Darunavir, used in combination with ritonavir, is an inhibitor of the isoenzymes CYP3A, CYP2D6 and P-glycoprotein. The simultaneous use of the PRESIST® / ritonavir combination and preparations that are metabolized predominantly by the CYP3A, CYP2D6 isoenzymes and carried by the P-glycoprotein may cause an increase in plasma concentrations of such drugs, which in turn may cause a prolongation or prolongation of the therapeutic effect, occurrence of side effects.
Recommendations for concurrent use with other antiretroviral drugs
Integrase inhibitors
Dolutegravir
The combination of PRESIST® / ritonavir (600/100 mg twice daily) did not have a clinically significant effect on the concentration of dolutegravir in plasma.Comparison of the results of studies with retrospective pharmacokinetic data showed that dolutegravir does not have a clinically significant effect on the pharmacokinetics of darunavir. With the simultaneous use of the PRESIST® / ritonavir and dolutegravir combination, dose adjustment is not required.
Elvitegravir
With the simultaneous use of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and elvitegravir, the dose of elvitegravir should be 150 mg once daily.
Pharmacokinetic data and recommendations for dosing when using other doses of darunavir, as well as when used with the combination of elvitegravir / cobicystate, are absent. Therefore, simultaneous use of the PRESIST® / ritonavir combination at doses other than 600/100 mg twice daily and elvitegravir is not recommended.
It is not recommended to use the combination of PRESIST® / ritonavir and elvitegravir in the presence of a co-bicystate simultaneously.
Raltegravir
Based on the results of several clinical studies, it is suggested that raltegravir can cause a slight decrease in the concentration of darunavir in blood plasma.At present, the effect of raltegravir on the concentration of darunavir in blood plasma does not seem clinically significant. It is not necessary to correct the dosage of PRESISTA® when combined with a low dose of ritonavir and raltegravir.
Nucleoside / nucleotide reverse transcriptase inhibitors
Didanosine
The combination of PRESIS® / ritonavir (600/100 mg twice daily) simultaneously with didanosine can be used without dose adjustment. Didanosine it is recommended to use on an empty stomach, it can be taken 1 hour before or 2 hours after the PRESIS® / ritonavir, which is taken with food.
Tenofovir
The results of the study of the interaction between tenofovir (tenofovir disoproxil fumarate 300 mg / day) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that the concentration of tenofovir in plasma increased by 22%. This change is not clinically significant. With the simultaneous use of tenofovir and darunavir, the renal excretion of both drugs did not change. Tenofovir had no significant effect on the concentration of darunavir in plasma. With the simultaneous use of the PRESISTA® / ritonavir combination and tenofovir, dose adjustment is not required.
Other nucleoside reverse transcriptase inhibitors
Other nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) are eliminated mainly by the kidneys, and therefore the probability of their interaction with the darunavir / ritonavir combination is negligible.
Non-nucleoside reverse transcriptase inhibitors
Delavirdine
The simultaneous use of the PRESIST® / ritonavir and delavirdine combination may increase the concentration of darunavir and delavirdine due to inhibition of the CYP3A isoenzyme. Suitable doses of the PRESIS® / ritonavir and delavirdine combination are not established. The simultaneous use of the PRESIST® / ritonavir and delavirdine combination is not recommended.
Etravirine
When studying the interaction of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and etravirine, a decrease in the concentration of etravirin by 37% was found and no significant changes in the concentration of darunavir were observed. Thus, the combination of PRESIS® / ritonavir can simultaneously be administered with 200 mg of etravirine 2 times a day without changing the dose.
Efavirenz
A study was made of the interaction between the darunavir / ritonavir combination (300 mg / 100 mg twice daily) and efavirenz (600 mg once daily).In the presence of efavirenz, the concentration of darunavir in plasma was decreased by 13%. On the other hand, plasma concentration of efavirenz increased by 21% when used concomitantly with the darunavir / ritonavir combination. This interaction is not clinically relevant, and therefore the combination of PRESIS® / ritonavir and efavirenz can be used simultaneously without correction of the doses of the drugs.
Nevirapine
The results of the study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and nevirapine (200 mg twice daily) showed that the plasma concentrations of darunavir did not depend on the presence of nevirapine. However, with simultaneous use with the darunavir / ritonavir combination, nevirapine plasma concentration increased by 27% (compared with the control). This interaction is considered clinically insignificant, and therefore the combination of darunavir / ritonavir and nevirapine can be used simultaneously without changing their doses.
