Prezista

General characteristics. Structure:

In 1 tablet, film coated, 400 mg contain:

Active agent: a darunavira of ethanoarmour of 433,64 mg 400 mg of a darunavir are equivalent.

Excipients: просолв (are a part cellulose microcrystallic, silicon dioxide colloid anhydrous) – 369,53 mg, кросповидон – 16,67 mg, silicon dioxide colloid anhydrous – 7,59 mg, magnesium stearate – 6,17 mg, dye of Opadray the II light orange 85F93377 ( are a part partially hydrolyzed polyvinyl alcohol, a macrogoal 3350, titanium dioxide (E171), talc, an aluminum varnish on the basis of dye of a sunset of yellow (E110) – 33,34 mg.

In 1 tablet, film coated, 600 mg contain:

Active agent: Darunavira of ethanoarmour of 650,46 mg 600 mg of a darunavir are equivalent.

Excipients: просолв (are a part cellulose microcrystallic, silicon dioxide colloid anhydrous) – 554,30 mg, кросповидон – 25,01 mg, silicon dioxide colloid anhydrous – 11,38 mg, magnesium stearate – 9,25 mg, dye of Opadray the II orange 85F13962 ( dioxide (E171), talc, an aluminum varnish on the basis of dye of a sunset of yellow (E110) of-50,02 mg are a part partially hydrolyzed polyvinyl alcohol, a macrogoal 3350, titanium.

Description: tablets of 400 mg: light orange, oval tablets, film coated, with an engraving on one of the parties "400MG", and on another – "TMS". Tablets of 600 mg: orange, oval tablets, film coated, with an engraving on one of the parties "600MG", and on another – "TMS".

Pharmacological properties:

Pharmacodynamics. Action mechanism. Darunavir is inhibitor of dimerization and catalytic activity of protease of a human immunodeficiency virus of the I type (VICh-1). Drug selectively inhibits splitting of polyproteins of Gag-Pol of HIV in the cells infected with viruses, preventing formation of full-fledged virus particles.

Darunavir strongly contacts VICh-1 protease (KD 4,5 × 10-12 M). Darunavir is steady against effects of the mutations causing resistance to protease inhibitors. Darunavir does not inhibit any of 13 studied cellular proteases of the person.

Pharmacokinetics. Pharmacokinetic properties of the darunavir applied in a combination with ritonaviry were studied at healthy volunteers and at HIV-positive patients.

Concentration of a darunavir in plasma were higher at the patients infected with VICh-1 than at healthy people. This distinction can be explained with higher concentration of an alpha 1-acid glycoprotein at the patients infected VICh-1 that leads to increase in quantity of the darunavir connected with an alpha 1-acid glycoprotein of plasma. Darunavir is metabolized generally by CYP3A4 isoenzyme. Ritonavir inhibits an isoenzyme of CYP3A4 of a liver and, thereby, significantly increases concentration of a darunavir in plasma.

Absorption. After intake дарунавир it is quickly soaked up in digestive tract.

The maximum concentration of a darunavir in plasma in the presence of a low dose of a ritonavir is reached in 2,5 – 4,0 h. Absolute bioavailability of one dose of a darunavir (600 mg) at intake made about 37% and increased approximately to 82% in the presence of a ritonavir (100 mg two times a day). The general influence of a ritonavir on bioavailability of a darunavir consisted approximately in 14-fold increase in concentration of a darunavir in plasma after one intake of 600 mg of a darunavir in a combination with ritonaviry (100 mg two times a day).

At reception on an empty stomach relative bioavailability of a darunavir in the presence of a low dose of a ritonavir was 30% lower, than at inclusion in food time. Therefore, drug PREZISTA needs to be accepted together with ritonaviry during food. Character of food did not influence concentration of a darunavir in plasma.

Distribution. About 95% of a darunavir contact proteins of plasma, is preferential with an alpha 1-acid glycoprotein.

Metabolism. In in vitro experiments on microsomes of a liver of the person it was shown what дарунавир is exposed to preferential oxidizing metabolism. Darunavir is metabolized preferential in a liver by system of P450 cytochrome, almost exclusively CYP3A4 isoenzyme. The research in which healthy volunteers accepted 14C-darunavir showed that the most part of radioactivity in plasma after one reception of 400 mg of a darunavir and 100 mg of a ritonavir fell to the share of not changed darunavir. At the person at least 3 oxidizing metabolites of a darunavir are identified; activity of all these metabolites concerning the HIV wild type made less than 1/10 from activity of the darunavir.

Removal. After a single dose of 400 mg of a 14C-darunavir and 100 mg of a ritonavir about 79,5% and 13,9% of radioactivity were found in Calais and urine respectively. About 41,2% and 7,7% of radioactivity in Calais and urine respectively fell to the share of not changed darunavir. The final elimination half-life of a darunavir made about 15 h at its inclusion in combinations with ritonaviry. The clearance of a darunavir after intravenous administration of 150 mg made 32,8 l/h (without ritonavir) and 5,91 l/h in the presence of a low dose of a ritonavir.

Special groups of patients. Children. The pharmacokinetics of a darunavir in a combination with ritonaviry at children aged from 6 up to 18 years and weighing not less than 20 kg is comparable with pharmacokinetics at the adult patients receiving a combination PREZISTA/ritonavir of 600/100 mg 2 times a day.

The pharmacokinetics of a darunavir in a combination with ritonaviry at children aged from 3 up to 6 years and weighing from 10 kg to 20 kg is comparable with pharmacokinetics at the adult patients receiving a combination PREZISTA/ritonavir of 600/100 mg 2 times a day.

Elderly patients. The population pharmacokinetic analysis at HIV-positive patients showed lack of significant distinctions of pharmacokinetic parameters of a darunavir in an age group of 18 - 75 years (this analysis included 12 HIV-positive patients at the age of 65 years and are more senior).

Sexual distinctions. The population pharmacokinetic analysis revealed a little higher (16,8%) concentration of a darunavir at HIV-positive women, than at HIV-positive men. This distinction is not clinically significant.

Patients with renal failures. Results of a research with use of a 14C-darunavir in a combination with ritonaviry showed that about 7,7% of the accepted dose of a darunavir were excreted with urine in not changed look. At patients with renal failures the pharmacokinetics of a darunavir was not studied, but the population pharmacokinetic analysis showed lack of significant change of pharmacokinetic parameters of a darunavir at HIV-positive patients with moderately expressed renal failures (clearance of serumal creatinine of 30-60 ml/min., n = 20).

