Presista - instructions for use, doses, side effects, contraindications

core: hypromellose 2910 13.20 mg, siliconized cellulose microcrystalline 177.72 mg, crospovidone 33.00 mg, silicon dioxide colloidal anhydrous 3.30 mg, magnesium stearate 5.50 mg;

film sheath: OUTSIDE ™ II dark red 85F15,004 44.00 mg.

The composition of the OUADRAY II dark red 85F150004 includes partially hydrolysed polyvinyl alcohol 40,000% by weight, Macrogol 3350 (Macrogol 4000) 20.200% by weight, titanium dioxide 8.850% by weight, talc 14.800% by mass, iron oxide red E172 16.150% by weight.

Description:

Oval tablets covered with a film shell of red-brown color, engraved on one side of the "800", and on the other - "T".On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.10 Darunavir

Pharmacodynamics:

Darunavir is an inhibitor of dimerization and catalytic activity of the protease of human immunodeficiency virus type 1 (HIV-1). The drug selectively inhibits the cleavage of polyproteins Gag-Pol HIV in viral-infected cells, preventing the formation of full-fledged viral particles.

Darunavir strongly binds to HIV-1 protease (K_D 4,5x10^-12 M). Darunavir is resistant to the effects of mutations that cause resistance to protease inhibitors. Darunavir does not inhibit any of the 13 human cell proteases studied.

Pharmacokinetics:

The pharmacokinetic properties of darunavir, used in combination with ritonavir, have been studied in healthy volunteers and in HIV-infected patients. The concentrations of darunavir in plasma were higher in patients infected with HIV-1 than in healthy people. This difference can be explained by higher concentrations of alpha-1-acid glycoprotein in patients infected with HIV-1, which leads to an increase in the amount of darunavir associated with the alpha-1-acid plasma glycoprotein. Darunavir is metabolized mainly by isoenzymes CYP3A. Ritonavir inhibits isoenzymes CYP3A and thereby substantially increases the concentration of darunavir in plasma.

Suction

After oral administration darunavir quickly absorbed in the gastrointestinal tract. The maximum concentration of darunavir in plasma in the presence of a low dose of ritonavir is achieved in 2.5-4.0 hours. The absolute bioavailability of a single dose of darunavir (600 mg) when ingested was approximately 37% and increased to approximately 82% in the presence of ritonavir (100 mg two times a day). The general effect of ritonavir on the bioavailability of darunavir consisted in an approximately 14-fold increase in the concentration of darunavir in plasma after ingestion of 600 mg of darunavir in combination with ritonavir (100 mg twice daily).

When taking an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir was 30% lower than when taken with meals. Therefore, the drug PRESIS® should be taken with ritonavir during meals. The nature of the food did not affect the concentration of darunavir in the plasma.

Distribution

About 95% of darunavir binds to plasma proteins, predominantly with an alpha-1-acid glycoprotein.

Metabolism

In experiments in vitro on human liver microsomes it was shown that darunavir is subjected primarily to oxidative metabolism. Darunavir is metabolized predominantly in the liver by the cytochrome P450 system, almost exclusively by the isoenzyme CYP3A4. A study in which healthy volunteers took ¹⁴C-darunavir, showed that most of the radioactivity in the plasma after a single dose of 400 mg of darunavir and 100 mg of ritonavir was accounted for by the unchanged darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; the activity of all these metabolites against wild-type HIV was less than 1/10 of that of darunavir itself.

Excretion

After a single dose of 400 mg ¹⁴C-darunavir and 100 mg of ritonavir were 79.5% and 13.9% of radioactivity was detected in feces and urine, respectively. The proportion of unchanged darunavir accounted for about 41.2% and 7.7% of radioactivity in feces and urine, respectively. The final half-life of darunavir was about 15 hours when taken in combination with ritonavir. The clearance of darunavir after intravenous administration of 150 mg was 32.8 l / h (without ritonavir) and 5.9 l / h in the presence of a low dose of ritonavir.