Rilpivirine
The results of the study of the interaction between the PRESIST® / ritonavir combination (800 mg / 100 mg once daily) with rilpivirin (150 mg once daily) showed no clinically significant effect on the concentration of darunavir.
The concentration of rilpivirin increased by 130% when used concomitantly with the PRESIST® / ritonavir combination. This interaction is considered clinically insignificant, and therefore the combination of PRESIS® / ritonavir and rilpivirine can be used simultaneously without changing their doses.
Protease Inhibitors
Ritonavir
In general, the effect of improving the pharmacokinetics of darunavir ritonavir was manifested in the fact that the concentrations of darunavir in plasma increased approximately 14-fold after taking one dose of darunavir (600 mg) and 100 mg of ritonavir twice a day. Therefore, the drug PRESISTA® should be used in combination with a low dose of ritonavir to increase the bioavailability of darunavir.
The combination of lopinavir / ritonavir
The results of the study of the interaction between the darunavir / ritonavir combination (1200 mg / 100 mg twice daily) or 1200 mg of darunavir without ritonavir and the combination of lopinavir / ritonavir (400 mg / 100 mg twice daily or 533 mg / 133.3 mg twice per day) showed that in the presence of lopinavir / ritonavir, the concentration of darunavir in plasma decreased by 40%. It is not recommended to use the combination of lopinavir / ritonavir simultaneously with the PRESIS® / ritonavir.
Saquinavir
The study of the interaction of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily) showed that the concentration of darunavir in plasma decreased by 26% in the presence of saquinavir and ritonavir; on the other hand, the combination of darunavir / ritonavir did not affect the concentration of saquinavir in plasma. It is not recommended to apply saquinavir simultaneously with the drug PRESISE® regardless of the use of a small additional dose of ritonavir.
Atazanavir
The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and atazanavir (300 mg once daily) showed no significant change in the concentrations of darunavir and atazanavir in plasma when administered concomitantly. Atazanavir can be used concomitantly with the darunavir / ritonavir combination.
Indinavir
In a study of the interaction between darunavir / ritonavir (400 mg / 100 mg twice daily) and indinavir (800 mg twice daily), the concentration of darunavir in plasma increased by 24% in the presence of indinavir and ritonavir; In the presence of the darunavir / ritonavir combination, plasma concentrations of indinavir increased by 23%.When used in conjunction with the PRESISTA® / ritonavir combination, the dose of indinavir in patients who do not tolerate it can be reduced from 800 mg twice daily to 600 mg twice daily.
Other protease inhibitors
Until now, the interaction between the PRESIST® / ritonavir combination and protease inhibitors in addition to lopinavir, saquinavir, atazanavir and indinavir has not been studied, and therefore, protease inhibitors not listed here should not be used concomitantly with the darunavir / ritonavir combination.
CCR5 receptor antagonists
With the simultaneous use of the PRESIST® / ritonavir combination maraviroc should be administered at a dosage of 150 mg 2 times a day. In a study of the interaction between the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and maraviroc (150 mg twice daily), the concentration of maraviroc increased by 305%. The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.
Recommendations for simultaneous use with preparations of other classes
Drugs that reduce the acidity of gastric juice
Antacid preparations (aluminum / magnesium hydroxide, calcium carbonate)
No interaction between the PRESIS® / ritonavir combination and antacid preparations is expected. The combination of PRESIS® / ritonavir and antacid preparations can be applied simultaneously without dose adjustment.
H2-gistaminovyh receptors blockers (cimetidine, famotidine, nisatidine, ranitidine)
The simultaneous use of ranitidine (150 mg twice daily) and the PRESISTA® / ritonavir combination (400/100 mg twice daily) had no effect on the concentration of darunavir in plasma. Combination of PRESIS® / ritonavir and antagonists H2-receptors can be used simultaneously without dose adjustment.
Proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
The simultaneous use of omeprazole (20 mg per day) and the PRESISTA® / ritonavir combination (400/100 mg twice daily) had no effect on the concentration of darunavir in plasma. The combination of PRESIS® / ritonavir and proton pump inhibitors can be applied simultaneously without dose adjustment.
