the use of lopinavir/rntonavir once daily in adult patients with 3 or more lopinavir-resistant mutations.
Use of Kaletra® tablets in combination with omeprazole and rantendine does not require dose adjustments.
In patients with suspected hypersensitivity to lopinavir (clinically or laboratory) who received antiretroviral therapy earlier in combination with efavirenz, nevirapine, amprenavir or nelfinavir the dose of Kaletra® tablets should be increased up to 500/125 mg (5 tablets of 100/25 mg) 2 times a day. When concomitant use with these drugs, Kaletra® tablets should not be administered once daily.
The mode of administration of Kaletra® tablets once daily in pediatric patients has not been studied. Adult dose of Kaletra® tablets (400/100 mg twice daily) without concomitant use of efavirenz, nevirapine, nelfinavir or amprenavir can be used in children with body weight 35 kg or more or body surface area (BSA) 1.4 m2 or more. The tables below are recommended for dosage determination for children with a body weight less than 35 kg or with a PPT of 0.6 to 1.4 m2.
For children with a PPT less than 0.6 m or for children less than 3 years old, there is an oral formulation of Kaletra®. Tables 1 and 2 contain dosing guidelines for Kaletra® 100/25 mg tablets based on PPT.
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, nimmunosuppressants and phosphodiesterase 5 (PDE-5) inhibitors) may lead to increased plasma concentrations of other drugs, therapeutic or adverse effects of which may increase or prolong. In drugs that are extensively metabolized by CYP3A isoenzyme and have high presystemic metabolism, when taken simultaneously with lopinavir/ritonavir a significant increase in AUC (more than 3-fold) is more often observed.
Drugs that are contraindicated specifically because of undesirable interaction and possibility of serious side effects are presented in the “Contraindications”.
Lopinavir/ritonavir is metabolized by 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 were not observed when used simultaneously with ketoconazole.
Concomitant use of lopinavir/ritonavir and other drugs that inhibit the CYP3A isoenzyme may increase plasma concentrations of lopinavir.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Stavudip and lamivudine
No changes in lopinavir pharmacokinetics were observed with concomitant use of lopinavir/ritonavir with stavudine and lamivudine.
It is recommended to take didanosine 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 the drug may reduce plasma concentrations of zidovudine and abacavir. The clinical significance of this potential interaction is unknown.
Research has shown that lopinavir/ritonavir increases the plasma concentration of tenofovir. The mechanism of this interaction is unknown. Patients taking lopinavir/ritonavir and tenofovir should be monitored for tenofovir-related side effects.
Increased 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)
No changes in lopinavir pharmacokinetics were observed in healthy adult patients during concomitant use of nevirapine and
lopinavir/ritonavir. Results from a study involving HIV-positive children showed decreased concentrations of lopinavir during concomitant use with nevirapine. It is believed that the effects of nevirapine on HIV-positive adult patients may be similar to those in children, which may result in decreased lopinavir concentrations. The clinical significance of the pharmacokinetic interaction is unknown. Lopnavir/ritonavir in combination with nevirapine should not be used once daily.
Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg twice daily has no effect on lopinavir plasma concentrations compared to using lopinavir/rtonavir at 400/100 mg twice daily without efavirenz. Increasing the lopinavir/ritonavir tablet dose to 600/150 mg (six (6) 100/25 mg tablets) twice daily when used concomitantly with efavirenz significantly increased lopinavir plasma concentrations by approximately 36% and ritonavir concentrations by approximately 56% to 92% compared to the lopinavir/ritonavir 400/100 mg tablet dose (four (4) 100/25 mg tablets) when taken twice daily without efavirenz.
Efavirenz and nevirapine induce the CYP3A isoenzyme and thus may reduce plasma concentrations of other HIV protease inhibitors when used in combination with lopinavir/ritonavir. Lopnavir/ritonavir with efavirenz should not be taken once daily.
Delavirdine can increase plasma concentrations of lopinavir.
