PREZISTA

Active material: Darunavir
When ATH: J05AE10
CCF: Viricide, active against HIV
ICD-10 codes (testimony): B24
When CSF: 09.01.04.02
Manufacturer: JOHNSON & JOHNSON LTD (Russia)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated light orange, Oval, Engraved “400 MG” on one side and “Central nervous system” – another.

Excipients: prosolv (microcrystalline cellulose, Colloidal anhydrous silica), krospovydon, Colloidal anhydrous silica, magnesium stearate, Opadry II dye light orange 85 F93377 (partially hydrolyzed polyvinyl alcohol, macrogol 3350, Titanium dioxide (E171), talc, Aluminum lacquer based dye sunset (E110)).

60 PC. – plastic bottles (1) – packs cardboard.

Pills, Film-coated orange, Oval, Engraved “600 MG” on one side and “Central nervous system” – another.

Excipients: prosolv (microcrystalline cellulose, Colloidal anhydrous silica), krospovydon, Colloidal anhydrous silica, magnesium stearate, Opadry Orange II dye 85 F13962 (partially hydrolyzed polyvinyl alcohol, macrogol 3350, Titanium dioxide (E171), talc, Aluminum lacquer based dye sunset (E110)).

60 PC. – plastic bottles (1) – packs cardboard.

Pharmacological action

Viricide, HIV protease inhibitor 1 type (HIV-1). Darunavir is an inhibitor of dimerization and catalytic activity of the HIV-1 protease. The drug selectively inhibits cleavage of Gag-Pol polyproteins by HIV in infected cells by viruses, preventing the formation of high-grade viral particles.

Darunavir binds strongly to HIV-1 protease (K_D 4.5 x 10^-12M). 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.

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. Consequently, large amounts of darunavir bind to α₁-sour plasma glycoprotein.

Darunavir is extensively metabolized in the liver mainly CYP3A isozymes. Ritonavir inhibits CYP3A isozymes in liver and, thereby, significantly increases the concentration of darunavir plasma.

Absorption

Once inside darunavir is rapidly absorbed from the gastrointestinal tract. C_max darunavir 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 600 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, Prezista tablet^® It should be taken with ritonavir during meals. The nature of food does not affect the concentration of darunavir plasma.

Distribution

Darunavir binding to plasma proteins (mainly with α₁-acid glycoprotein) is about 95%.

Metabolism

In in vitro experiments on human liver microsomes was shown, that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by the liver enzyme system P450, almost exclusively of CYP3A4. 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. The man 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 one ¹⁴C-darunavir in dose 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 T_1/2 darunavir was about 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

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 the study using ¹⁴C-darunavir in combination 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 (CC 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. In a study using a drug Presista^® in divided doses in combination with ritonavir (600/100 mg) 2 times / day was shown, that stable pharmacokinetic parameters of darunavir in patients with mild (A class of Child-Pugh, n=8) and moderate hepatic impairment (In the class of Child-Pugh, n=8) They were comparable with those parameters in healthy individuals. Effect of heavy human liver on the pharmacokinetics of darunavir has not been studied.

Testimony

- the treatment of HIV infection in adults (in combination with low dose ritonavir and other antiretrovirals).

Dosage regimen

The drug is taken orally. The drug Prezista^® should always be given in combination with low dose ritonavir (100 mg) as a means of, improves its pharmacokinetic properties, as well as in combination with other antiretroviral drugs. The appointment of ritonavir should be considered prior to initiating therapy Prezista combination^®/ritonavir.

Patients should not alter or discontinue therapy without consulting with their physician.

Patient, previously untreated protease inhibitors, recommended dose preparation Presista^® is 800 mg 1 times / day in combination with ritonavir at a dose of 100 mg 1 time / day; combination taken with food. The type of food does not influence the absorption of darunavir.

Patient, previously treated with protease inhibitors, recommended dose preparation Presista^® is 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.

In patients easy or moderate impaired liver dose adjustment is required. There is currently no data on the use of the combination of Prezista^®/ritonavir in patients with severely impaired hepatic function, therefore, specific recommendations for the dosage regimen for this category of patients is not defined. a combination of Prezista^®/ritonavir must be used with caution in patients severe hepatic impairment.

In patients impaired renal function correction combination doses Presista^®/ritonavir is not required.