Antagonists of alpha-1-adrenergic receptors (alfuzosin)
The concentration of alfuzosin in plasma can be increased when used concomitantly with the PRESIST® / ritonavir combination.The simultaneous use of alfuzosin and the PRESIST® / ritonavir combination is contraindicated.
Antianginal agents (ranolazine)
The concentration of ranolazine in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination due to inhibition of CYP3A isoenzymes. The simultaneous use of ranolazine and the combination of PRESIS® / ritonavir is contraindicated.
Antiarrhythmic drugs (bepripid, disopyramide, dronedaron, mexiletine, system lidocaine, quinidine, amiodarone, flecainide, propafenone)
The combination of PRESIS® / ritonavir can increase serum concentrations of these antiarrhythmic agents. With the simultaneous use of this combination and listed antiarrhythmic agents, it is recommended that care be taken and, if possible, monitoring the concentrations of these agents in the plasma. Contraindicated simultaneous use of the PRESIST® / ritonavir combination with amiodarone, bepridil, dronedarone, quinidine and lidocaine in systemic administration.
Digoxin
In all studies on the interaction of combination PREZISTA® / ritonavir (600/100 mg 2 times a day) and a single dose of digoxin (0.4 mg) was shown to increase the final digoxin concentration in the plasma by 77%.It is recommended that a minimum dose of digoxin be initially prescribed and that its serum concentration be measured to obtain the desired clinical effect when used concomitantly with the PRESISTA / ritonavir combination.
Anticoagulants
Apixaban, dabigatran, rivaroxaban
With simultaneous use of the PRESISTA® / ritonavir combination and the anticoagulants listed above, the concentration of anticoagulant in the plasma may increase due to inhibition of the isoenzyme CYP3A or P-glycoprotein. The recommended dose of apixaban when used concomitantly with the PRESIST® / ritonavir combination is 2.5 mg 2 times a day. Combination PRESIS® / ritonavir and dabigatran should be used with caution and should not be used in patients with severe renal failure. It is not recommended to simultaneously use the PRESISTA® / ritonavir combination and rivaroxaban.
Warfarin
The combination of PRESIS® / ritonavir can affect the concentrations of warfarin in the plasma. With the simultaneous use of warfarin and this combination it is recommended to monitor the international normalized relationship.
Anticonvulsant drugs (phenobarbital, phenytoin and carbamazepine)
Phenobarbital and phenytoin are inducers of CYP450 enzymes. The combination of PRESIS® / ritonavir is not recommended in combination with these drugs, as this can cause a significant reduction in the concentration of darunavir in the plasma and, consequently, a decrease in its therapeutic effect.
The study of the interaction between the PRESIST® / ritonavir combination (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the concentration of darunavir does not change in this case, while the concentration of ritonavir decreases by 49%. The concentration of carbamazepine is increased by 45%. A dose change for the PRESIS® / ritonavir combination is not required. If simultaneous use of the PRESISTA® / ritonavir and carbamazepine combination is necessary, patients should be observed in connection with the potential for side effects of carbamazepine. Carbamazepine concentrations should be measured, and its doses should be adjusted in accordance with clinical manifestations. Thus, doses of carbamazepine can be reduced by 25-50% when combined with a PRESISTA / ritonavir combination.
Antihistamines
Astemizole, terfenadine
With the simultaneous use of these antihistamines with the PRESISTA® / ritonavir combination, the concentration of antihistamines in the plasma may increase. The simultaneous use of the PRESIST® / ritonavir combination with astemizole and terfenadine is contraindicated.
Anti-malarial drugs
When investigating the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and the combination of artemether / lumefantrine (80/480 mg, 6 doses taken at 0, 8, 24, 36, 48 and 60 hours) an increase in the concentration of lumefantrine by 2.75 times, while the concentration of darunavir did not change. The concentration of artemether and its active metabolite, dihydroartemisinin, decreased by 16% and 18%, respectively. The combination of PRESIST® and artemether / lumefantrine can be used without dose adjustment. However, due to the increased concentration of lumefantrine, this combination should be used with caution.
