When ritonavir is administered in combination with other protease inhibitors (for example, in cases where ritonavir is used to reduce the metabolism of other protease inhibitors), information on possible drug interactions contained in the instructions on the use of appropriate protease inhibitors should be taken into account.
With the simultaneous use of drugs that increase activity CYP3A (eg, phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampicin and rifabutin), an increase in clearance of ritonavir and a decrease in its plasma concentrations are expected.
Tobacco smoking is associated with a decline AUC ritonavir by 18%.
Ritonavir is characterized by a high affinity for certain cytochrome P450 isoenzymes (RMS). In order to reduce the affinity of ritonavir, these enzymes can be arranged as follows: CYP3A4 > CYP2D6 > CYP2C9 > CYP2C19 >> CYP2A6, CYP1A2, CYP2E1. There is evidence that ritonavir can induce the activity of glucuronosyltransferase, isozymes CYP1A2, CYP2C9 and CYP2C19; Thus, a decrease in plasma concentrations of concomitantly prescribed drugs and loss of therapeutic effects during the use of ritonavir may necessitate a change in the dose of these drugs. The simultaneous use of ritonavir and drugs that are metabolized predominantly with the participation of CYP3A can lead to an increase in plasma concentrations of another drug, which may be accompanied by an increase and an increase in the duration of its therapeutic and side effects.With the simultaneous administration of such drugs with ritonavir, careful monitoring of therapeutic and side effects is required. If you simultaneously use drugs that are heavily metabolized with the participation of CYP3A, you may need to reduce their dose. With the simultaneous use of ritonavir and disopyramide, mexiletine, nefazodone and fluoxetine, cardiac and neurological side effects were identified.
Alprazolam
The simultaneous use of alprazolam and ritonavir leads to a statistically significant decrease in mean values FROMmOh alprazolam (a decrease of 16%), but not to a statistically significant decrease in mean AUC values (by 12%). Similarly, a statistically significant effect was revealed on the sedation effect curve, but not on the severity of sedation.
Amprenavir
According to the literature, while concomitant administration with ritonavir, an increase in the concentration of the protease inhibitor of HIV-amprenavir is possible.
Boszentan
With the simultaneous use of bosentan and ritonavir, an increase in CmOh and AUC bosentan. The appointment and selection of a dosage of bosentan should be made in accordance with its instruction for use.
Bupropion
Bupropion is mainly metabolized with the participation of isoenzyme CYP2B6. With simultaneous application of bupropion and repeated use of doses of ritonavir, a decrease in the concentrations of bupropion is expected.
Buspirone
Buspirone is mainly metabolized with the participation of CYP3A4. With the simultaneous use of buspirone and drugs that inhibit CYP3A, such as ritonavir, a significant increase in buspirone concentrations is expected. With concomitant administration with ritonavir, a dose reduction or a lower dose of buspirone is required.
Clarithromycin
Simultaneous administration of ritonavir in a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours is accompanied by a pronounced inhibition of the metabolism of clarithromycin. With concomitant administration with ritonavir CmOh clarithromycin is increased by 31%, Cmin - by 182%, AUC - by 77%. Almost complete inhibition of the formation of 14- [R] -hydroxyclamirithromycin. Due to the wide therapeutic range of clarithromycin in patients with normal renal function, dose reduction is not required. However, in patients with renal insufficiency,conduct correction doses as follows: patients with a creatinine clearance of 30 to 60 ml / min clarithromycin dose should be reduced by 50%, with creatinine clearance <30 mL / min reception clarithromycin contraindicated. Clarithromycin should not be prescribed concomitantly with ritonavir in doses exceeding 1000 mg / day.
Colchicine
With the simultaneous use of colchicine in combination with ritonavir, an increase in colchicine concentration was observed. The appointment and selection of colchicine dose should be made in accordance with its instruction for use.
Delavirdine
Delavirdine is an inhibitor of metabolism, carried out with the participation of CYP3A. When concomitant administration used in clinical practice delavirdine 400 mg doses three times a day and ritonavir 600 mg twice daily (n= 12 HIV-infected patients), an increase in the equilibrium values of CmOh and AUC by about 50% and the value of Cmin about 75%. Based on the comparison of the data, it was concluded that the pharmacokinetics of delavirdine under the influence of ritonavir did not change. With concomitant administration with delavirdine, consideration should be given to reducing the dose of ritonavir.