Special patient groups

Children

The pharmacokinetics of darunavir in combination with ritonavir in children aged 6 to 18 years and a mass of at least 20 kg is comparable to pharmacokinetics in adult patients receiving the PRESIS® / ritonavir combination 600/100 mg twice daily. The pharmacokinetics of darunavir in combination with ritonavir in children 3 to 6 years of age and in masses of 10 kg to 20 kg are comparable to pharmacokinetics in adult patients receiving the PRESIS® / ritonavir combination 600/100 mg twice daily.

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in pharmacokinetic parameters of darunavir in the age group 18-75 years (12 HIV-infected patients aged 65 years and older were included in this analysis).

Sexual differences

Population pharmacokinetic analysis revealed slightly higher (16.8%) concentrations of darunavir in HIV-infected women than in HIV-infected men. This difference is not clinically relevant.

Patients with impaired renal function

The results of the study using ¹⁴C-darunavir in combination with ritonavir showed that about 7.7% of the accepted dose of darunavir was excreted unchanged in urine.In patients with impaired renal function, the pharmacokinetics of darunavir were not studied, but population pharmacokinetic analysis showed no significant change in the pharmacokinetic parameters of darunavir in HIV-infected patients with moderate renal impairment (serum creatinine clearance of 30-60 ml / min, n=20).

Patients with hepatic impairment

Darunavir is metabolized and excreted mainly by the liver. In a study using several doses of PRESISTA® in combination with ritonavir (600/100 mg) twice daily, it was shown that the stable pharmacokinetic parameters of darunavir in patients with a lung (class A in Child-Pugh, n= 8) and moderate impairment of liver function (Child-Pugh class B, n= 8) were comparable with those of healthy individuals. The effect of severe liver dysfunction on the pharmacokinetics of darunavir has not been studied.

Indications:

Treatment of HIV infection in adult patients (in combination with low-dose ritonavir and other antiretroviral drugs).

Contraindications:

- Hypersensitivity to darunavir or to any auxiliary substance included in the preparation;

- aboutsimultaneous administration of the drug PRESISTA® and ritonavir in low doses with drugs, the clearance of which is predominantly determined by the isoenzyme cytochrome P450 CYP3A4, and an increase in plasma concentration is associated with the occurrence of serious and / or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, alfuzosin, colchicine (in patients with renal or hepatic insufficiency), sildenafil (used for the therapy of pulmonary arterial hypertension), terfenadine, midazolam (orally), triazolam, cisapride, pimozide, ranolazine, sertindole, quetiapine, preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergomethrin), a combination of lopinavir / ritonavir, amiodarone, beprideil, dronedaron, quinidine, lidocaine with systemic administration, simvastatin, lovastatin (see also the section "Interactions with other drugs"). When using PRESISTA® and ritonavir in low doses, patients should not simultaneously use drugs containing rifampicin, as well as preparations containing St. John's wort extract, as simultaneous application can lead to a decrease in the concentration of darunavir in plasma. This can lead to loss of therapeutic effect and development of resistance;

- thepatic insufficiency (class C according to Child-Pugh);

- dUp to 18 years of age (for this dosage).

Carefully:

- In patients with impaired liver function of mild and moderate degree (Child-Pugh class A and B);

- in patients with an allergy to sulfonamides.

Pregnancy and lactation:

There were no full-scale studies of darunavir in pregnant women. Studies in animals have not revealed darunavir's toxic activity or negative impact on reproductive function and fertility.

The combination of PRESIST® / ritonavir drugs can be given to pregnant women only when the expected benefit of its use for a future mother outweighs the potential risk to the fetus.

It is not known whether darunavir penetrate into breast milk. Studies in rats have shown that the drug penetrates into the milk. Given the possibility of HIV transmission with breast milk,as well as the risk of serious side effects in infants due to exposure to darunavir, HIV-infected women receiving PRESIS® should abstain from breastfeeding.

Dosing and Administration:

Inside. The drug PRESIS® should always be prescribed in combination with a low dose of ritonavir as a remedy to improve its pharmacokinetic characteristics, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before starting therapy with the PRESISTA® / ritonavir combination.

Patients should be instructed about taking PRESISTA® with a low dose of ritonavir no later than 30 minutes after eating.