Patients with abnormal liver functions. Darunavir is metabolized and brought preferential by a liver. In a research using several doses of drug PREZISTA in a combination with ritonaviry (600/100 mg) it was twice a day shown that stable pharmacokinetic parameters of a darunavir at patients with a lung (a class A on Chayld-Pyyu, n=8) and a moderate abnormal liver function (a class B on Chayld-Pyyu, n=8) were comparable with those parameters at healthy faces. The effect of a heavy abnormal liver function on pharmacokinetics of a darunavir was not studied.

Indications to use:

Treatment of HIV infection at adult patients (in a combination with a low dose of a ritonavir and other anti-retrovirus drugs).

Route of administration and doses:

Inside. Always it is necessary to appoint drug PREZISTA in a combination with a low dose of a ritonavir as the means improving its pharmacokinetic characteristics and also in a combination with other anti-retrovirus drugs. The possibility of purpose of a ritonavir has to be considered prior to therapy by a combination PREZISTA/ritonavir. Patients have to be instructed about administration of drug of PREZISTA with a low dose of a ritonavir no later than 30 minutes after end of food.

After the beginning of therapy by drug PREZISTA patients should not change or stop therapy without consultation with the attending physician.

Adult patients:

The patients who were earlier not receiving   protease inhibitors - 800 mg of 1 times a day in a combination from 100 mg of a ritonavir, during food.

The patients who were earlier receiving the protease inhibitors which do not have the mutations causing resistance to a darunavir * - 800 mg of 1 times a day in a combination from 100 mg of a ritonavir, during food.

The patients who were earlier receiving the protease inhibitors having at least 1 mutation causing resistance to a darunavir * - 600 mg 2 times a day in a combination from 100 mg of a ritonavir, during food.

* The mutations causing resistance to a darunavir: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Features of use:

Patients need to be informed that modern anti-retrovirus drugs do not cure HIV infection and do not prevent transfer of HIV. Patients should explain need of observance of the appropriate measures of precaution.

Elderly patients: information on treatment by a combination PREZISTA/ritonavir of patients at the age of 65 years is also more senior is very limited, it is necessary to be careful at treatment of such patients drug PREZISTA as to their thicket liver dysfunction meets, and they more often have associated diseases or accept a combination therapy.

Absolute bioavailability after one-time reception of 600 mg of a darunavir made about 37% and increased approximately to 82% after reception of a darunavir in a combination from 100 mg of a ritonavir two times a day. The cooperative effect of improvement of pharmacokinetics of a darunavir ritonaviry was expressed approximately in 14-fold increase in concentration of a darunavir in plasma after reception of one dose of this drug (600 mg) in a combination from 100 mg of a ritonavir two times a day. Thus, drug PREZISTA needs to be accepted only in a combination with a low dose of a ritonavir as the pharmacokinetic amplifier.

Increase in the specified dose of a ritonavir does not lead to significant increase in concentration of a darunavir in plasma and therefore the dose of a ritonavir is not recommended to be raised.

Tablets PREZISTA contain yellow sunset dye (E110) and therefore can cause allergic reactions.

Skin reactions of heavy degree. At 0,4% of patients at reception ПРЕЗИСТАбыли skin reactions of heavy degree which can be followed by fever and/or increase in activity of hepatic transaminases are recorded. Stephens-Johnson's syndrome was fixed seldom (<0,1%). In the post-registration period the toxic epidermal necrolysis, DRESS a syndrome (medicinal rash with an eosinophilia and system manifestations) and acute generalized exanthematous пустулез were fixed very seldom (<0,01%). At emergence of signs or symptoms of skin reactions of heavy degree (the rash of a heavy current or rash accompanied with fever, a febricula, fatigue, muscle or joints pains, blisters, defeats of an oral cavity, conjunctivitis, hepatitis and/or an eosinophilia, etc.) administration of drug of PREZISTA need to be stopped immediately.

Rash (all types) was observed at 10,3% of the patients accepting drug PREZISTA. Rash generally was easy or average degree, and was often observed within the first four weeks of treatment and decreased at therapy continuation. In 0,5% of cases rash was the cause of cancellation of a combination PREZISTA/ritonavir. Rash was more often observed at the patients accepting at the same time ралтегравир and a combination PREZISTA/ritonavir in comparison with the patients receiving separately ралтегравир or a combination PREZISTA/ritonavir. Rash which developing was connected with administration of drug arose with an identical frequency in all three groups. Rash was easy or moderate severity and did not limit therapy. Rash was not the cause of cancellation of therapy.

Darunavir contains sulphonamide group. Purpose of PREZISTA to patients with an allergy to sulfonamides has to be made with care. In clinical trials of a combination PREZISTA/ritonavir degree and frequency of developing of rash were identical at patients irrespective of existence of an allergy to sulfonamides in the anamnesis.

Patients with associated diseases. Patients with liver diseases. Data on use of a combination PREZISTA/ritonavir at patients with a heavy abnormal liver function are absent; therefore, it is not possible to make specific recommendations about dosing. Based on data that stable pharmacokinetic parameters at use of a darunavir for patients with a lung and moderate degree an abnormal liver function (a class A and B on Chayld-Pyyu) are comparable with parameters at healthy faces, dose adjustment to patients with a lung and moderate degree is not required by an abnormal liver function (a class A and B on Chayld-Pyyu).

Hepatotoxic. At use of a combination PREZISTA/ritonavir development of the hepatitis caused by use of medicines is possible (for example, an acute hepatitis, cytolytic hepatitis). Hepatitis was observed at 0,5% of the patients receiving a combination therapy PREZISTA/ritonavir. Patients with abnormal liver functions, including with chronic active hepatitis B or C, have an increased risk of development of heavy side effects from a liver.

It is necessary to carry out monitoring of the corresponding laboratory indicators before purpose of a combination therapy PREZISTA/ritonavir and during treatment. It is necessary to consider the possibility of control of increase in activity of AST/ALT at patients with chronic hepatitis, cirrhosis or at patients at whom a superactivity of transaminases before therapy and, especially, within the first several months of a combination therapy by a combination PREZISTA/ritonavir was observed.

In case of detection of abnormal liver functions or deterioration in their weight (including clinically significant increase in activity of liver enzymes and/or such symptoms as fatigue, anorexia, nausea, jaundice, urine of dark color, morbidity at a liver palpation, a hepatomegalia) it is necessary to consider the possibility of interruption or cancellation of therapy by a combination PREZISTA/ritonavir.

Patients with diseases of kidneys. Kidneys are of little importance in clearance of a darunavir and therefore at patients with diseases of kidneys the general clearance of a darunavir practically does not decrease. Darunavir and ритонавир possess high extent of linkng with proteins of plasma and therefore the hemodialysis or peritoneal dialysis do not play an essential role in removal of these drugs from an organism.

