Prezista

General characteristics. Structure:

Active agent:

Darunavir of 75 mg (there correspond 81,31 mg of a darunavir of ethanolat).

Darunavir of 150 mg (there correspond 162,62 mg of a darunavir of ethanolat).

Excipients: PROSOLV SMCC HD90 (are a part cellulose microcrystallic, silicon dioxide colloid anhydrous), кросповидон, silicon dioxide colloid anhydrous, magnesium stearate.

Cover: dye of Opadray the II white 85F18422 ( dioxide (E171), talc are a part partially hydrolyzed polyvinyl alcohol, a macrogoal 3350, titanium).

Description: tablets of 75 mg: white, kapsulovidny tablets, film coated, with an engraving on one of the parties "75", and on another – "TMS". On a break of a tablet of white or almost white color.

Tablets of 150 mg: white, oval tablets, film coated, with an engraving on one of the parties "150", and on another – "TMS". On a break of a tablet of white or almost white color.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Darunavir is inhibitor of dimerization and catalytic activity of protease of a human immunodeficiency virus of the 1st 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 x 10-12 mol/l). Darunavir is steady against 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 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 alfa1-acid glycoprotein at the patients infected with VICh-1 and therefore large numbers of a darunavir contact an alfa1-acid glycoprotein of plasma.

Darunavir is metabolized generally by CYP3A4 isoenzymes. Ritonavir inhibits isoenzymes of CYP3A4 of a liver and, thereby, significantly increases concentration of a darunavir in plasma.

Absorption. After intake дарунавир it is quickly absorbed 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 cumulative pharmacokinetic effect of a ritonavir 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, pill PREZISTA needs to be taken 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 alfa1-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 intensively metabolized 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. 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 PREZISTA/ritonavir 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 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 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 adults and children aged from 6 years and with the body weight of 20 kg and more, earlier receiving anti-retrovirus therapy (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 PREZISTA/ritonavir.

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

Adult patients:

Dosages of 75 mg and 150 mg are developed for use in children's practice. For achievement of therapeutic doses these dosages demand reception of a large number of tablets from adults that on the one hand complicates their proglatyvaniye, with another – can cause allergic reactions because of the increased intake of the excipients which are contained in tablets therefore they have to be applied only at unavailability of other dosages.

The patients who were earlier receiving protease inhibitors. The recommended dose of drug PREZISTA makes 600 mg 2 times a day in a combination from 100 mg of a ritonavir 2 times a day; the combination is accepted during food. The type of food does not influence absorption of a darunavir.

For the patients who were earlier receiving protease inhibitors carrying out genotypic analyses is recommended.

Children:

The patients from 6 to 18 years who were earlier receiving anti-retrovirus therapy. The recommended dose PREZISTA/ritonavir for children from 6 to 18 years and with a body weight not less than 20 kg depends on body weight (see the table below) and should not exceed the recommended dose for adult patients (600/100 mg 2 times a day). Pill PREZISTA has to be taken about ritonaviry 2 once a day during food. The type of food does not influence absorption of a darunavir.

The recommended dose of tablets PREZISTA and a ritonavira for patients from 6 to 18 years which were earlier receiving anti-retrovirus therapy

Body weight (kg) / dose: 

≥ 20 kg – <30 kg 375 mg of PREZISTA/50 of mg of a ritonavir 2 times a day

≥ 30 kg – <40 kg 450 mg of PREZISTA/60 of mg of a ritonavir 2 times a day

≥ 40 kg 600 mg of PREZISTA/100 of mg of a ritonavir 2 times a day.

In case of the admission of a dose of PREZISTA and/or a ritonavir within 6 hours after usual time of reception, it is necessary to accept the appointed dose of PREZISTA and/or a ritonavir as soon as possible. If after usual time of administration of drug there passed more than 6 hours, it is recommended to adhere to the established scheme of administration of drug. These recommendations are based on a 15-hour elimination half-life of a darunavir in the presence of a ritonavir and the set mode of administration of drug every 12 hours.

Patients with abnormal liver functions. With an easy or moderate abnormal liver function of dose adjustment it is not required from patients. Information on use of a combination therapy PREZISTA/ritonavir at heavy abnormal liver functions is absent; therefore, it is not possible to make specific recommendations about dosing.

Patients with renal failures. With renal failures change of doses in a combination PREZISTA/ritonavir is not required from patients.

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 dysfunction of a liver meets and they more often have associated diseases or receive the accompanying 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. 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.