Antidepressants
Paroxetine and sertraline
The study of the interaction between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and a combination of PRESISE® / ritonavir (400 mg / 100 mg twice daily)that the concentration of darunavir in plasma did not depend on the presence of sertraline or paroxetine. On the other hand, in the presence of the PRESIST® / ritonavir combination, plasma concentrations of sertraline and paroxetine decreased by 49 and 39%, respectively. In cases where selective serotonin reuptake inhibitors must be used concomitantly with PRESISTA® and ritonavir, the dose of these inhibitors must be carefully selected based on the clinical evaluation of the antidepressant effect. In addition, in patients receiving a stable dose of sertraline or paroxetine, which are started to be treated with the PRESISTA® / ritonavir combination, it is necessary to carefully monitor the severity of the underlying effect of the antidepressant.
Amitriptyline, imipramine, nortriptyline, trazodone, desipramine
The combined use of PRESIST® / ritonavir with the above antidepressants can cause an increase in the antidepressant concentration in the plasma due to inhibition of the CYP2D6 and / or CYP3A4 isoenzymes. This can cause side effects such as nausea, dizziness, lowering blood pressure, fainting.If necessary, the combined use of these drugs and the PRESISTA / ritonavir combination is recommended to conduct clinical monitoring of the patient's condition, it may be necessary to adjust the dose of antidepressant.
Sedatives / hypnotics
Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldiem
The combined use of PRESIST® / ritonavir with these sedatives / hypnotics may increase their plasma concentrations due to the inhibition of CYP3A isoenzymes. When combined, clinical monitoring is recommended and the possibility of reducing the dose of a sedative / hypnotic drug should be considered. When combined with parenterally administered midazolam, careful clinical monitoring and immediate action should be taken in the event of respiratory depression or prolonged sedation. Consider the possibility of reducing the dose of parenterally administered midazolam, especially if more than one dose of midazolam is used. The use of PRESIS® / ritonavir with oral midazolam or triazolam is contraindicated.
Neuroleptics
Pimozide
With the simultaneous use of the PRESISTA® / ritonavir and pimozide combination, it is possible to increase the concentration of pimozide in the plasma by inhibiting the isoenzymes CYP3A and CYP2D6. The simultaneous use of pimozide and the combination of PRESIS® / ritonavir is contraindicated.
Sertindole
Simultaneous use of sertindole and PRESIST® / ritonavir combination is contraindicated.
Risperidone, thiorizadine
In the combined use of risperidone or thiorizadine with the PRESISTA® / ritonavir combination, their plasma concentrations may increase, resulting in a reduction in the dosage of risperidone and thiorizadine when combined.
Quetiapine
When quetiapine is combined with the PRESISTA® / ritonavir combination, the concentration of quetiapine in plasma can be increased by inhibiting the CYP3A isoenzyme with PRESISTA®. The simultaneous use of the PRESIST® / ritonavir and quetiapine combination is contraindicated, as this may lead to an increase in toxicity associated with quetiapine. An increase in the concentration of quetiapine in the blood plasma can lead to coma.
Colchicine
When colchicine is used together with the PRESISTA® / ritonavir combination, colchicine concentration in the plasma may increase. The following scheme for changing the dose of colchicine is recommended.For the treatment of gout exacerbations for patients receiving the PRESISTA® / ritonavir combination, the recommended dose of colchicine is 0.6 mg, followed by 0.3 mg after 1 hour. The course of treatment should be repeated no earlier than 3 days later. For the prevention of exacerbations for patients receiving the PRESISTA® / ritonavir combination, the recommended dose of colchicine is 0.3 mg every other day or every other day. For the treatment of familial Mediterranean fever for patients receiving the PREZIST® / ritonavir combination, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg twice daily). Patients with reduced renal or hepatic function colchicine when combined with PRESIS® / ritonavir is contraindicated.
Blocks of "slow" calcium channels (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)
Plasma concentrations of "slow" calcium channel blockers may increase with simultaneous use with the PRESISTA® / ritonavir combination by inhibiting the CYP3A and / or CYP2D6 isoenzymes. In such cases it is necessary to closely monitor the condition of patients.
Clarithromycin
The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and clarithromycin (500 mg twice daily) showed that the concentration of clarithromycin in the plasma increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function, it is recommended to reduce the dose of clarithromycin.
Dexamethasone (for systemic use)
Dexamethasone when injected into the bloodstream induces the CYP3A isoenzyme in the liver, which leads to a decrease in the plasma concentration of darunavir. This can lead to a decrease in its therapeutic effect. It is advisable to use caution when using concomitant dexamethasone and darunavir.