Patients with hemophilia. There are messages on strengthening of bleedings, including spontaneous skin hematomas and a hemarthrosis, for patients with hemophilia of type A and B, treated protease inhibitors. Some of these patients received blood-coagulation factors of VIII. More than in half of the described cases treatment by inhibitors of protease continued without interruption or was resumed after temporary suspension. It was suggested about a causal relationship between treatment by inhibitors of protease and strengthening of bleeding at patients with hemophilia, however the mechanism of such communication is not installed. The patients with hemophilia receiving a combination PREZISTA/ritonavir should be informed on a possibility of strengthening of bleedings.

Hyperglycemia. At the patients receiving anti-retrovirus therapy including protease inhibitors, the revealed diabetes mellitus cases, a hyperglycemia or deterioration in a current of already existing diabetes mellitus are described for the first time. Some of these patients had a heavy hyperglycemia and in some cases was followed by ketoacidosis. At many patients associated diseases some of which demanded treatment by the drugs promoting development of a diabetes mellitus or hyperglycemia took place.

Redistribution of fat and metabolic disturbances. The combined anti-retrovirus therapy can cause in HIV-positive patients redistribution of fatty tissue (lipodystrophy). There are no data on the remote effects of this phenomenon now, and its mechanism is in many respects not clear. The hypothesis of communication between a visceral lipomatoz and inhibitors of protease, and also between a lipoatrophia and nukleozidny inhibitors of the return transcriptase is stated. The increased risk of emergence of a lipodystrophy is connected with such factors as advanced age, and also with long therapy by anti-retrovirus drugs and the metabolic disturbances accompanying it. At clinical inspections of the HIV-positive patients receiving anti-retrovirus drugs it is necessary to pay attention to physical signs of redistribution of fat. It is recommended to measure the maintenance of serumal lipids and glucose of blood on an empty stomach. Disturbances of lipidic metabolism it is necessary to treat the corresponding drugs.

Osteonecrosis. Despite a multifactorial etiology (use of glucocorticosteroid hormones, alcohol intake, heavy degree of immunosuppression, the raised body weight index), osteonecrosis cases, in particular at patients with a HIV disease at a late stage and/or at patients, receiving the combined anti-retrovirus therapy a long time were noted. Patients have to be informed on need of immediate visit of the doctor in case of in case of joint pains, constraint in joints or difficulties of movements.

Inflammatory syndrome of recovery of immunity. At HIV-positive patients with a heavy immunodeficiency at the beginning of the combined anti-retrovirus therapy emergence of inflammatory reaction of an organism to asymptomatic or residual opportunistic infections is possible that can lead to serious clinical complications or deterioration in symptomatology. Usually such reactions are observed in the first weeks or months of use of the combined anti-retrovirus therapy. It is possible to give a Cytomegaloviral retinitis, generalized and/or local mikobakterialny infections and the pneumonia caused by Pneumocystis (carinii) jiroveci as examples. It is necessary to define weight of any symptoms of an inflammation and to carry out the corresponding therapy.

Autoimmune diseases (such as Greyvs's disease) were also noted at emergence of an inflammatory syndrome of recovery of immunity. However time prior to the beginning of a disease can vary, and such diseases can begin months later after the beginning of therapy.

Interaction with other medicines. Darunavir and ритонавир are CYP3A4 isoenzyme inhibitors. PREZISTA/ritonavir and other drugs which are metabolized preferential by CYP3A4 isoenzyme can lead simultaneous use of a combination to increase in concentration of such drugs in plasma owing to what their therapeutic and side effects can amplify or be extended.

Darunavir is metabolized by CYP3A4 isoenzyme. The concomitant use of the drugs inducing activity of CYP3A4 can increase clearance of a darunavir therefore concentration of a darunavir in plasma will decrease. The concomitant use of a darunavir with CYP3A4 inhibitors can reduce clearance of a darunavir therefore concentration of a darunavir in plasma will increase.

Influence on ability to manage vehicles and mechanisms. Researches on studying of influence of a combination PREZISTA/ritonavir on ability to manage vehicles and mechanisms were not conducted. However, it is necessary to take into account the fact that at some patients during the treatment including reception of a combination PREZISTA/ritonavir dizziness was observed. At emergence of dizziness it is necessary to refrain from performance of the specified types of activity.

Side effects:

The most frequent side effects during clinical trials and in the post-registration period were: diarrhea, nausea, rash, headache and vomiting.

The most frequent serious side effects were: acute renal failure, myocardial infarction, inflammatory syndrome of recovery of immunity, thrombocytopenia, osteonecrosis, diarrhea, hepatitis and fever.

Side effects are given according to system and organ classification and with distribution on emergence frequency. In each frequency group side effects are presented as reduction of their gravity.

Frequency of side effects is determined as follows: very often (≥1/10 cases), it is frequent (≥1/100 and <1/10 cases), infrequently (≥1/1000 and <1/100 cases), is rare (≥1/10000 and <1/1000 cases) and frequency is unknown (it is impossible to estimate frequency from available data).

Infectious and parasitic diseases:

- infrequently - a herpes infection;

Disturbances from blood and lymphatic system:

- infrequently - thrombocytopenia, a neutropenia, anemia, a leukopenia;

- often - an eosinophilia.

Disturbances from immune system:

- infrequently - an inflammatory syndrome of recovery of immunity, (medicinal) hypersensitivity.

Disturbances from endocrine system:

- infrequently - a hypothyroidism, increase in concentration of thyritropic hormone in blood.

Disturbances from a metabolism and food:

- often - a lipodystrophy (including a lipogipertrofiya, a lipodystrophy, a lipoatrophia), a diabetes mellitus, a gipertriglitseridemiya, a hypercholesterolemia, a lipidemia;

- infrequently - gout, anorexia, a loss of appetite, decrease in body weight, increase in body weight, a hyperglycemia, insulin resistance, decrease in concentration of lipoproteins of high density, increase in appetite, a polydipsia, increase in activity of a lactate dehydrogenase in blood. 

Disturbances of mentality:

- often - sleeplessness;

- infrequently - a depression, a disorientation, alarm, sleep disorders, abnormal dreams, nightmares, decrease in a libido;

- seldom - confusion of consciousness, change of mood, concern.

Disturbances from a nervous system:

- often - a headache, peripheral neuropathy, dizziness;

- infrequently - block, paresthesia, a hypesthesia, a dysgeusia, disturbances of attention, memory disturbance, drowsiness;

- seldom - a faint, spasms, an ageusia, disturbance of a rhythm of phases of a dream.

Disturbances from an organ of sight:

- infrequently - a conjunctiva hyperemia, dryness of a mucous membrane of eyes;

- seldom - a vision disorder.

Disturbances from an acoustic organ and balance:

- infrequently - vestibular dizziness.