Desipramine
With simultaneous application of ritonavir at a dose of 500 mg every 12 hours and a single dose of desipramine 100 mg, an increase occurs AUC desipramine on average by 145%. Patients receiving this combination of drugs should consider the need to reduce the dose of desipramine.
Didanosine
In a pharmacokinetic study, it was shown that with simultaneous application of ritonavir at a dose of 600 mg every 12 hours and didanosine at a dose of 200 mg every 12 hours, the equilibrium values of Cmax and AUC didanosine by 16% and 13%, respectively. In this case, the effect on the pharmacokinetics of ritonavir was negligible or absent. Changes in didanosine dose with simultaneous application with ritonavir are not required; however, the interval between doses of these two drugs should be at least 2.5 hours in order to avoid their pharmaceutical incompatibility.
Digoxin
Simultaneous application of ritonavir (300 mg twice daily) and digoxin leads to a significant increase in digoxin levels. With the simultaneous administration of ritonavir and digoxin, care should be taken and appropriate serumdigoxin concentrations.
Efavirenz
In healthy volunteers receiving 500 mg of ritonavir twice a day and efavirenz in a dose of 600 mg once a day, the equilibrium values AUC efavirenz increased by 21%. At the same time there was an increase AUC ritonavir by 17%
Fentanyl
As ritonavir inhibits isoenzyme CYP3A4, an increase in the concentration of fentanyl in blood plasma is possible. When ritonavir and fentanyl are used concomitantly, therapeutic effects and side effects (including respiratory depression) should be closely monitored.
Fusidic acid
With the simultaneous use of inhibitors of viral proteases, including ritonavir, and fusidic acid, an increase in the level of fusidic acid is expected, as well as an increase in plasma concentrations of HIV protease inhibitors.
The simultaneous use of ritonavir and fusidic acid is contraindicated.
Preparations of St. John's Wort
Patients receiving ritonavir it is contraindicated to simultaneously use preparations containing St. John's Wort (Hypericum perforatum), since in this case a decrease in plasma concentrations of ritonavir is possible.This effect is presumably associated with induction of the isoenzyme CYP3A4 and may lead to a decrease in therapeutic efficacy and development of resistance to ritonavir.
Indinavir
Ritonavir inhibits the metabolism of indinavir, which is carried out by isoenzyme CYP3A. In healthy individuals, with the appointment of ritonavir in a dose of 200 to 400 mg twice daily with a single dose of indinavir from 400 to 600 mg, there was an increase AUC indinavir from 185 to 475%, CmOh - from 21% to 110% and Cmin - in 11-33 times in comparison with the same values fixed at appointment of indinavir in a dose from 400 mg to 600 mg in the form of monotherapy. With simultaneous application of 400 mg of ritonavir and 400 mg of indinavir twice daily during meals, similar values were obtained AUC, an increase in the values Cmin 4 times and a decrease in CmOh from 50% to 60% compared with similar indices obtained with the appointment of indinavir in a dose of 800 mg three times a day on an empty stomach. Simultaneous use of ritonavir and indinavir leads to an increase in serum concentrations of indinavir. Data on the efficacy and safety of this combination of drugs in patients are limited.When indinavir is used in doses of 800 mg twice daily in combination with ritonavir, the risk of nephrolithiasis may increase. Adequate hydration and monitoring of these patients is recommended.
Ketoconazole
With the simultaneous use of ritonavir (500 mg every 12 hours) and ketoconazole (200 mg per day), the mean values AUFROM24 and Cmax ketoconazole by 244% and 55%, respectively. The mean half-life of ketoconazole increased from 2.7 to 13.2 hours. Mean AUc24 and Cmax ritonavir increased by 18% and 10%, respectively. Correction of a dose of ritonavir is not required; but ketoconazole at a dose of 200 mg / day or higher should be used in combination with ritonavir with caution and, perhaps, a decrease in the dose of ketoconazole should be considered.
Maraviroc
The simultaneous use of maraviroc with ritonavir leads to an increase in the concentration of maraviroc. When used concomitantly with ritonavir, the dosage of maraviroc should be reduced. The dosage of maraviroc should be selected in accordance with its instructions for use.