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 transaminases of a liver are recorded. Stephens-Johnson's syndrome was recorded seldom (<0,1%). In the post-marketing period the toxic epidermal necrolysis was recorded 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, an obshchimnedomoganiye, muscle or joints pains, blisters, defeats of an oral cavity, conjunctivitis, hepatitis and/or an eosinophilia) administration of drug of PREZISTA needs to be stopped immediately. Rash (all types) was observed at 10,3% of the patients accepting PREZISTA. Rash generally was easy or moderate 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.

Darunavir contains sulphonamide group. Appointment Prezistapatsiyentam with an allergy to sulfonamides has to be made with care. In clinical trials PREZISTA/ritonavir degree and frequency of developing of rash were identical at patients with an allergy to sulfonamides in the anamnesis and without it.

Patients with associated diseases. Patients with liver diseases.

Data on use PREZISTA/ritonavir at patients with a heavy abnormal liver function are absent. Based on data that stable pharmacokinetic parameters at use of a darunavir for persons with an easy and moderate abnormal liver function are comparable with parameters at healthy faces, dose adjustment is not required to patients with an easy and moderate abnormal liver function.

Hepatotoxic. At use of a combination PREZISTA/ritonavir is observed the hepatitis caused by use of medicines (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 PREZISTA/ritonavir was observed. In case of detection of abnormal liver functions or deterioration in their weight (including clinically significant increase in activity of "hepatic" 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 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 relationship of cause and effect 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 HIV - the infected 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.

Syndrome of immune reactivation. 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 as examples. It is necessary to define weight of any symptoms of an inflammation and to carry out the corresponding therapy. Osteonecrosis cases, especially at patients with the standard risk factors, HIV infection at a late stage or being on the long combined anti-retrovirus therapy were noted. Frequency of an osteonecrosis is unknown.

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 driving and moving mechanisms. Researches about influence of use of a combination PREZISTA/ritonavir on ability to driving and moving mechanisms were not conducted. However by consideration of ability of the patient to driving and moving mechanisms, it is necessary to consider the dizziness noted at some patients receiving therapy by a combination PREZISTA/ritonavir.

Side effects:

The most frequent side effects (≥ 2%) average or heavy degree (2 and more degrees) are diarrhea, a gipertriglitseridemiya, rash, nausea, a hypercholesterolemia and a headache. The most frequent side effects of heavy degree (3-4 degrees) are increase in activity of "hepatic" and pancreatic enzymes.

 2,6% of patients stopped therapy in connection with emergence of side effects.

Information on side effects at the adult patients who were earlier receiving anti-retrovirus therapy at use of 600/100 mg PREZISTA/ritonavir 2 times a day is given below.

Undesirable side effects are grouped in bodies and frequency of emergence. Frequency was determined as: very often ≥ 10%, are frequent - 1-10%, infrequently - 0,1-1%.

From system of a hemopoiesis and lymphatic system:

- infrequently: thrombocytopenia, neutropenia, anemia, increase in quantity of eosinophils, leukopenia.

From cardiovascular system:

- infrequently: myocardial infarction, stenocardia, lengthening of an interval of QT, sinus bradycardia, tachycardia, heart consciousness, increase in arterial pressure, blood "inflows".

From a respiratory organs:

- infrequently: short wind, cough, nasal bleeding, a rhinorrhea, irritation in a throat.

From system of digestion:

- very often: diarrhea;

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

- infrequently: pancreatitis, gastritis, a gastroesophagal reflux, stomatitis, including aphthous, a hematemesis, dryness in a mouth, discomfort in a GIT, a lock, increase in activity of a lipase, an eructation, disturbance of sensitivity of an oral cavity, a cheilitis, dryness of lips, a fur.

From gepatobiliarny system:

- often: increase in activity of alaninaminotranspherase and aspartate aminotransferase;

- infrequently: hepatitis, including cytolytic, a stenosis of a hepatic artery, a hepatomegalia, increase in activity of transaminase, an alkaline phosphatase, gammaglutamiltransferaza, increase in content of bilirubin in blood

From a nervous system:

- often: headache, peripheral neuropathy, dizziness;

- infrequently: faint, spasms, apathy, paresthesia, hypesthesia, ageusia, dysgeusia, disturbance of concentration of attention, memory disturbance, drowsiness, disturbance of phases of a dream.

Mental disturbances:

- often: sleeplessness;

- infrequently: depression, confusion of consciousness, disorientation, concern, differences of mood, sleep disorder, unusual dreams, dreadful dreams, decrease in a libido.

From an urinary system:

- infrequently: renal failure (including acute), nephrolithiasis, increase in concentration of creatinine, decrease in clearance of creatinine, proteinuria, bilirubinurea, dysuria, nokturiya, pollakiuria.