Disturbances from heart:

- infrequently - a myocardial infarction, stenocardia, increases in a tooth of QT on the electrocardiogram, tachycardia;

- seldom - an acute myocardial infarction, a sinus bradycardia, a heart consciousness.

Disturbances from vessels:

- infrequently - increase in arterial pressure, "inflows".

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- infrequently - short wind, cough, nasal bleeding, irritation in a throat;

- seldom - a rhinorrhea.

Disturbances from digestive tract:

- often - nausea, vomiting, pain in a stomach, increase in activity of amylase in blood, dyspepsia, abdominal distention, a meteorism;

- infrequently - pancreatitis, gastritis, a gastroesophageal reflux, aphthous stomatitis, desires to vomiting, dryness of a mucous membrane of an oral cavity, discomfort in a stomach, a lock, increase in activity of a lipase, an eructation, disturbance of sensitivity in an oral cavity;

- seldom - stomatitis, vomiting with blood, a cheilitis, dryness of a mucous membrane of lips, a fur.

Disturbances from a liver and biliary tract:

- often - increase in activity of alaninaminotranspherase;

- infrequently - hepatitis, cytolytic hepatitis, a liver steatosis, a hepatomegalia, increase in activity of transaminase, increase in activity of aspartate aminotransferase, increase in concentration of bilirubin in blood, increase in activity of an alkaline phosphatase in blood, increase in activity of a gammaglutamiltransferaza.

Disturbances from skin and hypodermic fabrics:

- often - rash (including macular, makulopapulyozny, papular, erythematic and pruritic), an itch;

- infrequently - a Quincke's disease, generalized rash, allergic dermatitis, a small tortoiseshell, eczema, an erythema, a hyperhidrosis, night perspiration, an alopecia, an acne, a xeroderma, pigmentation of nails;

- seldom - medicinal rash with an eosinophilia and system manifestations (DRESS syndrome), Stephens-Johnson's syndrome, a multiformny erythema, dermatitis, seborrheal dermatitis, injuries of skin, a xerodermia;

- frequency is unknown - a toxic epidermal necrolysis, acute generalized ekzentematozny пустулез.

Disturbances from skeletal and muscular and connecting fabric:

- infrequently - a mialgiya, an osteonecrosis, muscular spasms, muscular weakness, an arthralgia, extremity pain, osteoporosis, increase in activity of a kreatinfosfokinaza in blood;

- seldom - skeletal and muscular constraint, arthritis, constraint in joints.

 Disturbances from kidneys and urinary tract:

- infrequently - an acute renal failure, a renal failure, a nephrolithiasis, increase in concentration of creatinine in blood, a proteinuria, a bilirubinurea, a dysuria, a nokturiya, a pollakiuria;

- seldom - decrease in renal clearance of creatinine.

Disturbances from generative organs and a mammary gland:

- infrequently - erectile dysfunction, a gynecomastia.

The general frustration and disturbances in an injection site: often - an adynamy, fatigue;

- infrequently - fever, thorax pain, peripheral hypostasis, an indisposition, feeling of heat, irritability, pain;

- seldom - a fever, feeling sick, a skin xerosis.

Description of some side effects. 

Rash. In clinical trials rash of easy or average degree was generally observed.  Rash most often developed within the first four weeks of therapy and disappeared at continuation of administration of drug. At development of skin reactions of heavy degree see the section "Special Instructions".

During clinical trials at the patients who were earlier receiving therapy, rash irrespective of its reason, arose at reception of the schemes of treatment containing drug PREZISTA and ралтегравир than at administration of drug of PREZISTA without raltegravir or a raltegravir without drug PREZISTA more often. The rash caused by administration of drug developed with a similar frequency. The rash arising in clinical trials was easy and average degree and did not lead to the therapy termination.

Lipodystrophy. The combined anti-retrovirus therapy causes fat redistribution (lipodystrophy) in patients with HIV. The lipodystrophy was shown in the form of loss of peripheral and front subcutaneous fat, increase in intra belly and visceral fat, a hypertrophy of mammary glands and accumulation of dorsotservikalny fat ("a bull hump").

Disturbances from a metabolism. The combined anti-retrovirus therapy causes disbolism, such as a gipertriglitseridemiya, a hypercholesterolemia, insulin resistance, a hyperglycemia and a giperlaktatemiya.

Disturbances from skeletal muscular tissue. Increase in activity of a kreatinfosfokinaza, a mialgiya, a miositis and рабдомиолиз were (seldom) noted when using inhibitors of protease, especially in combination with nukleozidny inhibitors of the return transcriptase.

Osteonecrosis cases, especially at patients with the conventional risk factors, with a HIV disease at a late stage or a long time receiving the combined anti-retrovirus therapy were noted. Frequency of emergence of an osteonecrosis is unknown.

Inflammatory syndrome of recovery of immunity. Patients with HIV and heavy degree of an immunodeficiency at the time of the beginning of the combined anti-retrovirus therapy can have inflammatory reactions on asymptomatically the proceeding or residual infections. Also autoimmune diseases were observed (for example, Greyvs's disease). However time prior to the beginning of a disease can vary, and such diseases can begin months later after the beginning of therapy.

Bleedings at patients with hemophilia. Increase in frequency of spontaneous bleedings at the patients with hemophilia receiving anti-retrovirus inhibitors of protease was observed.

Patients with coinfections a virus of hepatitis B and/or C. At patients with these infections increase in activity of hepatic transaminases, than more often was found in patients without the accompanying viral hepatitis In or Page.

Interaction with other medicines:

Darunavir and ритонавир are CYP3A4 isoenzyme inhibitors. Simultaneous use of a combination PREZISTA/ritonavir and drugs which are metabolized preferential by CYP3A4 isoenzyme can cause increase in concentration of such drugs in plasma that, in turn, can be the cause of strengthening or prolongation of therapeutic effect, and also the reason of emergence of side effects.

The combination PREZISTA/ritonavir should not be applied along with drugs which clearance in many respects is defined by an isoenzyme of CYP3A4 and which increased concentration in plasma can cause serious and/or life-threatening side effects (narrow therapeutic range). Treat such drugs астемизол, алфузозин, sildenafit (applied to therapy of pulmonary arterial hypertension), терфенадин, midazolam (orally), to triazoles, цизаприд, Pimozidum, сертиндол and ergot alkaloids (for example, ergotamine, dihydroergotamine, ergometrine and methylergometrine), a combination lopinavir/ritonavir, Amiodaronum, bepridit, quinidine, lidocaine at system introduction, симвастатин, ловастатин. 

Rifampicin is the strong inductor of CYP450 enzymes. The combination PREZISTA/ritonavir cannot be used along with rifampicin as in such cases concentration of a darunavir in plasma can significantly decrease. Loss of therapeutic effect of drug PREZISTA can be a consequence of it. 