After initiating PRESISTA® therapy, patients should not change or discontinue therapy without consulting the attending physician.

Adult patients:

Patients who have not previously received protease inhibitors

Patients who previously received protease inhibitors

not having mutations that cause resistance to darunavir *:

have at least 1 mutation that causes resistance to darunavir *

800 mg once a day in combination with 100 mg ritonavir, while eating

600 mg twice a day in combination with 100 mg ritonavir, while eating

* Mutations causing resistance to darunavir: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74R, L76V, I84U and L89V

For patients who have previously received protease inhibitors, genotypic assays are recommended.

If it is not possible to perform genotypic tests, patients who have not previously received protease inhibitors should take the PRESISTA / ritonavir combination once a day 800 mg / 100 mg, and patients who have previously received protease inhibitors are recommended to take the PRESISTA / ritonavir combination 2 times a day 600 mg / 100 mg.

The type of food does not affect the absorption of darunavir. Ritonavir (100 mg) is used as an enhancer of the pharmacokinetics of darunavir.

Elderly patients

Information on use in elderly patients is limited. Therefore, the combination of PRESIS® / ritonavir should be used with caution in patients of this age group.

Patients with hepatic impairment

In patients with mild or moderate degree of impaired liver function, dose adjustment is not required.Information on the use of combined PRESISTA® / ritonavir therapy for severe violations of liver function is absent; therefore, it is not possible to give specific recommendations for dosing.

Patients with impaired renal function

In patients with impaired renal function, dose changes in the PRESIST® / ritonavir combination are not required.

Skipping a PRESIS® / ritonavir combination

If the delay in receiving the PRESISTA® / ritonavir combination is less than 12 hours, the missed dose should be taken as soon as possible with food and the usual dosing regimen should be resumed.

If the delay in receiving the PRESISTA® / ritonavir combination is more than 12 hours, the missed dose should not be taken; the next dose is taken at the usual time.

Side effects:

The most frequent side effects during clinical trials and in postregistered period were: diarrhea, nausea, rash, headache and vomiting. The most frequent serious side effects were acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis and fever.

Side effects are given in accordance with the system-organ classification and the distribution by frequency of occurrence. In each frequency group, side effects are presented in order of decreasing severity.

The incidence of side effects is defined as follows: very often (≥1 / 10 cases), often (≥1 / 100 and <1/10 cases) infrequently (≥1 / 1000 and <1/100 cases), rarely (≥1 / 10000 and <1/1000 cases) and the frequency is unknown (it is impossible to estimate the frequency from the available data).