Side effect

Most side effects are expressed at moderate. The most common side effects (≥ 5%) moderate or severe degree (2-4 degrees) are diarrhea, headache, and abdominal pain. The most common side effects (≥1%) severe (3-4 degrees) a change in the blood laboratory parameters. Other side effects 3-4 severity were observed in less than 1% patients.

2.3% patients discontinued therapy due to the occurrence of side effects.

Data about side effects 2-4 severity in adult patients, who have not received antiretroviral therapy, when used 800/100 mg Prezysta^®/ritonavir 1 times / day given in Table 1, in comparison with the use of a combination of lopinavir / ritonavir 800/200 mg 1 time / day.

Table 1.

Changes in laboratory parameters 2-4 degree in patients, who have not received antiretroviral therapy, when used 800/100 mg Prezysta^®/ritonavir 1 times / day given in Table 2.

Table 2.

Data about side effects 2-4 degree in adult patients, previously treated with antiretroviral therapy, when used 600/100 mg Prezysta^®/ritonavir 2 times / day given in Table 3, in comparison with the use of a combination of lopinavir / ritonavir 400/100 mg 2 times / day.

Table 3.

Changes in laboratory parameters 2-4 degree in patients, previously treated with antiretroviral therapy, when used 600/100 mg Prezysta^®/ritonavir 1 times / day given in Table 4.

Table 4.

Side effects associated with combination antiretroviral therapy

Dermatological reactions: possible redistribution of body fat (lipodystrophy). This redeployment includes loss of peripheral and facial subcutaneous adipose tissue, the increase in the number of intraabdominal′nogo and visceral fat, hypertrophy of the mammary glands and fat accumulation in dorsocervikal′noj area (the formation of fatty hump).

Metabolism: hypertriglyceridemia, hypercholesterolemia, insulin resistance, giperglikemiâ, hyperlactatemia.

On the part of the bone-myshchenoy system: patients, receiving protease inhibitors, particularly in combination with a nonnucleoside reverse transcriptase inhibitors, Possible increased CK levels, myositis; rarely – raʙdomioliz.

Infection: in HIV-infected patients with severe immunosuppression during the initial combination antiretroviral therapy possible inflammatory response to asymptomatic or residual opportunistic infections.

HIV infected patients co-infected with hepatitis B and / or hepatitis C virus

In HIV-infected patients with concomitant HCV infection B and / or hepatitis C treatment is a combination of Prezista^®/Ritonavir is not accompanied by a higher incidence of side effects and changes of 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, except the increase in liver enzymes. For patients co-infected with hepatitis is considered adequate conduct standard clinical monitoring.

Contraindications

- Concomitant use of drugs with, which mainly clearance defined isoenzyme CYP3A4, and increasing concentration in plasma is associated with the occurrence of serious and / or life-threatening side effects (narrow therapeutic range) – with astemizole, terfenadine, midazolamom, triazolamom, cizapridom, pimozidom, preparations, containing ergot alkaloids (ergotamin, digidroergotamin, ergometrine and metilergometrin);

- Childhood and adolescence up 18 years (for a given dosage form);

- Hypersensitivity to the drug.

FROM caution used in patients with impaired hepatic function, if you are allergic to sulfonamides.

Pregnancy and lactation

Adequate and well-controlled clinical studies of the safety of darunavir during pregnancy was conducted.

Combination drugs Presista^®/Ritonavir can be assigned 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 Prezista drug^®, We should refrain from breast-feeding.

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.

Information about the treatment of the combination of Prezista^®/ritonavir patients aged 65 and older very limited. Care should be taken in the treatment of drug Prezista^® patients in this age group, as they have often observed liver dysfunction, they often suffer from co-morbidities, or receive concurrent therapy.

The absolute bioavailability after a single dose in a dose of darunavir 600 mg 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, Prezista drug^® It should be taken only in combination 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.

Prezista tablets^® contain yellow dye “sunset” (E110) and therefore may cause allergic reactions.

According to the summary data from clinical 10.3% patients, taking the drug Prezista^®, there was a rash. Rash was mostly mild or moderate and often observed during the first 4 weeks of treatment. IN 0.5 % cases of rash was the cause of drug withdrawal.

In 0.4% patients when taking the drug Prezista^® severe cases of rash were reported, accompanied by fever and / or increased activity of hepatic transaminases. Stevens-Johnson syndrome was rare (< 0.1%). If you experience severe rash, receiving Prezista drug^® must stop.