Nelfinavir
The interactions between ritonavir and nelfinavir are probably associated with both inhibition and induction of cytochrome P450.With simultaneous application of ritonavir at a dose of 400 mg twice a day, a statistically significant increase in M8 concentrations (the main active metabolite of nelfinavir) and a slight increase in nelfinavir concentrations are observed. In a study of 10 patients with nelfinavir 750 mg and ritonavir 400 mg twice daily, slightly higher values were obtained AUC (160%), CmOh (121%) and Cmin (123%) of nelfinavir in comparison with data for nelfinavir 750 mg three times daily in monotherapy. Value AUC for M8 increased by 347%.
Raltegravir
With simultaneous application of ritonavir in a dose of 100 mg twice a day in combination with raltegravir 400 mg once, a decrease in C12h, AUC and CmOh raltegravir by 1%, 16% and 24%% respectively.
Oral contraceptives and contraceptive patches
The simultaneous use of ritonavir at a dose of 500 mg every 12 hours and oral contraceptive with a fixed dose can lead to a decrease in the average values of CmOh and AUC by 32% and 40% respectively. Consideration should be given to the possibility of increasing the dose of oral contraceptives or contraceptive patches containing ethinyl estradiol, or the use of alternative methods of contraception.
Rifabutin
In a pharmacokinetic study, simultaneous use of ritonavir 500 mg every 12 hours and rifabutin resulted in an increase in the values AUC in 4-35 times for rifabutin and its active metabolite 25-O-deaetyltrifabutin, respectively. The significance of this interaction was confirmed in clinical studies.
It is recommended to reduce the dose of rifabutin by at least 3/4 as compared to the usual dose of 300 mg / day (for example, 150 mg every other day or three times a week). A larger dose reduction may be required.
Rivaroxaban
The simultaneous use of rivaroxaban with ritonavir may cause an increase in rivaroxaban concentration, which may lead to an increased risk of bleeding.
Saquinavir
Ritonavir actively inhibits the metabolism of saquinavir, which leads to a significant increase in plasma concentrations of this drug. After applying a combination regimen using hard gelatin capsules of saquinavir (400 mg or 600 mg twice daily) and ritonavir (400 or 600 mg twice daily) for approximately four weeks in HIV-infected patients, the values AUC saquinavir were at least 17 times higher in comparison with the values AUC, obtained in patients with saquinavir 600 mg three times a day without ritonavir.
Contraindicated simultaneously apply saquinavir, ritonavir and rifampicin in connection with the risk of developing severe hepatotoxic effects (which are manifested by increased levels of transaminases).
Glucocorticosteroids (GCS)
Systemic corticosteroid effects, including Cushing's syndrome and suppression of the function of the adrenal cortex, have been described with concurrent use of ritonavir with inhaled or intranasal forms of fluticasone propionate or budesonide.
Joint use of ritonavir and fluticasone, as well as other glucocorticosteroids, which are metabolized with the participation of isoenzyme CYP3A4, is not recommended unless the potential benefit of such therapy exceeds the risk of systemic corticosteroid effects, including Cushing's syndrome and suppression of adrenal cortex function. Consider the replacement of fluticasone propionate or budesonide, especially if long-term therapy is needed.
Inhibitors of phosphodiesterase-5 (PDE-5)
Avanafil: in a clinical study with simultaneous application of ritonavir at a dose of 600 mg every 12 hours in combination with avanafilom in a dose of 50 mg there was an increase in AUC and FROMmOh avanafil approximately 13 and 2.4 times, respectively. The simultaneous use of ritonavir and avanafil is contraindicated.
Sildenafil: use sildenafil for the treatment of erectile dysfunction should be done with caution, in reduced doses (25 mg every 48 hours) and more often monitor side effects.
With the simultaneous use of ritonavir and sildenafil, a significant increase in sildenafil concentrations is expected (an increase AUC 11 times), which can lead to an increased risk of side effects associated with the use of sildenafil, including hypotension, syncope, changes in vision and prolonged erections.
The use of sildenafil for the treatment of pulmonary arterial hypertension with simultaneous administration of ritonavir is contraindicated.