HIV protease inhibitors
Lopinavir/ritonavir may increase amprenavir concentrations (administration of amprenavir at a dose of 750 mg twice daily plus lopinavir/ritonavir leads to increased AUC, similar Cmax, increased Cmin relative to amprenavir at a dose of 1200 mg twice daily). Concomitant use of lopinavir/ritonavir and amprenavir promotes reduction of lopinavir concentrations (see section “Dosage and administration”). The drug lopinavir/ritonavir in combination with amprenavir should not be taken once daily.
Research has shown that concomitant use of lopinavir/ritonavir with fosamprenavir reduces fosamprenavir and lopinavir concentrations.
Adequate safety and efficacy doses of fosamprenavir and lopinavir/ritonavir in combination have not been established. Concomitant use of increased dose of fosamprenavir (1400 mg twice a day) with lopinavir/ritonavir (533/133 mg twice a day) in patients who were previously on antiretroviral therapy resulted in increased frequency of gastrointestinal side effects and increased triglyceride concentrations during combination treatment without increasing antiviral effectiveness compared to standard doses of fosamprenavir/ritonavir. Simultaneous use of these two drugs is not recommended.
Lopinavir/ritonavir may increase concentrations of indinavir (when 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 at a dose of 800 mg, with similar AUCs). The dose of indinavir may need to be reduced with concomitant administration of lopinavir/ritonavir at a dose of 400/100 mg twice daily. Taking lopinavir/ritonavir in combination with indinavir once daily has not been studied.
Lopinavir/ritonavir may increase concentrations of nelfinavir and the nelfinavir metabolite M8 (when taking nelfinavir 1000 mg twice daily and lopinavir/ritonavir compared to taking nelfinavir 1250 mg twice daily, similar AUC, similar Cmax increased Cmin were observed). Concomitant use of lopinavir/ritonavir and nelfinavir results in decreased concentrations of lopinavir. Lopinavir/ritonavir in combination with nelfinavir should not be taken once daily.
When used with lopinavir/ritonavir with an additional 100 mg of ritonavir twice daily, lopinavir AUC increased by 33% and Cmin increased by 64% compared to taking lopinavir/ritonavir 400/100 mg.
Lopnavir/ritonavir increases saquinavir concentrations (taking saquinavir 800 mg twice daily plus lopnavir/ritonavir compared to taking saquinavir 1200 mg three times daily leads to increased AUC, Cmax and Cmin). The dose of saquinavir when concomitantly used with lopinavir/ritonavir 400/100 mg twice daily may need to be decreased The administration of lopinavir/ritonavir in combination with saquinavir on a once daily dosing regimen has not been studied.
When tipranavir (500 mg twice daily) was used concomitantly with ritonavir (200 mg twice daily) and with lopinavir/ritonavir (400/100 mg twice daily), a 47% and 70% reduction in AUC and Cmin of lopinavir was observed, respectively. Therefore, concomitant use of lopinavir/ritonavir and tipranavir with low-dose ritonavir is not recommended.
Fentanyl: Because lopnavir/ritonavir inhibits the CYP3A4 isoenzyme, plasma concentrations of fentanyl may be increased.
If lopnavir/ritonavir and fentanyl are used concurrently, therapeutic and side effects (including respiratory depression) should be closely monitored.
Antiarrhythmic drugs (amiodarone, bepridil, lidocaine (systemic) and quinidine)
Concurrent use with lopinavir/ritonavir may increase their concentrations. Caution is necessary when using the drugs and monitoring therapeutic concentrations if possible.
A literature review showed that concomitant use of ritonavir (300 mg every 12 hours) and digoxin resulted in a significant increase in blood concentrations of digoxin. Caution is necessary when using lopinavir/ritonavir concomitantly with digoxin with adequate monitoring of serum digoxin concentrations.
