Darunavir
When ATH:
J05AE10
Pharmacological action
Viricide, HIV protease inhibitor 1 type ( HIV -1). The drug selectively inhibits the cleavage of Gag polyproteins – Pol HIV infected infected cells, preventing the formation of high-grade viral particles. Darunavir binds strongly with HIV protease -1 (KD 4.5 x 10-12 M). Darunavir resistant k mutatsiyam, inducing resistance to protease inhibitors. Darunavir does not inhibit any of the 13 studied human cellular proteases.
Pharmacokinetics
The pharmacokinetic properties of darunavir, used in combination with ritonavir, We studied in healthy volunteers and in HIV-infected patients.
Absorption
Once inside darunavir is rapidly absorbed from the gastrointestinal tract. Darunavir Cmax in plasma in the presence of low doses of ritonavir is reached in 2.5-4.0 no. The absolute bioavailability of darunavir when administered in a single dose 800 mg was approximately 37% and increased to approximately 82% in the presence of ritonavir (100 mg 2 times / day). Overall pharmacokinetic effect of ritonavir consisted approximately 14-fold increase in the plasma concentration of darunavir after a single oral administration 600 mg of darunavir in combination with ritonavir (100 mg 2 times / day).
When fasting the relative bioavailability of darunavir in the presence of low dose ritonavir was on 30% below, than when during a meal.
Hence, darunavir tablets should be taken with ritonavir during meals. The nature of food does not affect the concentration of darunavir plasma. Darunavir plasma concentrations were higher in patients, HIV-1, than in healthy persons. This difference can be explained by higher concentrations of α1-acid glycoprotein in patients, HIV-1. As a result, large amounts of darunavir bind to α1-acid glycoprotein and plasma, thereby, increases in the plasma concentration of darunavir.
Distribution
Darunavir binding to plasma proteins (mainly to α1-acid glycoprotein) is about 95%.
Metabolism
Darunavir is extensively metabolized in the liver by the cytochrome P450 isoenzymes system, almost exclusively CYP3A4. Ritonavir inhibits CYP3A isoenzyme in the liver and, thereby, significantly increases the concentration of darunavir plasma. In in vitro experiments on human liver microsomes was shown, that darunavir primarily undergoes oxidative metabolism.
Research, in which healthy volunteers received 14C-darunavir, found, that most of the radioactivity in plasma after single administration 400 mg and darunavir 100 mg ritonavir accounted for the unmodified darunavir. A person identified at least 3 okislitelynыh metabolites darunavir; whose activity against wild-type HIV was less than 1/10 the activity of darunavir.
Deduction
After receiving a 14C dose of darunavir 400 mg ritonavir dose 100 about mg 79.5% and 13.9% radioactivity detected in the feces and urine, respectively,. The share unchanged darunavir accounted for approximately 41.2% and 7.7% radioactivity in feces and urine, respectively,. The final T1 / 2 of darunavir was approximately 15 hours at his reception in combination with ritonavir. The clearance of darunavir after / in a dose 150 mg was 32.8 l / h without ritonavir and 5.91 l / h in the presence of low doses of ritonavir.
Pharmacokinetics in special clinical situations
Pharmacokinetic studies of darunavir in combination with ritonavir in children has not yet been completed, and so currently available data are insufficient to recommend a particular dose. Population pharmacokinetic analysis in HIV infected patients showed no significant differences in the pharmacokinetic parameters of darunavir in the age group 18-75 years. This analysis included 12 HIV-infected patients aged 65 and older. Population pharmacokinetic analysis revealed slightly higher (16.8%) concentration of darunavir in HIV-infected women, than HIV-positive men. This difference is not clinically significant. Results of studies using 14C-darunavir with ritonavir showed, that about 7.7% the administered dose of darunavir is excreted with urine in unchanged form.
In patients with renal impairment the pharmacokinetics of darunavir has not studied, but a population pharmacokinetic analysis showed no significant changes in pharmacokinetic parameters of darunavir in patients with moderate to severe renal impairment (serum creatinine clearance 30-60 ml / min, n = 20). Darunavir is primarily metabolized and eliminated by the liver. Studies in patients with impaired liver function have not been conducted.