The combination PREZISTA/ritonavir cannot be applied along with the drugs containing extract of a St. John's Wort of made a hole (Hypericum perforatum) as it can be followed by significant decrease in concentration of a darunavir in plasma owing to what the therapeutic effect of drug PREZISTA can disappear.

Recommendations about simultaneous use with other anti-retrovirus drugs. Inhibitors of transfer of a molecular chain of an integraza.

Raltegravir. On the basis of results of a number of clinical trials it is assumed what ралтегравир can cause insignificant decrease in concentration of a darunavir in a blood plasma. Now influence of a raltegravir on concentration of a darunavir in a blood plasma is not represented clinically significant. Dose adjustment of drug PREZISTA at combined use with a low dose of a ritonavir and raltegraviry is not required.

Нуклеозидные / nucleotide inhibitors of the return transcriptase. Didanozin. 

The combination PREZISTA/ritonavir (600/100 mg 2 times a day) along with didanoziny can be used without dose adjustment. As диданозин it is recommended to apply on an empty stomach, it can be taken for 1 h to or in 2 h after reception of a combination PREZISTA/ritonavir which is accepted during food.

Tenofovir. Results of a research of interaction between tenofoviry (a tenofovira dizoproksit the fumarating 300 mg a day) and a combination darunavir/ritonavir (300 mg / 100 mg two times a day) showed that concentration of a tenofovir in plasma increased by 22%. This change is not clinically significant. At simultaneous use of a tenofovir and darunavir renal excretion of both drugs did not change.

Tenofovir did not exert significant impact on concentration of a darunavir in plasma. At simultaneous use of a combination PREZISTA/ritonavir and the tenofovira of correction of doses is not required.

Other nukleozidny inhibitors of the return of transcriptases. Other nukleozidny inhibitors of the return transcriptase (a zidovudine, залцитабин, эмтрицитабин, ставудин, ламивудин and абакавир) eliminirutsya preferential by kidneys and therefore probability of their interaction with a combination darunavir/ritonavir it is insignificant is small.

Nenukleozidny inhibitors of the return transcriptase.

Etravirin. When studying interaction of a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and an etravirina reduction of concentration of an etravirin by 37% was revealed and essential changes of concentration of a darunavir are not revealed. Thus, the combination PREZISTA/ritonavir can be appointed at the same time from 200 mg of an etravirin 2 times a day without change of a dose.

Efavirenz. The research of interaction between a combination darunavir/ritonavir (300 mg / 100 mg two times a day) and efavirenzy was conducted (600 mg once a day). In the presence of an efavirenz decrease in concentration of a darunavir in plasma for 13% was observed. On the other hand, concentration in plasma of an efavirenz increased by 21% at its simultaneous use with a combination darunavir/ritonavir. This interaction is not clinically significant and therefore the combination PREZISTA/ritonavir and эфавиренз can be applied at the same time without correction of doses of drugs.

Not Virapinum. Results of a research of interaction between a combination darunavir/ritonavir (400 mg / 100 mg two times a day) and not Virapinum (200 mg two times a day) showed that concentration in plasma of a darunavir did not depend on presence of not Virapinum. At the same time, at simultaneous use with a combination darunavir/ritonavir concentration of not Virapinum in plasma increased by 27% (in comparison with control). This interaction is considered clinically insignificant and therefore the combination darunavir/ritonavir and not Virapinum can be applied at the same time without change of their doses.

Rilpivirin. Results of a research of interaction between a combination PREZISTA/ritonavir (800 mg / 100 once a day) with rilpiviriny (150 mg once a day) did not show to mg clinically significant influence on concentration of a darunavir. Concentration of a rilpivirin increased by 130% at simultaneous use with a combination PREZISTA/ritonavir. This interaction is considered clinically insignificant and therefore the combination PREZISTA/ritonavir and рилпивирин can be applied at the same time without change of their doses.

Protease inhibitors. Ritonavir. In general the effect of improvement of pharmacokinetics of a darunavir ritonaviry was shown that concentration of a darunavir in plasma increased approximately by 14 times after reception of one dose of a darunavir (600 mg) and 100 mg of a ritonavir two times a day. Therefore, drug PREZISTA needs to be used in a combination with a low dose of a ritonavir for increase in bioavailability of a darunavir.

Combination lopinavir/ritonavir. Results of a research of interaction between a combination darunavir/ritonavir (1200 mg / 100 mg two times a day) or 1200 mg of a darunavir without ritonavir and a combination lopinavir/ritonavir (400 mg / 100 mg two times a day or 533 mg / 133,3 mg two times a day) showed that in the presence of a combination lopinavir/ritonavir concentration of a darunavir in plasma decreased by 40%. PREZISTA/ritonavir is not recommended to apply a combination lopinavir/ritonavir along with a combination.

Sakvinavir. The research of interaction of a darunavir (400 mg two times a day), a sakvinavira (1000 mg two times a day) and a ritonavira (100 mg two times a day) showed that concentration of a darunavir in plasma decreased by 26% in the presence of a sakvinavir and a ritonavir; on the other hand, the combination darunavir/ritonavir did not influence concentration of a sakvinavir in plasma. It is not recommended to apply саквинавир along with Prezistanezavisimo's drug from use of a small additional dose of a ritonavir.

Atazanavir. The research of interaction between a combination darunavir/ritonavir (400 mg / 100 two times a day) and atazanaviry (300 mg once a day) showed to mg lack of significant change of concentration of a darunavir and atazanavir in plasma at their simultaneous use. Atazanavir it is possible to use along with a combination darunavir/ritonavir.

Indinavir. In a research of interaction between a combination darunavir/ritonavir (400 mg / 100 mg two times a day) and indinaviry (800 mg two times a day) concentration of a darunavir in plasma increased by 24% in the presence of an indinavir and a ritonavir; in the presence of a combination darunavir/ritonavir concentration in plasma of an indinavir increased by 23%. When using in combination with a combination PREZISTA/ritonavir it is possible to reduce a dose of an indinavir at patients who badly transfer it from 800 mg two times a day to 600 mg two times a day.

Other inhibitors of protease. So far did not study interaction between a combination PREZISTA/ritonavir and protease inhibitors in addition to a lopinavir, a sakvinavir, an atazanavir and an indinavir and therefore the inhibitors of protease which are not listed here are not recommended to be applied along with a combination darunavir/ritonavir.

Antagonists of receptors of CCR5. At simultaneous use of a combination PREZISTA/ritonavir a maravirok has to be appointed in a dosage of 150 mg 2 times a day. In a research of interaction between a combination darunavir/ritonavir (600 mg / 100 mg two times a day) and maraviroky (150 mg 2 times a day) concentration of a maravirok increased by 305%. Influence of a maravirok on concentration of a darunavira/ritonavir was not noted.