Antitumor drugs (e.g., dasatinib, nilotinib, vincristine, vinblastine)
Their serum concentrations may increase when used concomitantly with lopinavir/ritonavir, which may result in the side effects usually associated with these antitumor drugs.
Possible effect on warfarin concentrations when used concomitantly with lopinavir/ritonavir. It is recommended to monitor INR (international normalized ratio).
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 of bupropion efficacy without exceeding the recommended dose, despite the observed increase in metabolism.
Concurrent use of ritonavir and trazodone may result in increased trazodone concentrations. Side effects have been observed: nausea, dizziness, hypotension, and fainting. Trazodone with a CYP3A4 isoenzyme inhibitor such as lopinavir/ritonavir should be used with caution and the trazodone dose should be reduced.
Anticonvulsants (phenobarbital, phenytoin, carbamazepine)
It is known that these drugs can induce the CYP3A4 isoenzyme and thus reduce lopinavir concentration. Lopnavir/ritonavir should not be used once daily in combination with phenobarbital, phenytoin or carbamazepine.
In addition, concomitant use of phenytoin and lopnavir/ritonavir leads to moderate reductions in steady-state phenytoin concentrations.
Phenytoin concentrations should be monitored when the drug is used concomitantly with lopinavir/rtonavir.
Serum concentrations of ketoconazole and itraconazole may be increased by lopinavir/ritonavir. High doses of ketoconazole and itraconazole (over 200 mg/day) are not recommended.
A study has shown that concurrent use of ritonavir at a dose of 100 mg every 12 hours reduced the equilibrium AUC of voriconazole by an average of 39%; therefore concurrent use of lopinavir/ritonavir and voriconazole should be avoided.
A moderate increase in AUC of clarithromycin when used concomitantly with lopinavir/ritonavir has been noted. The dose of clarithromycin should be reduced in patients with renal or hepatic impairment.
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 the dose of rifabutin may be necessary.
Because of the significant reduction in lopinavir concentrations, rifampicin should not be taken in combination with the standard lopinavir/ritonavir dose.
Use of rifampicin with standard dose lopinavir/ritonavir may lead to loss of virologic response and possible development of resistance to lopinavir/ritonavir or to a class of HIV protease inhibitors or other concomitantly used antiretroviral drugs.
Increases in ALT and ACT activity have been noted in studies with higher doses of lopinavir/ritonavir when used concomitantly with rifampicin; this phenomenon may depend on the sequence of doses.
When used concomitantly, lopinavir/ritonavir should be started at standard doses for approximately 10 days before using rifampicin. The lopinavir/ritonavir dose should be increased. Close monitoring of liver function is recommended.
It is possible that the therapeutic concentration of atovaquone may decrease when used concomitantly with lopinavir/ritonavir. Increased doses of atovahon may be necessary.
Dexamethasone may induce the CYP3A4 isoenzyme and may decrease lopinavir concentrations.
Fluticasone: Concomitant use of lopinavir/ritonavir and fluticasone can significantly increase plasma concentrations of fluticasone and decrease serum concentrations of cortisol. Use should be used with caution. It is recommended that alternatives to fluticasone be considered, especially with long-term use.
Systemic effects of glucocorticosteroids, including Icenko-Cushing’s syndrome and suppression of the adrenal cortex, have been reported when ritonavir is used simultaneously with inhaled or nasally administered fluticasone.
Similar results have been observed with concomitant use of lopinavir/ritonavir and other inhaled glucocorticosteroids that are metabolized similarly to fluticasone, such as budesonide. Particular caution should be exercised if lopinavir/ritonavir and any of the inhaled or nasally administered glucocorticosteroids are used concomitantly.
Consider reducing the glucocorticosteroid dose while carefully monitoring local and overall reactions or switching to a glucocorticosteroid that is not a substrate for CYP3A4 (e.g., beclomethasone). Also, in case of discontinuation of glucocorticosteroid therapy, a gradual dose reduction over an extended period should be carried out.