From an organ of sight:

- infrequently: decrease in clearness of sight, conjunctival hyperemia, xerophthalmus.

From an acoustic organ:

- infrequently: вертиго.

From immune system:

- infrequently: syndrome of immune reactivation.

From endocrine system:

- infrequently: a hypothyroidism, increase in production of the stimulating hormones of a thyroid gland.

From skin and soft tissues:

- often: rash (including makulezny, makulopapulezny, papular, erythematic and pruritic), itch;

- infrequently: generalized rash, dermatitis, including allergic, face edema, urticaria, eczema, erythema, hyperhidrosis, night perspiration, alopecia, acne, seborrheal dermatitis, xeroderma, change of pigmentation of nails.

It is revealed in the post-marketing period: toxic epidermal necrolysis.

From a musculoskeletal system and connecting fabric:

- infrequently: mialgiya, muscular spasms, weakness of muscles, arthritis, arthralgia, muscle tension, rigidity of joints, extremity pains, osteoporosis, increase in activity of a kreatininfosfokinaza.

It is revealed in the post-marketing period: osteonecrosis.

From reproductive system and mammary glands:

- infrequently: erectile dysfunction, gynecomastia.

Metabolic disturbances and disturbances of food:

- often: lipodystrophy (including lipogipertrofiya, lipodystrophy, lipoatrophia), gipertriglitseridemiya, giperkholesterolemiya, lipidemia;

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

Disturbances of the general character:

- often: adynamy, fatigue;

- infrequently: fervescence, pains in a breast, peripheral hypostases, feeling of an indisposition, a fever, feeling of heat, irritability, pains, a pathological xeroderma.

Other disturbances:

- infrequently: herpes simplex.

Frequency, type and severity of side effects at use ПРЕЗИСТА® for children and teenagers are comparable with those at adult patients.

Side effects at the combined anti-retrovirus therapy.

At HIV-positive patients the combined anti-retrovirus therapy can be followed by redistribution of fatty tissue of an organism (lipodystrophy). This redistribution includes loss of peripheral and front hypodermic fatty tissue, increase in amount of intraabdominal and visceral fat, a hypertrophy of mammary glands and accumulation of fat in dorsotservikalny area (formation of a fatty hump).

The combined anti-retrovirus therapy can cause the following metabolic disturbances also: gipertriglitseridemiya, hypercholesterolemia, insulin resistance, hyperglycemia and giperlaktatemiya.

HIV-positive patients with a heavy immunodeficiency during the initial combined anti-retrovirus therapy can have inflammatory reactions to asymptomatic or residual opportunistic infections. At the patients receiving protease inhibitors, especially in a combination with nenukleozidny inhibitors of the return transcriptase activity of a kreatinfosfokinaza can increase, arise a miositis and, seldom, рабдомиолиз.

HIV-positive patients with the accompanying infection a virus of hepatitis B and/or a virus of hepatitis C. 

At HIV-positive patients with the accompanying infection a virus of hepatitis B and/or hepatitis About treatment by a combination PREZISTA/ritonavir is not followed by higher frequency of side effects and changes of laboratory indicators (in comparison with HIV - the infected patients without hepatitis B and/or hepatitis C). The pharmacokinetics of a darunavir and ritonavir at patients with the accompanying infections of hepatitis B and/or C was similar to that at patients with HIV monoinfection, except for increase in activity of enzymes of a liver. 

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 Amiodaronum, bepridit, quinidine, system lidocaine, астемизол, альфузозин, sildenafit ( in case of use for therapy of pulmonary arterial hypertension), терфенадин, peroral midazolam, to triazoles, цизаприд, примозид, сертиндол, симвастатин, ловастатин and ergot alkaloids (for example, ergotamine, dihydroergotamine, ergometrine and methylergometrine). Rifampicin is the powerful inductor of isoenzymes of CYP450 cytochrome. The combination PREZISTA/ritonavir cannot be applied 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. 

Нуклеозидные / nucleotide inhibitors of the return transcriptase.

Didanozin. The combination PREZISTA/ritonavir (600/100 mg 2 times a day) along with didanoziny can be applied 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 of PREZISTA/ритонавир 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 PREZISTA/ritonavir and the tenofovira of correction of doses is not required. 

Other nukleozidny inhibitors of the return transcriptase. 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. However 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 PREZISTA/ritonavir and эфавиренз it is possible to apply 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.

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. 

Combination lopinavir/ritonavir. Results of a research of interaction between a combination darunavir/ritonavir (1200mg/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 533mg/133,3mg two times a day) showed that in the presence of a combination lopinavir/ritonavir concentration of a darunavir in plasma decreased by 40%. It is not recommended to apply a combination lopinavir/ritonavir along with PREZISTA/combination ритонавир.