Testimony
Treatment of HIV infection in adults, previously treated with anti-retroviral drugs (in the complex therapy).
Dosage regimen
The drug is taken orally. The drug darunavir should always be used in combination with ritonavir at a dose of 100 mg as a means of, improves its pharmacokinetic properties, as well as in combination with other antiretroviral drugs.
For adults, the recommended dose of darunavir 600 mg 2 times / day in combination with ritonavir dose 100 mg 2 times / day; combination taken with food. The type of food does not influence the absorption of darunavir. Ritonavir (100 mg 2 times / day) used to optimize the pharmacokinetics of darunavir.
Unlikely, that a further increase in the dose of darunavir or ritonavir can cause additional gain clinically significant antiviral activity. There is currently no data on the use of the combination of darunavir / ritonavir in patients with impaired hepatic function, therefore, specific recommendations for the dosage regimen for this category of patients is not defined.
In patients with impaired renal function dose adjustment combination darunavir / ritonavir is not required.
Side effect
The frequency of certain side effects: Often (>10%), often (>1%, <10%), sometimes (> 0.1% and <1%). In the calculation took into account the frequency of side effects of at least moderate severity (2 degrees and more), who had the opportunity causal relationship with the treatment combination of darunavir / ritonavir.
Metabolism: often - hypertriglyceridemia; sometimes – anorexia, hypercholesterolemia, hyperlipidemia, diabetes, decreased appetite, obesity, the redistribution of body fat, giponatriemiya, polydipsia. Combination antiretroviral therapy may also cause insulin resistance, hyperglycemia and hyperlactatemia. Combination therapy using aitiretrovirusnaya protease inhibitors of HIV-infected patients may be accompanied by the redistribution of body fat (lipodystrophy), which manifests the loss of peripheral and facial subcutaneous fat, increase in the number of intra-abdominal and visceral fat, breast hypertrophy and accumulation of fat in the back of the neck.
From the central and peripheral nervous system: often - headache; sometimes – confusion, disorientation, irritability, emotional instability, nightmares, alarm, perifericheskaya neuropathy, gipesteziya, memory impairment, paraesthesia, drowsiness, tranzitornaya ishemicheskaya attack.
From the digestive system: often – diarrhea, vomiting, nausea, abdominal pain, constipation; sometimes – flatulence, abdominal distention, dry mouth, dyspepsia.
On the part of the organ of hearing: sometimes - dizziness.
Cardio-vascular system: myocardial infarction, tachycardia, arterial hypertension.
The respiratory system: sometimes – breathlessness, cough, Ikotech.
On the part of the musculoskeletal system: sometimes – arthralgia, pain in the limbs, myalgia, osteopenia, osteoporosis. Patients, receiving protease inhibitors, particularly in combination with a nonnucleoside reverse transcriptase inhibitors, can increase the level of creatine kinase, myositis and rarely occur – raʙdomioliz.
From the urinary system: sometimes – acute renal failure, nephrolithiasis, polyuria.
Reproductive system: sometimes - gynecomastia. Dermatological reactions: sometimes – lipoatrophy, night sweat, eczema, alopecia, hyperhidrosis, maculopapular rash. Allergic reactions: sometimes – atopic dermatitis, toksikodermiya, drug dermatitis; in a few cases – erythema multiforme, Stevens-Johnson syndrome.
From the laboratory parameters: side effects 3 and 4 severity of the patients, was first treated with a combination of darunavir / ritonavir – increase in TG (8.6%), amilazы (6.6%), total cholesterol (4.9%), GGT (3.8%), increase in APTT (3.6%), increase in lipase (3.5%), GOLD (2.4%), ACT (2.2%) and reducing the number of leukocytes (6.4%), the percentage of neutrophils (4.7%), total absolute neutrophil count (4.2%) and the number of lymphocytes (3.8%). Other disorders in laboratory parameters were observed in less than 2% patients. Other: sometimes - folliculitis, asthenia, fever, fatigue, chills, hyperthermia, peripheral edema.
In HIV-infected patients with severe immune deficiency during the initial combination antiretroviral therapy may experience an inflammatory reaction to asymptomatic or residual opportunistic infections. HIV infected patients co-infected with hepatitis B and / or hepatitis C virus.