Dihydropyridine “slow” calcium channel blockers (e.g., felodipine, nifedipine, nicardipine). Increased serological concentrations of these drugs may be observed when taking lopinavir/ritonavir.
Drugs taken for erectile dysfunction (phosphodiesterase 5 inhibitors (PDE-5)
Particular caution should be exercised when using sildenafil, tadalafil to treat erectile dysfunction in patients taking lopinavir/ritonavir. Concomitant use of lopinavir/rtonavir with these drugs may significantly increase their concentrations, which may lead to increased frequency of side effects, such as hypotension and prolonged erections.
Sildenafil: Use sildenafil with caution to treat erectile dysfunction in reduced doses of 25 mg every 48 hours with special monitoring of side effects.
Use of sildenafil concomitantly with lopinavir/ritonavir is contraindicated for pulmonary hypertension.
Tadalafil: use with caution in reduced doses, no more than 10 mg every 72 hours, with careful monitoring of side effects.
Vardenafil: concomitant use is contraindicated.
Patients treated with lopinavir/ritonavir are contraindicated in concomitant administration of preparations containing St. John’s wort, since this combination may reduce plasma concentrations of lopinavir/ritonavir. This effect may occur due to induction of CYP3A4 isoenzyme and may lead to loss of therapeutic effect and development of resistance.
HMG-CoA reductase inhibitors
Plasma concentrations of HMG-CoA reductase inhibitors highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, may be significantly increased with concomitant use of lopinavir/ritonavir. Since increased concentration of HMG-CoA reductase inhibitors may contribute to myopathy, including rhabdomyolysis, concomitant use with lopinavir/ritonavir is not recommended. Concomitant use of lopinavir/ritonavir with lovastatin and simvastatin is contraindicated. Metabolism of atorvastatin and rosuvostatin is less dependent on CYP3A isoenzyme.
. When using atorvastatin concomitantly with lopinavir/ritonavir an average of 4.7-fold increase in Cmax and 5.9-fold increase in AUC of atorvastatin was observed, and when using rosuvostatin concomitantly with lopinavir/ritonavir a 2-fold increase in AUC and 5-fold increase in Cmax was observed so in combination with lopinavir/ritonavir the lowest doses of atorvastatin and rosuvostatin should be used. The results of the study of drug interaction between lopinavir/ritonavir and pravastatin showed no clinically significant interaction. The metabolism of pravastatin and fluvastatin does not depend on CYP3A4 isoenzyme, so there is no interaction with lopinavir/ritonavir for these drugs. If treatment with HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Concentrations of these drugs (such as cyclosporine, tacrolimus and sirolimus) may increase with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until blood concentrations of these drugs are stabilized.
lopinavir/ritonavir has been shown to decrease plasma concentrations of methadone. Monitoring of methadone plasma concentrations is recommended.
Buprenorphine at a dose of 16 mg once daily does not require a dose change.
Oral contraceptives or patch-form contraceptives
Since concentrations of ethinylestradiol may be reduced by concomitant use of lopinavir/ritonavir and estrogen-based oral contraceptives or patch-form contraceptives, alternative or additional contraceptive measures should be taken.
Drugs with which clinically significant interactions are not expected.
Studies of interaction of the drug show no clinically significant interaction with desipramine, omeprazole and ranitidine.
Based on known metabolic profiles, no clinically significant drug interactions are noted between Kaletra® and fluvastatin, dapsone, trimethoprim/sulfamethoxazone, azithromycin, or fluconazole in patients with normal liver and renal function.
Lopinavir/ritonavir is predominantly metabolized by the liver. Therefore, special caution should be exercised when using this drug in patients with reduced liver function. Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment.
Pharmacokinetic data show an increase in plasma concentrations of lopinavir by approximately 30% and a decrease in plasma protein binding in patients co-infected with HIV and hepatitis C virus and mild to moderate hepatic impairment.