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 increased 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 drug PREZISTA irrespective of 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 apply 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%. At use in combination with a combination PREZISTA/ritonavir it is possible to reduce a dose of an indinavir of upatsiyent which 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 dose 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) AUC of a maravirok increased to 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 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 blood serum for obtaining desirable clinical effect at co-administration with 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 isoenzymes of CYP450 cytochrome. 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 PREZISTA/ritonavir is not required. In need of co-administration PREZISTA/ritonavir and carbamazepine, the patient has to be under a postoyannymnablyudeniye of medical personnel in connection with possibility of side effects of use of carbamazepine. Concentration of carbamazepine have to be measured, iy doses have to be adjusted according to clinical manifestations. Takimobraz, doses of carbamazepine can be reduced by 25-50% at combined use with PREZISTA/ritonavir.

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 do vyzvattaky side effects as nausea, dizziness, a lowering of arterial pressure, a faint. In case of need combined use of the specified drugs and 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 (рисперидон, тиоризадин). At combined use of neuroleptics with PREZISTA/ritonavir their concentration in plasma can increase owing to what at combined use it is necessary to reduce doses of neuroleptics.

Colchicine. At combined use of colchicine with PREZISTA/ritonavir concentration of colchicine in plasma can increase. 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 (1 tablet), and 0,3 mg (½ tablets) 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 kombinatsiyuprezista/ritonavir the recommended dose of colchicine makes 0,3 mg every day иличерез 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 ПРЕЗИСТА®/ритонавиром.

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 situations 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 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 reception of a bozentan in a dose 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 corticosteroids, metaboliziruyemy by CYP3A4 isoenzyme, for example a budesonida. It is reasonable to use the drugs alternative to a flutikazon which are not CYP3A4 isoenzyme substrate (for example, beclomethasone).

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 at simultaneous use 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) raised a kontsentratsiyupravastatin 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 combined use of a pravastatin and 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.

Blockers of H2-histamine receptors and inhibitors of a proton pomp. 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 blockers of H2 receptors and inhibitors of a proton pomp 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.

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 and вориконазол. Ketokonazol, итраконазол and вориконазол are powerful inhibitors of an isoenzyme CYP3A4, and also its substrates. PREZISTA/ritonavir can lead system use of a ketokonazol, itrakonazol 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.

Clotrimazolum. Interaction of a combination PREZISTA/ritonavir with Clotrimazolum was not studied. At simultaneous use of Clotrimazolum and darunavir, and low doses of a ritonavir increase in concentration of a darunavir in plasma can be observed. At simultaneous use of combination ПРЕЗИСТА®/ритонавир and Clotrimazolum it is necessary to be careful and carry out clinical monitoring. 

Beta adrenoblockers (метопролол, Timololum). PREZISTA/ritonavir can lead combined use of beta adrenoblockers and a combination to increase in concentration of beta adrenoblockers. At a simultaneous 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 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 PREZISTA/ritonavir and buprenorphine it 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, decrease in arterailny pressure, the prolonged erection and faints). 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 isoenzymes of CYP450 cytochrome. In interaction studying 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 safety profile 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 of a vsutka), 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 and the increased control of side effects of a rifabutin.

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 CYP3A4 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, альфузозин, sildenafit (in case of use for therapy of pulmonary arterial hypertension), терфенадин, midazolam, to triazoles, цизаприд, Pimozidum, drugs containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergometrine) (see also undressed "Interactions with others.

 Concomitant use with drugs of the St. John's Wort which is made a hole rifampicin, a combination lopinavir/ritonavir (see also section "Interactions with Other Medicines").

Liver failure (a class C on Chayld-Pyyu).

Children's age up to 6 years.

With care:

− at patients with abnormal liver functions (classes A and B on Chayld-Pyyu).

− at patients with an allergy to sulfonamides.

− at patients 65 years are aged more senior.

− at a concomitant use of the medicines which are highly contacting an alfa1-acid glycoprotein.

− at patients with chronic hepatitises (including with a chronic viral hepatitis In and C).

− at patients with hemophilia.

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. For removal of not soaked up drug the gastric lavage or a cleansing enema is shown. Absorbent carbon can be applied. 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 75 mg, 150 mg.

75 mg: on 480 tablets in the bottle from polyethylene of high density closed by an aluminum film with the polypropylene cover protected from accidental opening by children.

150 mg: on 240 tablets in the bottle from polyethylene of high density closed by an aluminum film with the polypropylene cover protected from accidental opening by children.

Each bottle together with the instruction on a medical use is placed in a cardboard pack.