In this group of patients treated with a combination darunavir / ritonavir is not accompanied by a higher frequency of adverse events and changes in laboratory parameters, compared to HIV-infected patients without infection with hepatitis B virus and / or hepatitis C..
Pharmacokinetics darunavir and ritonavir at poliinfitsirovannыh patsientov bыla similar takovoy in patsientov with monoinfektsiey Vitsi. Patients with HIV infection is recommended routinely periodically tested for the presence of infection with hepatitis viruses.
Contraindications
Simultaneous treatment with drugs, clearance which is largely determined by CYP3A4, and increasing concentration in plasma is associated with the occurrence of serious and / or life-threatening side effects (therapeutic index) – with astemizole, terfenadine, midazolamom, triazolamom, cizapridom, pimozidom, preparations, containing ergot alkaloids (ergotamin, digidroergotamin, ergonovine and metilergonovin);
Children and teens under 18 years;
Hypersensitivity to darunavir and other ingredients.
To apply caution in patients with impaired hepatic function, if you are allergic to sulfonamides.
Pregnancy and lactation
There are no adequate and well-controlled studies safety of klininicheskih darunavir during pregnancy was conducted. The combination of drugs darunavir / ritonavir can be administered to pregnant women only if, when the expected benefit of therapy for the mother outweighs the potential risk to the fetus.
Unknown, whether darunavir is allocated with breast milk in humans. Considering the possibility of HIV transmission through breast milk, and the risk of serious side effects in infants, associated with exposure to darunavir, HIV-infected women, receiving the drug darunavir, We should refrain from breast-feeding. In experimental animal studies have not revealed the presence of toxic activity of darunavir or negative impact on the reproductive function and fertilnosg. Studies in rats have shown, that darunavir is excreted in breast milk.
Application for violations of liver function
There is currently no data on the use of the combination of darunavir / ritonavir in patients with impaired hepatic function, therefore, specific recommendations for the dosage regimen for this category of patients is not defined. This combination should be used with caution.
Application for violations of renal function
In patients with impaired renal function dose adjustment combination darunavir / ritonavir is not required.
Cautions
Patients should be informed about, that modern antiretroviral drugs do not cure HIV infection or prevent the transmission of HIV. Patients should clarify the need for compliance with the relevant precautionary measures. Currently available data are insufficient to recommend a dose of darunavir / ritonavir adult patients, who have not previously received antiretroviral therapy, and children.
Information about the treatment of a combination of
Darunavir / ritonavir patsientov in vozraste 65 and older very limited, must be used in the treatment of such patients the drug darunavir, because they have more frequent liver dysfunction and they are more likely to have comorbidities or receiving concomitant therapy. The absolute bioavailability after single dose 600 mg darunavir was approximately 37% and increased to approximately 82% after administration of darunavir in combination with 100 mg ritonavir 2 times / day. Summary effect of improving the pharmacokinetic characteristics darunavir ritonavir expressed approximately 14-fold increase in the plasma concentration of darunavir after a single dose of the drug (600 mg) in combination with 100 mg ritonavir 2 times / day.
Thus, drug darunavir should be taken only in conjunction with 100 mg ritonavir to optimize pharmacokinetic. Increasing the indicated dose of ritonavir does not lead to a significant increase in the plasma concentration of darunavir, and, therefore, dose ritonavir is not recommended to increase. Darunavir tablets contain yellow dye “sunset” (E110) and therefore may cause allergic reactions. Darunavir contains a sulfonamide group.
According to the summary clinical data, while taking darunavir were recorded severe cases of rash, including erythema multiforme and Stevens-Johnson syndrome, in some cases, fever and marked rise in liver transaminases.
If you experience severe rash, receiving darunavir must stop. Patients with liver disease darunavir and ritonavir are metabolised and eliminated primarily by the liver, therefore, patients with impaired liver function may increase concentrations of these drugs in the plasma. There is currently no data on the use of the combination of darunavir / ritonavir in patients with impaired hepatic function, therefore it is not possible to formulate concrete recommendations on doses.