Darunavir contains a sulfonamide group. In patients with an allergy to sulfonamides drug Prezista^® should be used with caution. In clinical studies, the combination Presista^®/ritonavir degree and frequency of the rash were similar in patients with and without allergy to sulfonamides history.

Application data combination Presista^®/ritonavir in patients with severe hepatic impairment There are no; Consequently, give specific recommendations for dosage is not possible. a combination of Prezista^®/ritonavir must be used with caution in patients with severe hepatic impairment. Based on the finding, that stable pharmacokinetic parameters in the application of darunavir in patients with mild to moderate hepatic impairment compared with parameters in healthy individuals, dose adjustment for patients with mild to moderate hepatic impairment is required.

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 deterioration of liver function combination treatment Presista^®/Ritonavir should suspend or cancel.

The 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.

There are reports of 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, receiving a combination of Prezista^®/ritonavir, should be informed of the possibility of increased bleeding.

In 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 result in 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 Prezista drug^® in combination with ritonavir is limited in humans. Healthy volunteers took up once 3200 mg of darunavir in solution and to 1600 mg as tablets Presista^® 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. You can use activated carbon. Darunavir largely bound to plasma proteins, however it is not removed in significant quantities by dialysis.

Drug Interactions

Darunavir and ritonavir are inhibitors of CYP3A isoenzyme. Simultaneous use of a combination Presista^®/ritonavir and preparations, are metabolized mainly isoenzyme CYP3A, It can cause an increase in the concentrations of these drugs in the plasma, what, in turn, It can be the cause of enhancing or prolonging the therapeutic effect, and side effects.

Darunavir metaboliziruetsya izofermentami CYP3A. Simultaneous administration of drugs, induce CYP3A activity may increase the clearance of darunavir, whereby the decrease in the plasma concentration of darunavir. Simultaneous treatment with darunavir CYP3A inhibitors can decrease the clearance of darunavir, resulting in increased plasma concentration of darunavir in.

a combination of Prezista^®/ritonavir should not be used in conjunction 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 (narrow therapeutic range). These drugs include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide and ergot alkaloids (eg, ergotamin, digidroergotamin, ergometrine and metilergometrin).

Rifampicin is a potent inducer of CYP450 isozymes. a combination of Prezista^®/ritonavir should not be used concurrently with rifampicin, since in such cases it is possible a marked decrease in the plasma concentration of darunavir. Consequently, the therapeutic effect may disappear preparation Presista^®.

a combination of Prezista^®/ritonavir should not be used in conjunction with drugs, containing extracts of Hypericum perforatum (Hypericum perforatum), tk. This can be accompanied by a marked decrease in the plasma concentration of darunavir, consequently possible disappearance of the therapeutic effect of the drug Presista^®.

Concomitant use with other antiretroviral

Nucleoside reverse transcriptase inhibitors

Didanosine

a combination of Prezista^®/ritonavir (600/100 mg 2 times / day) simultaneously with ddI can be used without dose adjustment.

Unnecessarily. didanosine is recommended on an empty stomach, it can be taken over 1 hours before or after 2 h then accepts combinations Prezista^®/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 combinations Presista^®/ritonavir and tenofovir correction dose 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

Etravirine

When studying the interaction combination Presista^®/ritonavir (600/100 mg 2 times / day) and etravirine was found to decrease the concentration of etravirine 37% and found no significant changes in the concentration of darunavir. However, the combination of Prezista^®/ritonavir may be administered concurrently with a dose of etravirine 200 mg 2 times / day without any dose change.

Efavirenz

It has been studied the interaction between the combination of darunavir / ritonavir (300 mg / 100 mg 2 times / day) and efavirenz (600 mg 1 time / day). In the presence of efavirenz darunavir observed decrease in plasma concentration 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, Prezista^®/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 darunavir / ritonavir, nevirapine plasma concentrations 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, Prezista drug^® must be used in combination with 100 mg of ritonavir to improve the pharmacokinetics of darunavir characteristics.

Lopinavir / ritonavir

The results of studies of the interaction between the combination of 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 drug Prezista^® regardless of the small additional 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 drug Prezista^® regardless of the use of a small additional dose ritonavir.

Atazanavir

When studying the interaction between a combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) and atazanavir (300 mg 1 time / day) indicated no significant change in their simultaneous application of darunavir and atazanavir concentrations in plasma. Atazanavir can be used simultaneously with the combination of darunavir / ritonavir.