Recommendations about simultaneous use with drugs of other classes.

Antiarrhytmic means (bepridit, system lidocaine, quinidine, Amiodaronum, флекаинид, пропафенон). The combination PREZISTA/ritonavir can increase concentration in serum of a bepridil, lidocaine, quinidine, Amiodaronum, flekainid and propafenon. At simultaneous use of the specified combination and the transferred antiarrhytmic funds it is recommended to be careful and, whenever possible, to carry out monitoring of concentration of these means in plasma.

Digoxin. In all researches on interaction of a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and a single dose of digoxin (0,4 mg) increase in final concentration of digoxin in plasma for 77% was shown. It is recommended to appoint originally the minimum dose of digoxin and to measure its concentration in serum кровидля obtaining desirable clinical effect at co-administration with a combination PREZISTA/ritonavir.

Anticoagulants. The combination PREZISTA/ritonavir can influence concentration of warfarin in plasma.

At simultaneous use of warfarin and this combination it is recommended to carry out monitoring of the international normalized relation.

Anticonvulsant drugs (phenobarbital, Phenytoinum and carbamazepine).

Phenobarbital and Phenytoinum are inductors of CYP450 enzymes. PREZISTA/ritonavir is not recommended to apply a combination in combination with the specified drugs as it can cause significant decrease in concentration of a darunavir in plasma and, therefore, reduction of its therapeutic effect. The research of interaction between a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and carbamazepine (200 mg 2 times a day) showed that concentration of a darunavir in that case does not change while concentration of a ritonavir decreases by 49%. Concentration of carbamazepine increases by 45%. Change of a dose for a combination PREZISTA/ritonavir is not required. In need of co-administration PREZISTA/ritonavir and carbamazepine, patients have to be observed in connection with possibility of side effects of use of carbamazepine. Concentration of carbamazepine have to be measured, and its doses have to be adjusted according to clinical manifestations. Thus, doses of carbamazepine can be reduced by 25-50% at joint appointment with a combination PREZISTA/ritonavir.

Antimalarial drugs. At a research of interaction between a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and a combination artemeter/lumefantrin (80/480 mg, 6 doses accepted at 0, 8, 24, 36, 48 and 60 hours) increase in concentration of a lumefantrin by 2,75 times while concentration of a darunavir did not change was shown.

Concentration of an artemeter and his active metabolite, digidroartemizinin, decreased by 16% and 18% respectively. The combination of drug PREZISTA and artemeter/lumefantrin can be used without correction of doses. However because of increase in concentration of a lumefantrin, this combination has to be used with care.

Antidepressants (Trazodonum, desipramine).

Combined use of PREZISTA/ritonavir with Trazodonum and desipramine can lead to increase in concentration of Trazodonum and desipramine in plasma. It can cause such side effects as nausea, dizziness, a lowering of arterial pressure, a faint. In case of need combined use of the specified drugs and a combination PREZISTA/ritonavir it is necessary to be careful and consider the possibility of use of smaller doses of Trazodonum and desipramine.

Benzodiazepines (midazolam parenterally). Combined use of PREZISTA/ritonavir with parenterally entered midazolam can lead to increase in concentration of midazolam in plasma. At combined use it is necessary to carry out careful clinical monitoring and to take urgent measures in case of respiratory depression or long sedation. It is necessary to consider the possibility of a dose decline of midazolam, especially in case of long therapy. PREZISTA/ritonavir's use with peroral midazolam is contraindicated.

Neuroleptics. Risperidon, тиоризадин.

At combined use of neuroleptics with a combination PREZISTA/ritonavir their concentration in plasma can increase owing to what at combined use it is necessary to reduce doses of neuroleptics.

Kvetiapin. Because drug PREZISTA inhibits CYP3A4 isoenzyme, concentration of a kvetiapin in blood increases at combined use with drug PREZISTA. Combined use of a kvetiapin and drug PREZISTA contraindicated as at the same time toxicity of a kvetiapin can amplify. Increase in concentration of a kvetiapin can lead to a coma.

Colchicine. At combined use of colchicine with a combination PREZISTA/ritonavir can increase concentration of colchicine in plasma. The following scheme of change of a dose of colchicine is recommended. For therapy of exacerbations of gout for the patients receiving a combination PREZISTA/ritonavir, the recommended dose of colchicine makes 0,6 mg, with the subsequent reception of 0,3 mg in 1 hour. It is necessary to repeat a course of treatment not earlier, than in 3 days. For prevention of aggravations for the patients receiving a combination PREZISTA/ritonavir, the recommended dose of colchicine makes 0,3 mg every day or every other day. For therapy of family Mediterranean fever for the patients receiving a combination PREZISTA/ritonavir, the maximum dose of colchicine has to make 0,6 mg once a day (or 0,3 mg twice a day). Patients with reduced function of kidneys or a liver should not appoint colchicine at combined use with PREZISTA/ritonavir.

Blockers of "slow" calcium channels. Concentration in plasma of blockers of "slow" calcium channels (for example, a felodipina, nifedipine, a nikardipin) can increase at their simultaneous use with a combination PREZISTA/ritonavir. In such cases it is necessary to watch closely a condition of patients.

Klaritromitsin. The research of interaction between a combination darunavir/ritonavir (400 mg / 100 mg two times a day) and klaritromitsiny (500 mg two times a day) showed that concentration of a klaritromitsin in plasma increased by 57% whereas concentration of a darunavir was left without changes. At patients with renal failures it is recommended to reduce a dose of a klaritromitsin. 

Dexamethasone. Dexamethasone at receipt in a blood stream induces CYP3A4 isoenzyme in a liver that leads to reduction of concentration in plasma of a darunavir. It can lead to decrease in its therapeutic effect. It is recommended to be careful at simultaneous use of dexamethasone and a darunavir.

Bozentan. At simultaneous use of a bozentan and combination PREZISTA/ritonavir can increase concentration of a bozentan in plasma. The initial dose of a bozentan of 62,5 mg or every other day depending on individual portability is recommended every day to the patients receiving a combination PREZISTA/ritonavir within at least 10 days. For the patients accepting бозентан and beginning therapy with a combination PREZISTA/ritonavir PREZISTA/ritonavir is recommended to cancel бозентан at least in 36 hours prior to therapy. At least in 10 days after the beginning of therapy PREZISTA/ritonavir it is necessary to continue by a combination reception of a bozentan in a dosage of 62,5 mg every day or every other day depending on individual portability.

Flutikazon, будесонид. At simultaneous use of an inhalation flutikazon and combination PREZISTA/ritonavir concentration of a flutikazon in plasma can increase.