In patients with impaired hepatic function a combination of darunavir / ritonavir should be used with caution. Patients with liver disease, including chronic active hepatitis, during combination antiretroviral therapy may increase the frequency of liver dysfunction, and therefore it is necessary to monitor the biochemical parameters in accordance with standard practice. In identifying these patients signs of worsening liver function treated with a combination darunavir / ritonavir should suspend or cancel.
Patients with kidney disease Kidneys play a minor role in the clearance of darunavir, therefore, patients with kidney disease almost total clearance of darunavir is not reduced. Darunavir and ritonavir are highly plasma protein binding, therefore hemodialysis or peritoneal dialysis does not play a significant role in the removal of these drugs from the body. Hemophiliacs have been reported increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia A and B, treated with protease inhibitors.
Some of these patients had received Factor VIII. More than half of the reported cases of treatment with protease inhibitors was continued without interruption or resumed after a pause for a while. It was suggested a causal relationship between protease inhibitor therapy and increased bleeding in patients with hemophilia, However, the mechanism of such a connection is not established. Hemophiliacs, poluchayushtih kombinatsiyu darunavir / ritonavir, should be informed of the possibility of increased bleeding. Giperglikemiâ
Patients, receiving antiretroviral therapy, including protease inhibitors, describe new cases of diabetes, Hyperglycemia or worsening of existing diabetes. Some of these patients had severe hyperglycemia and, in some cases accompanied by ketoacidosis. Many patients had comorbidities, some of which required treatment with, contributing to the development of diabetes or hyperglycemia.
Fat redistribution and metabolic disorders Combination antiretroviral therapy may cause HIV-infected patients, fat redistribution (lipodystrophy). There is currently no data on the long-term consequences of this phenomenon, and its mechanism is not clear in many respects. A hypothesis about the connection between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. Increased risk of lipodystrophy associated with such factors, as the old age, as well as with long-term treatment with antiretroviral drugs and the accompanying metabolic disorders.
In clinical surveys of HIV-infected patients, antiretrovirals, you must pay attention to the physical signs of fat redistribution. It is recommended to determine the content of lipids and fasting blood glucose. Lipid metabolism disorder should be treated with appropriate drugs.
Immune reactivation syndrome In HIV-infected patients with severe immune deficiency at the start of combination antiretroviral therapy may appear the inflammatory response of the body to asymptomatic or residual opportunistic infections, which causes serious clinical complications or worsening symptoms. Typically, such reactions occur in the first weeks or months of combination antiretroviral therapy. As examples of CMV retinitis, generalized and / or local mycobacterial infections and pneumonia, caused by Pneumocystis carinii. It is necessary to determine the severity of any symptoms of inflammation and conduct appropriate therapy.
Overdose
Information on acute overdose while taking the drug darunavir in combination with ritonavir in humans is limited. Healthy volunteers took up once 3200 mg of darunavir in solution and to 1600 mg tablets darunavir in combination with ritonavir, wherein the side effects observed. Treatment: spetsificheskiy antidote unknown.
In case of overdose should be general supportive therapy with monitoring of vital signs. To launch the drug nevsosavsheysya shown gastric lavage or enema. It can be used activated carbon. Darunavir largely bound to plasma proteins, therefore it is not removed in significant quantities.
Drug Interactions
Darunavir and ritonavir are inhibitors of CYP3A4. The simultaneous use of a combination of darunavir / ritonavir and drugs, are metabolized by CYP3A4 isoenzyme primarily, It can cause an increase in the concentrations of these drugs in the plasma, what, in turn, It may be the cause of a stronger or more durable therapeutic effect, and side effects. The combination of darunavir / ritonavir should not be administered concurrently with drugs, clearance which is largely determined by CYP3A4 isoenzyme and elevated concentrations in plasma which can cause serious and / or life-threatening side effects (low therapeutic index).
These drugs include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide and ergot alkaloids (eg, ergotamin, digidroergotamin, ergonovine and metilergonovin). Concomitant use with other antiretroviral agents Nucleoside Reverse Transcriptase Inhibitors Didanosine Didanosine is recommended to use an empty stomach, and so it can be taken as 1 hours before or after 2 h then take a combination darunavir / ritonavir, which is taken with food.