Indinavir

When studying the interaction between a 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 Presista^®/ritonavir indinavir Dozois Reservoir at patsientov, 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 Presista^®/protease inhibitors ritonavir and lopinavir in 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.

CCR5 receptor antagonists

With simultaneous use of combinations Presista^®/ritonavir maraviroc should be administered at a dose 150 mg 2 times / day. In a study of the interaction between the combination of darunavir / ritonavir (600 mg / 100 mg 2 times / day) and maraviroc (150 mg 2 times / day) concentration was increased to maraviroc 305%. Effects on the concentration of maraviroc darunavir / ritonavir not noted.

The simultaneous use of other medications

Antiarrhythmics (bepridil, lidocaine for systemic use, quinidine, Amiodarone, flekainid, propafenone)

Prezista combination^®/Ritonavir may increase the plasma concentration bepridil, lidocaine (when administered systemically), quinidine and amiodarone, flecainide and propafenone. Therefore, while the application of a combination Presista^®/ritonavir and these antiarrhythmics require caution and, possibly, monitoring of the plasma concentrations.

Digoxin

In all studies, the interaction of a combination of Prezista^®/ritonavir (600/100 mg 2 times / day) and a single dose of digoxin (400 g) It has been shown to increase the final digoxin concentrations in plasma 77%. Recommended minimum dose initially assign and determine digoxin in blood serum concentration to obtain the desired clinical effect, while the appointment with this combination.

Antykoahulyantы

Prezista combination^®/Ritonavir can affect the plasma concentration of warfarin. 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 CYP450 isozymes. a combination of Prezista^®/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.

Investigation of the interaction between a combination of Prezista^®/ritonavir (600/100 mg 2 times / day) and carbamazepine (200 mg 2 times / day) found, that darunavir concentration in this case does not change, while the concentration of ritonavir decreased by 49%. The concentration of carbamazepine is increased by 45%. dose changes for Prezista^®/ritonavir is not required. If necessary, co-administration of Prezista^®/ritonavir and carbamazepine should monitor the status of patients due to the possibility of side effects of carbamazepine. It should control the concentration of carbamazepine in plasma and adjust the dose in line with clinical manifestations. Thus, carbamazepine dose may be reduced to 25-50% with a joint appointment with the combination of Prezista^®/ritonavir.

Antidepressants (trazodone, desipramine)

With simultaneous use of combinations Presista^®/ritonavir with trazodone and desipramine, trazodone may increase the concentration in plasma and desipramine. This may cause such side effects, nausea, dizziness, hypotension, fainting. If necessary, concomitant use of these drugs and combinations Presista^®/ritonavir is required caution, should consider the use of trazodone and desipramine in smaller doses, especially in the case of long-term therapy.

Benzodiazepines (midazolam parenteralyno)

With simultaneous use of combinations Presista^®/ritonavir with midazolam administered parenterally can lead to increased plasma concentrations of midazolam. When the joint application should be careful clinical monitoring and take immediate action in the event of respiratory depression or long-sedating. Should consider reducing the dose of midazolam, especially in the case of long-term therapy.

Use of a combination Presista^®/ritonavir with oral midazolam is contraindicated.

Antipsychotic drugs (risperidone, tioridazin)

If concomitant use of neuroleptics with a combination of Prezista^®/ritonavir concentrations in plasma may increase. Therefore, while the application of lower doses should antipsychotics (neuroleptics).

Calcium channel blockers

Plasma concentrations of calcium channel blockers (eg, Felodipine, Nifedipine, nikardipina) may increase when an application with a combination of Prezista^®/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, ʙudezonid

With simultaneous use of inhaled fluticasone propionate and combinations Presista^®/ritonavir may increase the concentration of fluticasone propionate in plasma. A similar interaction may occur when using other corticosteroids, metabolized isoenzyme CYP3A4, such as budesonide. It is advisable to use drugs, Alternative fluticasone propionate, non-CYP3A4 substrate (eg, beclomethasone).

Preparations from the group of statins

In metabolized statin, such as simvastatin, rosuvastatin and lovastatin, It plays an important role of CYP3A4, therefore their concentration can significantly increase the plasma when applied simultaneously with a combination Presista^®/ritonavir. It is not recommended to use a combination of Prezista^®/odnovremenno with ritonavir lovastatinom, rosuvastatin, 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. If necessary, concomitant administration of pravastatin and combinations Presista^®/ritonavir is recommended to start taking a statin at the lowest possible dose and increase the dose until clinical effect, controlling the side effects of the drug.