Tadalafil: for the treatment of erectile dysfunction tadalafil should be used with caution. Its dose should not exceed 10 mg once every 72 hours and be used under strict control of side effects.
When ritonavir and tadalafil are used concomitantly, in cases where the latter is used to treat pulmonary arterial hypertension, the dose of tadalafil should be selected in accordance with its instruction for use.
Vardenafil: Vardenafil should be used with caution. Its dose should not exceed 2.5 mg once every 72 hours and used under strict control of adverse events.
Sulfamethoxazole / trimethoprim
With simultaneous application of ritonavir in a dose of 500 mg every 12 hours and sulfamethoxazone / trimethoprim decreases AUC sulfamethoxazone by 20% and increase AUC trimethoprim by 20%. Changes in the dose of sulfamethoxazone / trimethoprim with simultaneous ritonavir therapy are not required.
Theophylline
With simultaneous application of ritonavir in a dose of 500 mg every 12 hours and theophylline there is a decrease AUC theophylline by 43%. You may need to increase the dose of theophylline.
Trazodone
With the simultaneous use of ritonavir and trazodone, an increase in trazodone concentrations can be observed. There were side effects such as nausea, dizziness, lowering blood pressure and fainting.Caution should be applied trazodone simultaneously with the inhibitor of isoenzyme CYP3A4, such as ritonavir, as well as consider reducing the dose of trazodone.
Antineoplastic agents (dasatinib, nilotinib, vincristine, vinblastine)
When used simultaneously with ritonavir, the serum concentrations of these drugs may increase, which may lead to an increase in the incidence of side effects.
Voriconazole
With simultaneous administration of ritonavir at a dose of 400 mg every 12 hours, the equilibrium values decrease AUC voriconazole averaged 82%; thus, the simultaneous administration of these drugs is contraindicated.
Warfarin
In a pharmacokinetic study, multiple dosing of ritonavir (400 mg twice daily) had a different effect on the pharmacokinetics of warfarin enantiomers. Changes in Values AUC S-warfarin were not statistically significant, but under the influence of ritonavir they underwent significant fluctuations. With simultaneous administration of ritonavir, a decrease AUC less active Renantiomer of warfarin on average by 33%.The effect of ritonavir associated with these changes on the anticoagulant effect of warfarin on the basis of these pharmacokinetic data is difficult to predict. At the beginning of simultaneous application of ritonavir and warfarin, frequent monitoring of INR (the international normalized relationship) is indicated.
Zidovudine
With simultaneous administration of ritonavir 300 mg every 6 hours and zidovudine at a dose of 200 mg every 8 hours, the values of CmOh and AUC zidovudine, respectively, by 27% and 25%. In this case, the effect on the pharmacokinetics of ritonavir was negligible or absent. Changes in the dose of zidovudine when used concomitantly with ritonavir are not required.
Inhibitors of HMG-CoA reductase
Metabolism of HMG-CoA reductase inhibitors simvastatin and lovastatin significantly depends on isoenzyme CYP3A4, thus, the combined use of ritonavir with simvastatin or lovastatin is contraindicated because of the increased risk of myopathy, including rhabdomyolysis. Care should also be taken to reduce doses while simultaneously using atorvastatin, which is metabolized to a lesser extent by the CYP3A4 isoenzyme.If the patient shows the use of HMG-CoA reductase inhibitors, should be used pravastatin or fluvastatin.
Antagonists of α1-adrenoceptor
Based on the results of the study of drug interaction with ketoconazole, another potent inhibitor of isozyme CYP3A4 and alfuzosin in the presence of ritonavir (600 mg, 2 times a day), one would expect a significant increase in the concentration of alfuzosin. therefore alfuzosin it is contraindicated to be used together with ritonavir.
HIV viral protease inhibitors
It is reported that the use of tipranavir in combination with ritonavir in a dose of 200 mg was accompanied by the development of hepatitis with clinical manifestations and hepatic decompensation with lethal outcomes in several cases. Particular caution should be exercised in patients with concomitant infection, chronic hepatitis B and C, since they are at increased risk of hepatotoxic effects of these drugs.