Tenofovir
The study of interaction between tenofovir (tenofovir disoproxil fumarate – 300 mg / day) kombinatsiey and darunavir / ritonavir (300 mg / 100 mg 2 times / day) shown, tenofovir concentration in plasma increased 22%. This change is not clinically significant.
With simultaneous use of tenofovir and darunavir renal excretion of both drugs did not change. Tenofovir did not have a clinically meaningful effect on the plasma concentration of darunavir.
With simultaneous use of a combination of darunavir / ritonavir and tenofovir dose adjustment is not required. Other nucleoside reverse transcriptase inhibitors (zidovudine, zalьcitabin, эmtricitabin, stavudine, lamivudine and abacavir) Report mostly kidneys, therefore, the probability of their interaction with a combination of darunavir / ritonavir is negligible.
Non-nucleoside reverse transcriptase inhibitors
Efavirenz
It has been studied the interaction between the combination of darunavir / ritonavir (300 mg / 100 mg 2 times / day) and efavirezom (600 mg 1 time / day). In the presence of zfavirenza observed reduction in the concentration of darunavir in the plasma 13%.
On the other hand, efavirenz concentration in the blood plasma increased 21% when applied simultaneously with the combination of darunavir / ritonavir. This interaction is not clinically significant, therefore darunavir / ritonavir and efavirenz can be used simultaneously without correction doses of drugs.
Nevirapine
The results of studies of the interaction between the combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) and nevirapine (200 mg 2 times / day) shown, that the plasma concentration of darunavir not dependent on the presence of nevirapine.
At the same time, while the use of a combination of darupavir / ritonavir concentrations of nevirapine in plasma increased 27% (compared with the control). This interaction is considered clinically insignificant, so the combination of darunavir / ritonavir and nevirapine can be used simultaneously without changing their doses.
Protease inhibitors
Ritonavir
In general, the effect of optimizing the pharmacokinetics of darunavir with ritonavir showed in that, darunavir concentrations in plasma increased about 14 time after a single dose of darunavir (600 mg) and 100 mg ritonavir 2 times / day.
Hence, darunavir drug must be used in combination with 100 mg of ritonavir to improve the pharmacokinetics of darunavir characteristics. Combination lopinavir / ritonavir Rezulytatы issledovaniya interactions between kombinatsiey darunavir / ritonavir (300 mg / 100 mg 2 times / day) kombinatsiey and lopinavir / ritonavir (400 mg / 100 mg 2 times / day) shown, Chto in prisutstvii combination lopinavir / ritonavir (with or without the use of additional doses of ritonavir 100 mg) darunavir plasma concentrations increased 53%.
In the presence of darunavir concentrations of lopinavir plasma decreased by 19%, and in the presence of a combination of darunavir / ritonavir increased by 37%. It is not recommended to use a combination of lopinavir / ritonavir in conjunction with darunavir regardless of the little extra dose of ritonavir.
Saquinavir
Investigation of the interaction of darunavir (400 mg 2 times / day), saquinavir (1000 mg 2 times / day) and ritonavir (100 mg 2 times / day) found, that the concentration of darunavir in the plasma increased 26% in the presence of saquinavir and ritonavir; on the other hand, combination darunavir / ritonavir not affect the plasma saquinavir kontsentratsiyu. Not recommended for use in conjunction with saquinavir, regardless of darunavir use a little extra dose of ritonavir.
Investigation of the interaction between the combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) and atazanavir (300 mg 1 time / day) demonstrated no significant changes in the concentrations of darunavir and atazanavir in plasma in their simultaneous application. Atazanavir can be used simultaneously with the combination of darunavir / ritonavir.
Indinavir
In a study of the interaction between the combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) and indinavir (800 mg 2 times / day) darunavir plasma concentrations increased 24% in the presence of indinavir and ritonavir. In the presence of the combination of darunavir / ritonavir plasma concentrations of indinavir increased by 23%.
When used in conjunction with a combination of darunavir / ritonavir dose indinavir patients, who do not tolerate it, can be reduced to 800 mg 2 times / day to 600 mg 2 times / day.