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, a combination of Prezista^®/Ritonavir can be used in conjunction with antagonists of the histamine H₂-receptors and proton pump inhibitors without changing any of the doses of these drugs.

Immunosuppressive (cyclosporine, tacrolimus, sirolimus)

Plasma concentrations of cyclosporine, tacrolimus and sirolimus may increase in the case of use of these drugs in conjunction with a combination Presista^®/ritonavir. In these situations, it is recommended to control the concentration of an immunosuppressant in plasma.

Ketoconazole, itraconazole and voriconazole

Ketoconazole, itraconazole and voriconazole are potent inhibitors of CYP3A4, and its substrate. Systemic administration of ketoconazole, itraconazole, voriconazole and at the same time with a combination of Prezista^®/ritonavir may result in increased plasma concentrations of darunavir. On the other hand, this combination may increase the plasma concentrations of ketoconazole or itraconazole. 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. The concentrations of voriconazole in plasma may be reduced when combined with darunovirom / ritonavir. Voriconazole should not be used concurrently with darunovirom / ritonavir, concurrent use is possible only in the case, if the potential benefits from the use of voriconazole outweighs the potential risk.

Beta-blockers (metoprolol, timolol)

With simultaneous use of combinations Presista^®/ritonavir with beta-blockers may increase the concentration of beta-blockers. With the simultaneous use of these drugs and combinations Presista^®/ritonavir should be careful and conduct a careful clinical monitoring, It may also need to decrease the dose of beta-blockers.

Methadone

In the combination study the influence Presista^®/ritonavir (600/100 mg 2 times / day) on stable methadone maintenance therapy, It has been shown to decrease by 16% R-methadone concentration in plasma. Based on the pharmacokinetic and clinical results, correct dose of methadone during initiation of therapy Prezista^®/ritonavir is not required. However, the recommended clinical monitoring, tk. in some patients, maintenance therapy requires correction.

Buprenorphine / naloxone

Results of the study of interaction combination Presista^®/ritonavir with buprenorphine / naloxone combinations showed no effect Presista^®/ritonavir at concentration of buprenorphine in their joint application. The concentration of the active metabolite of buprenorphine - norbuprenorfina increased 46%. Correction dose buprenorphine is not required. When co-administered combination Presista^®/ritonavir and buprenorphine recommended careful clinical monitoring.

Estrogenosoderzhaschie oral contraceptives

The results of the study on the interaction between a combination of Prezista^®/ritonavir (600/100 mg 2 times / day) and ethinylestradiol and norethisterone show, that C_ss plasma ethinyl estradiol and norethisterone, respectively reduced to 44% and 14%. When applying the combination Presista^®/ritonavir is recommended to use alternative non-hormonal methods of contraception.

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. Caution is required while the use of inhibitors of PDE type 5 and combinations Presista^®/ritonavir. If necessary, use Presista^® 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 substrate and CYP450 isozymes. When studying the interaction combination Presista^®/ritonavir (600/100 mg 2 times / day) and rifabutin (150 mg a day) increase was observed at concentrations of darunavir 57%. Based on the safety profile of the combination Presista^®/ritonavir, darunavir increasing concentration in the presence of rifabutin does not require correction for a combination of doses combination Presista^®/ritonavir . Study of the interaction showed comparable concentration when using a dose of rifabutin 300 mg 1 time / day and 150 mg every other day in combination with Prezista combination^®/ritonavir (600/100 mg 2 times / day), and increasing the concentration of the active metabolite 25-O-dezatsetilrifabutina. When assigning this combination requires a reduction in the dose of rifabutin 75% from normal dose 300 mg / day and increased control of side effects of rifabutin.

Selective serotonin reuptake inhibitors

Investigation of the interaction between paroxetine (20 mg 1 time / day) or sertraline (50 mg 1 time / day) and a combination of Prezista^®/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 Presista^®/ritonavir plasma concentrations of sertraline and paroxetine decreased by 49% and 39% respectively. If necessary, the simultaneous application of a combination of Prezista^®/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 Prezista^®/ritonavir, you need to closely monitor the severity of the main effects of antidepressants.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children, at a temperature no higher than 30 ° C. Shelf life - 2 year.