Boszentan
With the simultaneous use of bosentan and the PRESISTA® / ritonavir combination, the concentration of bosentan in plasma may increase. Patients who receive the PRESIS® / ritonavir combination for a minimum of 10 days are advised to take the initial dose of bosentan 62.5 mg every other day or every other day, depending on individual tolerability. For patients receiving bosentan and initiating therapy with the PRESIS® / ritonavir combination, it is recommended to cancel bosentan at least 36 hours prior to the PRESIS® / ritonavir therapy. At least 10 days after initiation of PRESISTA® / ritonavir therapy, bosentan should be taken at a dosage of 62.5 mg every other day or every other day, depending on individual tolerability.
Fluticasone, budesonide, prednisone
With simultaneous use of systemic or inhaled / nasal budesonide, fluticasone or prednisone and PRESISTA® / ritonavir combination, plasma glucocorticosteroid concentrations may increase.
Simultaneous use may increase the risk of systemic effects of corticosteroid drugs, including Cushing's syndrome and suppression of adrenal function. If both prednisone and the PRESISTA® / ritonavir combination are used concomitantly, clinical monitoring should be performed. Alternative treatment options should be considered, especially for long-term use.
Antiviral drugs of direct action
NS3-4A inhibitors of hepatitis C protease
Boceprevir
In a study on the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and bocepreviram (800 mg 3 times daily), the concentration of darunavir decreased by 44%, and the concentration of bocetrevir decreased by 32%.Therefore, it is not recommended to use the PRESIS® / ritonavir combination with bocetrevir.
Telaprevir
In studies of the interaction between the PRESISTA® / ritonavir combination (600 mg / 100 mg twice daily) with telaprevir (750 mg every 8 hours), the concentration of darunavir decreased by 40%, and the concentration of bodyprevir decreased by 35%. The simultaneous administration of the PRESIS® / ritonavir combination by telaprevir is not recommended.
Symeprevir
With the simultaneous use of simeprevir and PRESISTA® / ritonavir (800/100 mg / day), concentrations of darunavir and simeprevir in plasma were increased by inhibition of CYP3A isoenzymes. In clinical studies of the interaction of the PRESISTA® / ritonavir and simeprevir combination, the concentration of the simeprevir in the plasma increased 2.59 times, the concentration of darunavir increased 1.18 times. Not recommended at the same time simeprevir and a combination of PRESIS® / ritonavir.
Herbal preparations
Preparations containing St. John's wort extract
Extract of St. John's wort reduces the concentration of darunavir and ritonavir in blood plasma (induction of liver enzymes).The combination of PRESIS® / ritonavir should not be used in conjunction with preparations containing St. John's wort extract. In case the patient began taking medications containing St. John's wort extract, stop them and, if possible, check the virus titres. The concentration of darunavir (as well as the concentration of ritonavir) may increase after discontinuation of drugs containing St. John's wort extract. This effect can persist for two weeks after the withdrawal of preparations containing St. John's wort extract.
Inhibitors of HMG-CoA reductase (atorvastatin, lovastatin, Pitavastatin, pravastatin, rosuvastatin, simvastatin)
In the metabolism of statins, such as simvastatin and lovastatin, the CYP3A isoenzymes play an important role, so their plasma concentrations can increase significantly when used concomitantly with the PRESISTA / ritonavir combination. Elevated concentrations of statins can cause myopathy, including rhabdomyolysis. The use of the PRESIST® / ritonavir combination with lovastatin or simvastatin is contraindicated.
The study of the interaction between atorvastatin (10 mg once daily) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that in this situation the concentration of atorvastatin in plasma was only 15% lower than with monotherapy with atorvastatin ( 40 mg once daily). If it is necessary to simultaneously use atorvastatin and a combination of darunavir / ritonavir, it is recommended to start with a dose of atorvastatin 10 mg once daily. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy.
The combination of darunavir / ritonavir (600 mg / 100 mg twice daily) increased the concentration of pravastatin in plasma after taking one dose of this drug (40 mg) by about 80%, but only in a part of the patients. If it is necessary to use pravastatin together with PRESISTA® / ritonavir combination, it is recommended to start taking pravastatin from the lowest possible doses and increase the dose until the clinical effect appears, controlling the manifestation of side effects of the drug.