Resistance / Cross-resistance
The potential for cross-resistance of HIV to HIV protease inhibitors has not been fully explored.Thus, it remains unknown what effect ritonavir therapy may have on the activity of concomitantly or consistently applied HIV protease inhibitors.
Table 1. Changes in the values of AUC and Cmax while concomitant administration of ritonavir with other drugs
| A drug | Effects on ritonavir and a dose of ritonavir | n | AUC % (95% CI *) | FROMmOh % (95% CI) |
| Clarithromycin 500 mg every 12 hours 4 days | 200 mg every 8 hours 4 days | 22 | ↑12% (2, 23%) | ↑15% (2,28%) |
| Didanosine 200 mg every 12 hours 4 days | 600 mg every 12 hours 4 days | 12 | ↔ | ↔ |
| Flucanazole 400 mg on the first day, 200 mg per day for 4 days | 200 mg every 6 hours 4 days | 8 | ↑12% (5, 20%) | ↑15% (7,22%) |
| Fluoxetine 30 mg every 12 hours 8 days | 600 mg once | 16 | ↑19% (7, 34%) | ↔ |
| Rifampicin 600 mg or 300 mg per day for 10 days | 500 mg every 12 hours 20 days | 7,9* | ↓35% (7, 55%) | ↓25% (-5, 46%) |
| Zidovudine 200 mg every 8 hours 4 days | 300 mg every 6 hours 4 days | 10 | ↔ | ↔ |
↑ increase
↓ decrease
↔ lack of changes
* CI - confidence interval
Perhaps a significant (threefold or more) increase AUC when co-administered with ritonavir in the following drugs: alfentanil, fentanyl, lidocaine, erythromycin, carbamazepine, nefazodone, sertraline, itraconazole, ketoconazole, miconazole, loratadine, rifabutin, quinine, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil, tamoxifen, bromocriptine, atazanavir, darunavir, (phosph)amprenavir, indinavir, saquinavir, tipranavir, atorvastatin, ciclosporin, everolimus, tacrolimus, sirolimus (rapamycin), avanafil, sildenafil, shown for the treatment of erectile dysfunction, tadalafil, vardenafil, buspirone, dexamethasone, fluticasone, colchicine, bosentan, dasatinib, nilotinib.
Perhaps a moderate (1.5 to 3 times) increase AUC when co-administered with ritonavir in the following drugs: hydrocodone, oxycodone, propoxyphene, tramadol, disopyramide, mexiletine, clarithromycin, clonazepam, ethoxymidine, amitriptyline, clamipramine, desipramine, imipramine, maprotiline, nortriptyline, trimipramine, fluoxetine, paroxetine, trazodone, venlafaxine, dronabinol, ondansetron, metoprolol, penbutolol, pindolol, timolol, etoposide, paclitaxel, vinblastine, vincritin, maraviroc, rosuvastatin, chlorpromazine, haloperidol, perphenazine, risperidone, thioridazine, chlorazepate, diazepam, estazolam, flurazepam, zolpidem, prednisone, dexfenfluramine.
Perhaps a moderate (1.5 to 3 times) rise or fall AUC when co-administered with ritonavir in the following drugs: diclofenac, fluorobiprofen, ibuprofen, indomethacin, piroxicam, losartan, proguanil, lansoprazole, omeprazole, propranolol, cyclophosphamide, isophosphamide, glimepiride, glipizide, glyburide, tolbutamide,
There are no data on possible interactions with ritonavir for the following drugs: (LAAM), nabumethon, sulindac, tokainide, phenobarbital, doxepin, fluvoxamine, prochloropyrazine, promethazine, doxazosin, prazozin, terazosin, ethionamide, albendazole, chloroquine, metronidazole, Primarch, pyrimethamine, trimetrexate, betaxolol, daunorubicin, doxorubicin, metisergide, pentoxifylline, nevirapine, gemfibrozil, methylphenidate.
Possible reduction AUC when co-administered with ritonavir in the following drugs: codeine, hydromorphone, meperidine, morphine, ketoprofen, ketorolac, naproxen, theophylline, дивалпроекс, lamotrigine, phenytoin, bupropion, diphenoxylate, loperamide, metoclopramide, atovaquone, clofibrate, clozapine, lorazepam, oxazepam, propofol, temazepam, ethinyl estradiol.