Other protease inhibitors
So far we have not studied the interaction between a combination of darunavir / ritonavir and protease inhibitors lopinavir addition, saquinavir, atazanavir and indinavir, and therefore not listed here protease inhibitors is not recommended to be used simultaneously with a combination of darunavir / ritonavir. Concomitant use with other medications Rifampicin is a potent inducer of cytochrome P450 isoenzymes.
The combination of darunavir / ritonavir should not be used concurrently with rifampicin, since in such cases it is possible a marked decrease in the plasma concentration of darunavir. Because of this, perhaps the disappearance of the therapeutic effect of the drug darunavir. The combination of darunavir / ritonavir should not be used concurrently with drugs, containing extracts of Hypericum perforatum (Hypericum perforatum), tk. This can be accompanied by a marked decrease in the plasma concentration of darunavir, therefore possible disappearance of the therapeutic effect of the drug darunavir. Antiarrhythmics (bepridil, lidocaine for systemic use, quinidine, Amiodarone).
Combination darunavir / ritonavir may uvelichivaty concentrations in the plasma Bepridil, lidocaine (when administered systemically), quinidine and amiodarone, tk. in their metabolism plays an important role of CYP3A4. These antiarrhythmics have a small therapeutic range, therefore, while the application of the combination of darunavir / ritonavir may increase or prolong the therapeutic and adverse effects of antiarrhythmic drugs. Combination therapy is recommended the transfer of funds with care and, possibly, under the control of the concentration in blood plasma.
Antykoahulyantы
Combination darunavir / ritonavir may vliyaty warfarin concentrations in the plasma.
With simultaneous use of warfarin, and this combination is recommended to monitor the INR. Anticonvulsants (phenobarbital, phenytoin, and carbamazepine).
Phenobarbital, phenytoin and carbamazepine are inducers of cytochrome P450 enzymes. The combination of darunavir / ritonavir is not recommended for use in combination with these drugs, because it may cause a clinically significant reduction in plasma concentration of darunavir and, Consequently, reduction of its therapeutic effect.
Calcium channel blockers
Plasma concentrations of calcium channel blockers (eg, Felodipine, Nifedipine, nikardipina) may increase when an application with the combination of darunavir / ritonavir.
In such situations, you need to carefully monitor patients.
Clarithromycin
Investigation of the interaction between the combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) and clarithromycin (500 mg 2 times / day) found, that the concentration of azithromycin in plasma was increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function is recommended to reduce the dose of clarithromycin.
Dexamethasone
Dexamethasone at entry into the bloodstream induces CYP3A4 isoenzyme in the liver and, Consequently, reduces the plasma concentration of darunavir. This may reduce the therapeutic effect of darunavir. It is recommended to be careful while applying dexamethasone and darunavir.
Fluticasone propionate
With simultaneous use of inhaled fluticasone propionate and combinations of darunavir / ritonavir may increase the concentration of fluticasone propionate in plasma. It is advisable to use drugs, Alternative fluticasone propionate, especially when long-term therapy. The drugs of the statin in the metabolism of statins, Taki how simvastatin and lovastatin, It plays an important role of CYP3A4, therefore their concentration in the plasma can be increased significantly when used in conjunction with a combination of darunavir / ritonavir.
Considering this, it is not recommended to use a combination of darunavir / ritonavir together with lovastatin or simvastatin because of the increased risk of myopathy, including rhabdomyolysis. Investigation of the interaction between atorvastatin (10 mg 1 time / day) kombinatsiey and darunavir / ritonavir (300 mg / 100 mg 2 times / day) found, in this situation, the plasma concentration of atorvastatin was only 15% below, than monotherapy with atorvastatin (40 mg 1 time / day).
If necessary, simultaneous use of atorvastatin and a combination of darunavir / ritonavir is recommended to start with a dose of atorvastatin 10 mg 1 time / day. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy. Combination darunavir / ritonavir (600 mg / 100 mg 2 times / day) increased the concentration of pravastatin in the plasma after administration of a single dose of the drug (40 mg) about 80%, but in some patients. Currently, the clinical significance of this interaction is unknown. Until more information about this cooperation and its mechanism is not recommended for use in conjunction with a combination of pravastatin darunavir / ritonavir. Antagonists of histamine H2-receptors and proton pump inhibitors.