Similar interaction can be observed at use of other glucocorticosteroids, metaboliziruyemy by CYP3A4 isoenzyme, for example a budesonida. It is reasonable to use the drugs alternative to a flutikazon which are not CYP3A4 substrate (for example, beclomethasone).

Antiviral drugs of direct action. Hepatitis C protease NS3-4A inhibitors.

Botseprevir. In a research on interaction between a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and botsepreviry (800 mg 3 times a day), concentration of a darunavir decreased by 44%, and concentration of a botseprevir decreased by 32%. Thus, PREZISTA/ritonavir together with botsepreviry is not recommended to apply a combination.

Telaprevir. In researches of interaction between a combination PREZISTA/ritonavir (600 mg / 100 mg two times a day) with telapreviry (to 750 mg there are each 8 hours), concentration of a darunavir decreased by 40%, and concentration of a telaprevir decreased by 35%. The concomitant use of a combination PREZISTA/ritonavir with telapreviry is not recommended.

Vegetable drugs. The drugs containing extract of the St. John's Wort which is made a hole. Extract of the St. John's Wort which is made a hole lowers concentration of a darunavir and a ritonavir in a blood plasma (induction of enzymes of a liver). The combination PREZISTA/ritonavir should not be applied together with the drugs containing extract of the St. John's Wort which is made a hole. If the patient began to accept the drugs containing extract of the St. John's Wort which is made a hole it is necessary to stop their reception and, whenever possible, to check titres of viruses. Concentration of a darunavir (as well as concentration of a ritonavir) can increase after the termination of administration of drugs, containing extract of the St. John's Wort which is made a hole. Such effect can remain within two weeks after cancellation of the drugs containing extract of the St. John's Wort which is made a hole.

Drugs from group of statines. In metabolism of statines, such as симвастатин, розувастин and ловастатин, the large role is played by CYP3A4 isoenzyme therefore their concentration in plasma can significantly increase when using along with a combination PREZISTA/ritonavir. The increased concentration of statines can cause a myopathy, including рабдомиолиз. Considering told, PREZISTA/ritonavir along with lovastatiny, rozuvastiny or simvastatiny is not recommended to apply a combination. The interaction research between atorvastatiny (10 mg once a day) and a combination darunavir/ritonavir (300 mg / 100 mg two times a day) showed that in this situation concentration of an atorvastatin in plasma was only 15% lower, than at monotherapy atorvastatiny (40 mg once a day). In need of simultaneous use of an atorvastatin and a combination darunavir/ritonavir it is recommended to begin with a dose of an atorvastatin 10 mg once a day. Further it is possible to raise gradually a dose of an atorvastatin, being guided by clinical effect of therapy.

The combination darunavir/ritonavir (600 mg / 100 mg two times a day) increased concentration of a pravastatin in plasma after reception of one dose of this drug (40 mg) approximately for 80%, but only at a part of patients. In need of joint purpose of a pravastatin and a combination PREZISTA/ritonavir is recommended to begin reception of a pravastatin with the minimum possible doses and to increase doses before emergence of clinical effect, controlling manifestation of side effects of drug. The research of interaction between a combination PREZISTA/ritonavir (600 mg / 100 mg) with rozuvastatiny (10 mg) revealed increase in concentration of a rozuvastatin. In need of simultaneous use of a rozuvastatin and a combination PREZISTA/ritonavir is recommended to begin with the smallest dose of a rozuvastatin, gradually increasing a dose before obtaining clinical effect, constantly controlling safety of therapy.

Blockers of H2-histamine receptors and inhibitors of the proton pump. Use of an omeprazol (20 mg once a day) or ranitidine (150 mg two times a day) along with a combination darunavir/ritonavir (400 mg / 100 mg two times a day) did not exert impact on concentration of a darunavir in plasma. Considering these data, a combination PREZISTA/ritonavir it is possible to apply along with antagonists of H2 receptors and inhibitors of the proton pump without change of a dose of any of the specified drugs.

Inhalation beta-adrenergic agonists (салметерол). Simultaneous use of a salmeterol and combination PREZISTA/ritonavir is not recommended since the risk of emergence of side effects of a salmeterol from cardiovascular system can increase, including lengthening of an interval of QT, tachycardia and sinus tachycardia.

Immunodepressants (cyclosporine, такролимус, сиролимус). Concentration in plasma of cyclosporine, a takrolimus and sirolimus can increase in a case of use of these drugs along with a combination PREZISTA/ritonavir. In these situations it is recommended to control concentration of immunodepressive means in plasma.

Ketokonazol, итраконазол, Clotrimazolum and вориконазол. Ketokonazol, итраконазол, Clotrimazolum and вориконазол are strong inhibitors of an isoenzyme CYP3A4, and also its substrates.  PREZISTA/ritonavir can lead system use of a ketokonazol, itrakonazol, Clotrimazolum and vorikonazol along with a combination to increase in concentration of a darunavir in plasma. On the other hand, this combination can increase concentration in plasma of a ketokonazol or itrakonazol. It was confirmed with an interaction research between ketokonazoly (200 mg two times a day) and a combination darunavir/ritonavir (400 mg / 100 to mg two times a day) in which concentration of a ketokonazol and a darunavir increased by 212% and 42% respectively. In need of use of a combination darunavir/ritonavir along with ketokonazoly or itrakonazoly the daily dose of the last should not exceed 200 mg. Concentration of a vorikonazol in plasma can decrease at combined use with darunavirom/ritonaviry. Vorikonazol it is not necessary to apply along with darunavirom/ritonaviry, simultaneous use is possible only if the potential advantage of use of a vorikonazol exceeds potential risk. At combined use of Clotrimazolum and combination darunavir/ritonavir it is necessary to be careful, and also it is recommended to make constant clinical observation of the patient.

Beta adrenoblockers (метопролол, Timololum). PREZISTA/ritonavir can lead combined use of beta adrenoblockers and a combination to increase in concentration of beta adrenoblockers. At simultaneous use of the specified drugs and a combination PREZISTA/ritonavir it is necessary to be careful and carry out careful clinical monitoring, the dose decline of beta adrenoblockers can be also required.

Methadone. In a research of influence of a combination PREZISTA/ritonavir (600/100 mg 2 times a day) on a stable maintenance therapy methadone, showed reduction by 16% of concentration of R-methadone in plasma. On the basis of pharmacokinetic and clinical results, during the beginning of therapy PREZISTA/ritonavir is not required to dose adjustment of methadone. However it is recommended to carry out clinical monitoring as the maintenance therapy demands correction from some patients.

Buprenorphine/Naloxonum. Results of a research of interaction of a combination PREZISTA/ritonavir with buprenorphine/Naloxonum showed lack of influence of a combination PREZISTA/ritonavir on concentration of buprenorphine at their combined use. Concentration of an active metabolite of buprenorphine – a norbuprenorfin increased by 46%. Dose adjustment of buprenorphine was not required. At joint reception of a combination PREZISTA/ritonavir and buprenorphine is recommended to carry out careful clinical monitoring.