Patients with underlying hepatitis B or C disease or significant elevations of “hepatic” transaminase activity prior to treatment may be at increased risk for further elevation of transaminase activity.
There have been cases of hepatic dysfunction, including several deaths, since the drug was placed on the market, which occurred primarily among patients with advanced HIV infection who were simultaneously taking medications to treat the underlying disease – chronic hepatitis or cirrhosis. A causal relationship with lopinavir/ritonavir treatment has not been established. In these patients more careful monitoring of AST/ALT activity is necessary, especially during the first few months of treatment with lopinavir/ritonavir.
Initial diagnosis of diabetes mellitus, exacerbation of previously diagnosed diabetes mellitus and hyperglycemia have been reported in post-marketing follow-up in HIV-positive patients treated with HIV protease inhibitors. Some patients required administration or adjustment of doses of insulin or oral antidiabetic drugs. In some cases, diabetic ketoacidosis occurred. In those patients who discontinued treatment with HIV protease inhibitors, hyperglycemia sometimes persisted. Since these effects were reported voluntarily during clinical practice, it is not possible to estimate the frequency of these effects or to establish a causal relationship between treatment with HIV protease inhibitors and these effects.
Cases of pancreatitis have been reported in patients treated with lopinavir/ritonavir, including those with significant increases in triglyceride concentrations. Fatal cases have been reported. Although a causal relationship with lopinavir/ritonavir has not been established, significant increases in triglyceride concentrations are a risk for pancreatitis. Patients with advanced HIV infection may be at increased risk for increased triglyceride concentrations and pancreatitis, and patients with a history of pancreatitis may be at risk for recurrent pancreatitis during treatment with lopinavir/ritonavir.
There have been reported cases of increased bleeding, including spontaneous formation of subcutaneous hematomas and development of hemarthrosis, in patients with type A and B hemophilia treated with HIV protease inhibitors.
Some patients have received additional doses of clotting factor VIII. In more than half of the cases reported, treatment with HIV protease inhibitors was continued or started again. A causal relationship or mechanism of action between treatment with HIV protease inhibitors and these events has not been established.
PR interval prolongation
Moderate asymptomatic PR interval prolongation has been observed in some patients during lopinavir/ritonavir administration. Second- and third-degree atrioventricular block has rarely been reported during lopinavir/ritonavir administration in patients with organic heart disease and preexisting conduction system disorders or in patients taking PR interval prolonging agents (such as verapamil or atazanavir). In such patients, lopinavir/ritonavir should be used with caution.
The QTcF interval (corrected by Fridericia) was evaluated in a randomized, placebo-controlled cross-over study with active control (moxifloxacin 400 mg once daily) involving 39 healthy adult volunteers. Ten measurements were taken over 12 hours on day 3 of the study. The mean maximum difference in QTcF compared with placebo was 3.6 (6.3) ms and 13.1 (15.8) ms for the 400/100 mg twice daily and 800/200 mg twice daily doses of lopinavir/ritonavir, respectively. The changes observed with the above two regimens were approximately 1.5 and 3 times higher than those observed with the recommended once-daily or twice-daily lopinavir/ritonavir doses in equilibrium. None of the patients reported an increase in the QTcF > 60 ms interval from baseline; the QTcF interval did not exceed a potentially clinically significant threshold of 500 ms.
In the same study, patients taking lopinavir/ritonavir also showed a moderate increase in the PR interval on day 3. The maximum PR interval was 286 ms, and no development of grade II or III atrial-ventricular block was observed.
Redistribution of fat
Redistribution/accumulation of fat, including central obesity, increased fat deposition in the dorsocervical region (“bull hump”), peripheral wasting (reduction of fat in the extremities), facial wasting, chest enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term effects of these effects are currently unknown. A causal relationship has not been established.