Investigation of the interaction between the PRESIS® / ritonavir combination (600 mg / 100 mg) with rosuvastatin (10 mg) revealed an increase in the concentration of rosuvastatin.If it is necessary to simultaneously use rosuvastatin and PRESISTA® / ritonavir combination, it is recommended to start with the lowest dose of rosuvastatin, gradually increasing the dose to obtain a clinical effect, constantly monitoring the safety of therapy. Investigation of the interaction between the PRESIST® / ritonavir combination (800/100 mg / day) and Pitavastatin (4 mg / day) revealed a decrease in plasma pentavastatin concentration, which is not considered clinically significant. The combination of PRESIS® / ritonavir and Pitavastatin can be used simultaneously without dose adjustment.
Inhalation beta-adrenomimetics (salmeterol)
Simultaneous application of salmeterol and PRESISTA® / ritonavir combination is not recommended, because may increase the risk of side effects of salmeterol from the cardiovascular system, incl. lengthening of the QT interval, palpitations and sinus tachycardia.
Immunosuppressants (ciclosporin, tacrolimus, sirolimus)
Concentrations in the plasma of cyclosporine, tacrolimus and sirolimus may increase when these drugs are used simultaneously with the PRESISTA / ritonavir combination.In these situations, it is recommended to monitor the concentration of immunosuppressive agents in plasma. Simultaneous use of the PRESIS® / ritonavir and everolimus combination is not recommended.
Ketoconazole, itraconazole, posaconazole, clotrimazole and voriconazole
Ketoconazole, itraconazole, posaconazole, clotrimazole and voriconazole are strong inhibitors of the isoenzyme CYP3A, and some of them are also its substrates. Systemic use of these antifungal drugs concomitantly with the combination of PRESISTA® / ritonavir can lead to an increase in darunavir plasma concentrations. On the other hand, this combination can increase plasma concentrations of some of these antifungal agents. This was confirmed by a study of the interaction between ketoconazole (200 mg twice daily) and a combination of darunavir / ritonavir (400 mg / 100 mg twice daily) in which concentrations of ketoconazole and darunavir increased 212% and 42%, respectively. If a darunavir / ritonavir combination is required simultaneously with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg.With the simultaneous use of the PRESISTA® / ritonavir combination and posaconazole, clinical monitoring of the patient's condition is recommended. Concentrations of voriconazole in plasma may decrease when combined with darunavir / ritonavir. Voriconazole should not be used concomitantly with darunavir / ritonavir, concurrent use is only possible if the potential benefits of using voriconazole exceed the potential risk.
Care should be taken with co-administration of clotrimazole and the combination of darunavir / ritonavir, and it is also recommended that the patient be constantly monitored.
Beta-blockers (carvedilol, metoprolol, timolol)
The combined use of beta-blockers and the PRESISTA® / ritonavir combination may lead to an increase in the concentration of beta-blockers due to inhibition of the CYP2D6 isoenzyme. If both of these drugs and the PRESISTA / ritonavir combination are used concomitantly, care should be taken and clinical monitoring carefully conducted, and a dose reduction of beta-blockers may also be required.
Methadone
In a study of the effect of the PRESIST® / ritonavir combination (600/100 mg twice daily) on stable maintenance therapy with methadone, a 16% decrease in the concentration of R-methadone in plasma was shown. Based on pharmacokinetic and clinical results, correction of the dose of methadone during the initiation of PRESISTA® / ritonavir therapy is not required. However, it is recommended to conduct clinical monitoring, as in some patients maintenance therapy requires correction.
Buprenorphine / naloxone
The results of the study of the interaction between the PRESISTA® / ritonavir and buprenorphine / naloxone combination demonstrated the lack of influence of the PRESISTA® / ritonavir combination on the concentration of buprenorphine when combined.
The concentration of the active metabolite of buprenorphine - norbuprenorphine increased by 46%. Correction of the dose of buprenorphine was not required. When co-administration of the PRESIST® / ritonavir and buprenorphine combination, careful clinical monitoring is recommended.
Estrogen-containing oral contraceptives
The results of the study on the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and ethinyl estradiol and norethisterone indicate that,that the constant plasma concentration of ethinyl estradiol and norethisterone is reduced by 44% and 14%, respectively. Therefore, it is recommended to use alternative non-hormonal methods of contraception.