The estrogen-containing peroral contraceptive means. Results of a research on interaction between a combination PREZISTA/ritonavir (600/100 mg 2 times a day) both ethinylestradiol and Norethisteronum demonstrate that constant concentration in plasma of ethinylestradiol and Norethisteronum decreases respectively by 44% and 14%. Therefore, it is recommended to use alternative non-hormonal methods of contraception.

Inhibitors of phosphodiesterase of the 5th type (FDE-5). At therapy of erectile dysfunction. In one of researches studied concentration of a sildenafil after reception of one dose of this drug (100 mg), and also after reception of 25 mg of a sildenafil along with a combination darunavir/ritonavir (400 mg / 100 mg two times a day). Concentration of a sildenafil were similar in both situations. It is necessary to be careful at simultaneous use of FDE-5 inhibitors for therapy of erectile dysfunction and a combination PREZISTA/ritonavir. In need of use of PREZISTA and a ritonavir along with sildenafily, vardenafily or tadalafily the single dose of a sildenafil should not exceed 25 mg during 48 h, the single dose of a vardenafil should not be more than 2,5 mg during 72 h, and the single dose of a tadalafil should not exceed 10 mg during 72 h.

At therapy of pulmonary arterial hypertension. The safe and effective dose of a sildenafil for therapy of pulmonary arterial hypertension is not established. There is an increased risk of development of side effects of a sildenafil (including a vision disorder, arterial hypotension, the prolonged erection and a syncope). Thus, PREZISTA/ritonavir also sildenafit simultaneous use of a combination at therapy of pulmonary arterial hypertension contraindicated. For therapy of pulmonary arterial hypertension tadalafily at simultaneous use with a combination PREZISTA/ritonavir is required change of doses of a tadalafil. For the patients receiving a combination PREZISTA/ritonavir within at least one week, the initial dose of a tadalafil has to make 20 mg with possible increase up to 40 mg on the basis of individual portability once a day once a day. For the patients receiving tadalafit and beginning therapy with a combination PREZISTA/ritonavir, it is necessary to cancel PREZISTA/ritonavir tadalafit at least in 24 hours prior to therapy by a combination and it is necessary to avoid simultaneous use of a tadalafil during the beginning of therapy by a combination PREZISTA/ritonavir. In 1 week after the beginning of therapy by a combination PREZISTA/ritonavir it is necessary to resume reception of a tadalafil in a dose of 20 mg with possible increase up to 40 mg on the basis of individual portability once a day once a day.

Rifabutin. Rifabutin is substrate of CYP450 enzymes. In studying of interaction of a combination PREZISTA/ritonavir (600/100 mg 2 times a day) and a rifabutina (150 mg every other day) increase in concentration of a darunavir by 57% was observed. Based on a profile of safety of a combination PREZISTA/ritonavir, increase in concentration of a darunavir in the presence of a rifabutin does not demand dose adjustment for PREZISTA/ritonavir. Studying of interaction showed comparable concentration at use of 300 mg of a rifabutin of 1 times a day and 150 mg every other day in a combination with PREZISTA/ritonavir (600/100 mg 2 times a day), and also increase in concentration of active metabolite 25-O-dezatsetilrifabutina. At purpose of such combination patients need reduction of a dose of a rifabutin by 75% of a usual dose of 300 mg a day (for example, 150 mg every other day) and the increased control of side effects of a rifabutin.

Rifampicin. Rifampicin is the strong inductor of an isoenzyme CYP3A4, and causes significant decrease in concentration of other inhibitors of protease that can become the reason of virologic failure and development of resistance. In attempts to compensate this decrease in concentration by increase in a dose of other inhibitors of protease accepted with a low dose of a ritonavir reactions from a liver (increase in activity of enzymes of a liver) were observed. Combined use of rifampicin and combination PREZISTA/ritonavir contraindicated.

Selective serotonin reuptake inhibitors. The interaction research between paroksetiny (20 mg once a day) or sertraline (50 mg once a day) and a combination PREZISTA/ritonavir (400 mg / 100 mg two times a day) showed that concentration of a darunavir in plasma did not depend on presence of sertraline or a paroksetin. On the other hand, in the presence of a combination PREZISTA/ritonavir concentration in plasma of sertraline and a paroksetin decreased by 49 and 39% respectively. When selective serotonin reuptake inhibitors should be applied along with PREZISTA and ritonaviry, it is necessary to select carefully a dose of these inhibitors on the basis of clinical assessment of antidepressive effect. In addition, at the patients receiving a stable dose of sertraline or a paroksetin who begin to be treated a combination PREZISTA/ritonavir it is necessary to control expressiveness of the main effect of antidepressant attentively.

Contraindications:

Hypersensitivity to a darunavir or to any excipient which is a part of drug.

Concomitant use with drugs which clearance preferential is defined by an isoenzyme of P450 CYP3A4 cytochrome and which increase in concentration in plasma is accompanied by emergence of serious and/or life-threatening side effects (narrow therapeutic range). Treat such drugs астемизол, алфузозин, sildenafit (applied to therapy of pulmonary arterial hypertension), терфенадин, midazolam (orally), rifampicin, to triazoles, цизаприд, Pimozidum, сертиндол, кветиапин,   bepridit the drugs containing extract of the St. John's Wort which is made a hole the drugs containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergometrine), a combination lopinavir/ritonavir, Amiodaronum, quinidine, lidocaine at system introduction, симвастатин, ловастатин (see also section "Interactions with Other Medicines").

 Heavy liver failure (a class C on Chayld-Pyyu).

Children's age up to 18 years (for this dosage).

With care:

- at patients with an abnormal liver function of easy and average degree (a class A and B on Chayld-Pyyu).

- at patients with an allergy to sulfonamides.

Overdose:

Data on acute overdose at administration of drug of PREZISTA in a combination with ritonaviry at people are limited. Healthy volunteers accepted once up to 3200 mg of a darunavir in the form of solution and to 1600 mg in the form of tablets PREZISTA in a combination with ritonaviry, at the same time adverse effects are noted.

The specific antidote is unknown. At overdose it is necessary to carry out the general maintenance therapy with monitoring of the main physiological indicators. At the corresponding indications for removal of not soaked up drug it is necessary to cause vomiting. It is also possible to apply absorbent carbon. Darunavir preferential contacts proteins of plasma therefore significant removal of active substance by method of dialysis is improbable.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 400 mg, 600 mg.

On 60 tablets in a bottle from polyethylene of high density. Each bottle together with the application instruction is placed in a cardboard pack.