Increased lipid concentrations
Treatment with lopinavir/ritonavir may result in increased cholesterol and triglyceride concentrations. Triglyceride and cholesterol concentrations should be tested before starting lopinavir/ritonavir and periodically during treatment. If necessary, appropriate treatment of lipid metabolism disorders should be performed
Immune recovery syndrome
Immune recovery syndrome has been observed in HIV-infected patients receiving combined antiretroviral therapy including lopinavir/ritonavir. Against the background of immune function recovery at the beginning of combined antiretroviral therapy, an exacerbation of asymptomatic or residual opportunistic infections (infection caused by Mycobacterium avium and/or Pneumocystis jiroveci, cntomegalovirus infection, pneumonia, or tuberculosis) may occur, which may require additional examination and treatment.
It is known that many factors play a role in the etiology of osteonecrosis (use of GCS, alcohol abuse, high body mass index, severe immunosuppression, etc.). In particular, cases of patients with advanced HIV infection and/or long-term use of combined antiretroviral therapy are reported. Therefore, these patients should be advised to consult a physician if pain, joint stiffness and impaired motor function occur.
Administration of the drug in elderly patients
Clinical studies of lopinavir/ritonavir have not included patients over 65 years or more, in sufficient numbers to determine the characteristics of response for this age group. Caution should be exercised when using lopinavir/ritonavir in elderly patients, given the increased incidence of reduced liver, renal or cardiac function, comorbidities and concomitant therapy.
Use in Children
In HIV-infected patients under 12 years of age, the pattern of adverse effects observed during the clinical trial was similar to that in adult patients. Clinical trials continue to evaluate the antiviral activity of lopinavir/ritonavir in children. Administration of lopinavir/rntonavir on a once-daily dosing regimen has not been evaluated in pediatric patients.
Glucose tolerance decreases with increasing drug concentrations. Effect on driving and operating machinery.
During the treatment it is necessary to exercise caution while driving vehicles and engaging in other potentially dangerous activities that require high concentration and rapid psychomotor reactions, because the drug may cause dizziness and other side effects that may affect the mentioned abilities. Studies of the ability to drive motor transport and operate machinery have not been conducted.
The most frequent side effect associated with lopinavir/rtonavir administration was mild to moderate diarrhea.
Side effects possibly causally related to use of the drug, both clinical and laboratory, are listed below by frequency (very frequently ≥1/10, frequently ≥1/100 but <1/10, infrequently ≥1/1000 but <1/100, rarely ≥1/10000 but <1/1000).
- Infrequent: hypersensitivity reactions.
- Rarely: immune reconstitution syndrome.
- Gastrointestinal system
- Very common: diarrhea.
- Frequent: abdominal pain, flatulence, nausea, vomiting, irregular stools.
- Infrequent: dyspepsia, abdominal discomfort, dry mouth, hemorrhagic enterocolitis, fecal incontinence, gastritis, gastroesophageal reflux, pancreatitis, hepatitis.
- Rarely: dysphagia, lower abdominal pain, constipation, duodenitis, enterocolitis, enteritis, belching, esophagitis, stomach ulcers, hemorrhoids, mouth ulcers, periodontitis, rectal bleeding, stomatitis, hepatomegaly, cholecystitis, jaundice, liver steatosis and liver pain. Less than 2% had cholangitis.
Nervous system disorders:
- Frequently: headache.
- Infrequent: insomnia, paresthesia, decreased libido, depression, sleep disturbance, restlessness, nervousness, dizziness, peripheral neuropathy, drowsiness, perversion of taste.
- Rarely: agitation, confusion, emotional lability, disorientation, thought disorders, amnesia, ataxia, dyskinesia, encephalopathy, extrapyramidal syndrome, facial nerve paresis, muscle tone, migraine, neuropathy, loss of taste and tremor. In less than 2% were observed: apathy, cerebral infarction and seizures.
Cardiovascular system disorders:
- Infrequent: vascular disorders.
- Rarely: increased blood pressure, angina pectoris, atrio-ventricular block, myocardial infarction, palpitations, tricuspid valve failure, deep vein thrombosis, thrombophlebitis, varicose veins and vasculitis. In less than 2% were observed: atrial fibrillation, orthostatic hypotension.