Inhibitors of phosphodiesterase type 5 (PDE-5)
In the treatment of erectile dysfunction (avanafil, sildenafil, tadalafil, vardenafil)
One study examined sildenafil concentrations after taking one dose of this drug (100 mg), and after taking 25 mg of sildenafil concomitantly with the darunavir / ritonavir combination (400 mg / 100 mg twice daily). The concentrations of sildenafil were similar in both situations. Caution should be exercised while using PDE-5 inhibitors for the treatment of erectile dysfunction and the PRESISTA / ritonavir combination. If it is necessary to use PRESIST® and ritonavir simultaneously with sildenafil, vardenafil or tadalafil, a single dose of sildenafil should not exceed 25 mg within 48 hours, a single dose of vardenafil should not be more than 2.5 mg within 72 hours, and a single dose of tadalafil should not exceed 10 mg for 72 hours. The simultaneous use of the PRESIS® / ritonavir and avanafil combination is not recommended.
In the treatment of pulmonary arterial hypertension (sildenafil, tadalafil)
A safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension with concomitant use with the PRESIST® / ritonavir combination is not established. There is an increased risk of side effects of sildenafil (including visual impairment, arterial hypotension, prolonged erection and fainting). Thus, the simultaneous use of the PRESIST® / ritonavir and sildenafil combination in the treatment of pulmonary arterial hypertension is contraindicated. For the treatment of pulmonary arterial hypertension, tadalafil, when used concomitantly with the PRESISTA / ritonavir combination, requires a change in the dose of tadalafil. For patients receiving the PRESISTA® / ritonavir combination for at least one week, the initial dose of tadalafil should be 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerability. For patients receiving tadalafil and initiating therapy with the PRESIS® / ritonavir combination, you should cancel tadalafil at least 24 hours before the start of therapy with the PRESISTA® / ritonavir combination and simultaneous use of tadalafil should be avoided during the initiation of therapy with the PRESISTA® / ritonavir combination.1 week after the start of therapy with the PRESISTA® / ritonavir combination, tadalafil should be resumed at a dose of 20 mg once daily with a possible increase to 40 mg once daily on the basis of individual tolerability.
Anti-TB drugs
Rifabutin
Rifabutin is a substrate of CYP450 enzymes. In the study of the interaction of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and rifabutin (150 mg every other day), an increase in the concentration of darunavir by 57% was observed. Based on the safety profile of the PRESISTA® / ritonavir combination, increasing the concentration of darunavir in the presence of rifabutin does not require dose adjustment for PRESIST® / ritonavir. Interaction studies showed comparable concentrations with 300 mg rifabutin once daily and 150 mg every other day in combination with PRESISTA® / ritonavir (600/100 mg twice daily), as well as an increase in the concentration of the active metabolite 25-O-deacetyltrifabutin. When using this combination, patients need to reduce the dose of rifabutin by 75% of the usual dose of 300 mg per day (eg, 150 mg every other day) and increased control of the side effects of rifabutin.
Rifampicin and rifapentin
Rifampicin and rifapentin are inducers of CYP3A isoenzymes and cause a significant decrease in darunavir concentrations, which may cause a loss of the therapeutic effect of PRESIST®. In attempts to compensate for this decrease in concentrations by increasing the dose of other protease inhibitors taken with a low dose of ritonavir, liver reactions (increased activity of liver enzymes) were observed. The combined use of rifampicin and PRESISTA® / ritonavir is contraindicated. The combined use of rifapentin and PRESISTA® / ritonavir combination is not recommended.
Antineoplastic agents (dasatinib, everolimus, nilotinib, vinblastine, vincristine)
With the simultaneous use of the PRESIST® / ritonavir combination and antitumor drugs, an increase in plasma concentrations in the plasma is expected due to inhibition of CYP3A isoenzymes, which can cause unwanted reactions, usually associated with the administration of these drugs. It is advisable to use caution when using the PRESIST® / ritonavir combination and antineoplastic agents simultaneously.It is not recommended simultaneous use of everolimus and PRESIST® / ritonavir combination.
Ergot alkaloids (ergotamine, ergometrine, dihydroergotamine, methylergomethrin)
The concentration of ergot alkaloids in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination. The simultaneous use of ergot alkaloids and the combination of PRESIS® / ritonavir is contraindicated.
Cisapride
The concentration of cisapride in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination. Simultaneous use of cisapride and PRESIS® / ritonavir combination is contraindicated.