Omeprazole (20 mg 1 time / day) or ranitidine (150 mg 2 times / day) at the same time with a combination of darunanir / ritonavir (400 mg / 100 mg 2 times / day) It had no effect on the concentration of darunavir plasma. Considering this, combination of darunavir / ritonavir can be used in conjunction with antagonists of histamine H2-receptors and proton pump inhibitors without changing the dose of any of these drugs.
Immunosuppressive (cyclosporine, tacrolimus, sirolimus)
Plasma concentrations of cyclosporine, tacrolimus and sirolimus may increase in the event of use of these drugs at the same time with a combination of darunavir / ritonavir. In these situations, it is recommended to control the concentration of an immunosuppressant in plasma. Ketoconazole, Itraconazole Ketoconazole and voriconazole, itraconazole and voriconazole are potent inhibitors of CYP3A4, and its substrate. Systemic administration of ketoconazole, itraconazole and voriconazole simultaneously with a combination of darunavir / ritonavir may result in an increase in the plasma concentrations of darunavir.
On the other hand, this combination may increase the plasma concentrations of ketoconazole, itraconazole and voriconazole. This was confirmed by the study of the interaction between ketoconazole (200 mg 2 times / day) kombinatsiey and darunavir / ritonavir (400 mg / 100 mg 2 times / day), wherein the concentration of ketoconazole and darunavir rose 212% and 42% respectively.
If necessary, use a combination of darunavir / ritonavir simultaneously with ketoconazole or itraconazole last daily dose should not exceed 200 mg. In addition to the CYP3A4 metabolism of voriconazole and other enzymes involved, but, Nonetheless, when used in conjunction with a combination of voriconazole darunavir / ritonavir must consider the possibility of increasing the concentration of drug in plasma.
Methadone
In the case of methadone at the same time with a combination of darunavir / ritonavir should be monitored for the detection of patients withdrawal, inherent opiates, as ritonavir induces the metabolism of methadone, which reduces its concentration in plasma. In such situations, you can increase the dose of methadone, based on its therapeutic effect. Estrogenosoderzhaschie oral contraceptives ethinyl estradiol concentration in the plasma can be reduced as a result of induction of its metabolism by ritonavir.
When using estrogenosoderzhaschih oral contraceptives at the same time with a combination of darunavir / ritonavir should be used alternative or additional contraceptive method. Inhibitors of PDE type 5 One study examined the concentration of sildenafil following a single dose of the drug (100 mg), and after administration 25 silydenafila mg odnovremenno kombinatsiey with darunavir / ritonavir (400 mg / 100 mg 2 times / day). The concentrations of sildenafil were similar in both situations. Use caution while using PDE type 5 and combinations of darunavir / ritonavir.
If necessary, use of darunavir and ritonavir simultaneously sildenafilom, vardenafil or tadalafil Sildenafil single dose should not exceed 25 mg for 48 no, a single dose of vardenafil should not exceed 2.5 mg for 72 no, a single dose of tadalafil should not exceed 10 mg for 72 no.
Rifabutin
Rifabutin is an inducer and substrate of cytochrome P450 isoenzymes. Expected, that the use of rifabutin in conjunction with a combination of darunavir / ritonavir should cause an increase in plasma concentrations of rifabutin and a decrease in the concentration of darunavir. If necessary, apply a combination of both rifabutin darunavir / ritonavir is recommended to take rifabutin 150 mg 1 every two days.
Selective serotonin reuptake inhibitors
Investigation of the interaction between paroxetine (20 mg 1 time / day) or sertraline (50 mg 1 time / day) kombinatsiey and darunavir / ritonavir (400 mg / 100 mg 2 times / day) found, darunavir concentrations in plasma are not dependent on the presence of sertraline or paroxetine.
On the other hand, in the presence of a combination of darunavir / ritonavir plasma concentration of sertraline and paroxetine decreased by 49% and 39% respectively. If necessary, the simultaneous application of a combination of darunavir / ritonavir, you must carefully choose the dose of selective serotonin reuptake inhibitors, based on the clinical assessment of antidepressant action.
Besides, patients, receiving a stable dose of sertraline or paroxetine, which are beginning to treat the combination of darunavir / ritonavir, you need to closely monitor the severity of the main effects of antidepressants.