Skin and subcutaneous fatty tissue:
- Frequently: lipodystrophy.
- Infrequent: rash, acne, alopecia, allergic dermatitis, maculopapular rash, itching and hyperhidrosis.
- Rarely: dry skin, eczema, idiopathic capillaritis, exfoliative dermatitis, facial edema, nail structure disorders, seborrhea, skin discoloration, stretch marks, skin ulcers. Less than 2% had skin hypertrophy.
- Infrequent: myalgia, arthralgia,
- Rarely: osteoarthritis, low back pain and bone necrosis, joint disease. Less than 2% had muscle weakness. Metabolic and endocrine disorders
- Infrequent: dehydration, diabetes mellitus, Icenko-Cushing’s syndrome, obesity, anorexia, weight loss or gain.
- Rarely: male hypogonadism, decreased or increased appetite, hyperamylazemia, hyperlipazemia, hyperurecemia, hypophosphatemia, hypocholesterolemia, hypovitaminosis and hypothyroidism, lactacidosis, lipomatosis.
Renal and urinary tract disorders:
- Rarely: hematuria, nephrolithiasis, nephritis and abnormal laboratory values of urine, changes in urine odor.
Reproductive system disorders:
- Infrequent: erectile dysfunction.
- Rarely: amenorrhea, disorder of ejaculation, breast enlargement, gynecomastia, menorrhagia.
- Infrequent: bronchitis.
- Rarely: cough, shortness of breath, pulmonary edema. Bronchospasm was observed in less than 2%.
Blood system and hematopoietic organs:
- Rarely: anemia, leukopenia and lymphadenopathy.
- Infrequent: tinnitus.
- Rarely: visual disturbances, hyperacusis, and dizziness, balance disorders.
- Rarely: Bacterial infection, bronchopneumonia, inflammation of subcutaneous fatty tissue, folliculitis, furunculosis, gastroenteritis, otitis media, perineal abscess, pharyngitis, rhinitis, sialoadenitis, sinusitis and viral infection (including flu).
Benign, malignant and unspecified neoplasms (including cysts and polyps):
- Rarely: neoplasms (including benign neoplasms).
- Frequently: neoplasms (including benign skin neoplasms), cysts.
- Frequently: asthenia.
- Infrequent: pain, pain in the sternum, fever, edema, malaise.
- Rarely: chills, peripheral edema, chest pain, splenomegaly.
Changes in laboratory parameters:
- Very common: Increased concentration of total cholesterol, triglycerides; increased activity of gamma-glutamyl transpeptidase (GGTP);
- Frequently: Increased glucose concentrations, abnormal “liver” tests, increased serum aspartate aminotransferase (ACT), alanine aminotransferase (ALT), and amylase activity.
Profile of side effects in children was similar to that in adults. The most frequently observed were perversion of taste, vomiting, diarrhea, and rash.
Often also observed were: viral infections, constipation, pancreatitis, hepatomegaly, dry skin, fever, increased activated partial thromboplast time, decreased hemoglobin, decreased platelet count, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ALT, increased CPT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils.
Cases of toxic epidermal necrolysis, hepatitis, Stevens-Johnson syndrome, erythema multiforme and bradyarrhythmia have also been reported with lopinavir/ritonavir.
Clinical experience with acute lopinavir/ritonavir overdose in humans is currently limited. There is no specific antidote.
Treatment should include general supportive therapy, including monitoring of basic vital signs and observation of the patient’s clinical status. If necessary, unabsorbed drug is removed by gastric lavage and activated charcoal is prescribed. Since lopnavir/ritonavir is highly bound to plasma proteins, the use of dialysis is not advisable.
|Conditions of storage|
At the temperature from 15 to 30 ° C. Keep out of reach of children.
R-Pharm AO, Russia
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