System-Organ Class Frequency Category	Side effects
Infectious and parasitic diseases
Infrequently	DHerpetic infection
Violations of the blood and lymphatic system
Infrequently	Thrombocytopenia, neutropenia, anemia, leukopenia
Rarely	Eosinophilia
Immune system disorders
Infrequently	Immunodeficiency Syndrome, (drug) hypersensitivity
Disorders from the endocrine system
Infrequently	Hypothyroidism, increasing the concentration of thyroid-stimulating hormone in the blood
Disorders from the metabolism and nutrition
Often	Lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia
Infrequently	Gout, anorexia, decreased appetite, weight loss, weight gain, hyperglycemia, insulin resistance, a decrease in high-density lipoprotein concentrations, increased appetite, polydipsia, increased lactate dehydrogenase activity in the blood
Disorders of the psyche
Often	Insomnia
Infrequently	Depression, disorientation, anxiety, sleep disorders, pathological dreams, nightmares, decreased libido
Rarely	Confusion, mood swings, anxiety
Disturbances from the nervous system
Often	Headache, peripheral neuropathy, dizziness
Infrequently	Inhibition, paresthesia, hypoesthesia, dysgeusia, attention disorders, memory impairment, drowsiness
Rarely	Fainting, convulsions, agesia, disturbance of the rhythm of the phases of sleep
Disturbances on the part of the organ of sight
Infrequently	Hyperemia of the conjunctiva, dry eye mucosa
Rarely	Visual impairment
Violations from the organ of hearing and equilibria
Infrequently	Vestibular Dizziness
Heart Disease
Infrequently	Myocardial infarction, angina pectoris, QT tooth enlargement on an electrocardiogram, tachycardia
Rarely	Acute myocardial infarction, sinus bradycardia, palpitations
Vascular disorders
Infrequently	Increased blood pressure, "hot flashes"
Disturbances from respiratory fromSystems, organs of the chest and mediastinum
Infrequently	Shortness of breath, cough, nosebleeds, sore throat
Rarely	Rhinorrhea
Disorders from the gastrointestinal tract
Often	Diarrhea
Often	Nausea, vomiting, abdominal pain, increased amylase activity in the blood, indigestion, bloating, flatulence
Infrequently	Pancreatitis, gastritis, gastroesophageal reflux, aphthous stomatitis, desires for vomiting, dryness of the oral mucosa, discomfort in the abdomen, constipation, increased lipase activity, eructation, impaired sensation in the oral cavity
Rarely	Stomatitis, vomiting with blood, cheilitis, dryness of the mucous membrane of the lips, plaque in the tongue
Disturbances from the liver and bile ducts
Often	Increased activity of alanine aminotransferase
Infrequently	Hepatitis, cytolytic hepatitis, steatosis of the liver, hepatomegaly, increased transaminase activity, increased activity of aspartate aminotransferase,an increase in the concentration of bilirubin in the blood, an increase in the activity of alkaline phosphatase in the blood, an increase in the activity of gamma glutamyl transferase
Disturbances from the skin and subcutaneous tissues
Often	Rash (including macular, maculopapular, papular, erythematous and itchy), itching
Infrequently	Angioedema, generalized rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, pigmentation of nails
Rarely	Drug rash with eosinophilia and systemic manifestations (DRESSsyndrome), Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrheic dermatitis, skin lesions, xeroderma
Frequency unknown	Toxic epidermal necrolysis, acute generalized exenthematous pustulosis
Disturbances from musculoskeletal and connective tissue
Infrequently	Myalgia, osteonecrosis, muscle spasms, muscle weakness, arthralgia, pain in the extremities, osteoporosis, increased activity of creatine phosphokinase in the blood
Rarely	Musculoskeletal stiffness, arthritis, joint stiffness
Disorders from the kidneys and urinary tract
Infrequently	Acute renal failure, renal failure, renal stone disease, increased creatinine concentration in the blood, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria
Rarely	Decreased renal clearance of creatinine
Violations of the genitals and mammary gland
Infrequently	Erectile dysfunction, gynecomastia
General disorders and disorders at the site of administration
Often	Asthenia, fatigue
Infrequently	Fever, chest pain, peripheral edema, malaise, fever, irritability, pain
Rarely	Chills, bad health, skin xerosis

Description of some side effects

Rash

In clinical studies, mainly a mild to moderate rash was observed. The rash usually appeared during the first four weeks of therapy and disappeared with continued use of the drug. When developing severe skin reactions, see the section "Special instructions". In clinical trials in patients previously treated, the rash, regardless of its cause, more often occurred with the admission of treatment regimens containing PRESIST® and raltegravir, than when taking PRESIST® without raltegravir or raltegravir without PRESIST®. The rash caused by taking the drug appeared with a similar frequency. The rash that developed in clinical trials was mild and moderate and did not lead to discontinuation of therapy.

Lipodystrophy

Combined antiretroviral therapy causes fat redistribution (lipodystrophy) in patients with HIV. Lipodystrophy manifested itself in the form of loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, mammary gland hypertrophy, and accumulation of dorsocervical fat ("bovine hump").

Metabolic disorders

Combined antiretroviral therapy causes metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

Musculoskeletal disorders

Increased activity of creatine phosphokinase, myalgia, myositis and rhabdomyolysis (rarely) were observed with the use of protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors.

Osteonecrosis has been reported, especially in patients with recognized risk factors, with HIV disease at a later stage or for a long time receiving combined antiretroviral therapy. The incidence of osteonecrosis is unknown.

Immunodeficiency Syndrome

In patients with HIV and severe immunodeficiency, at the onset of combined antiretroviral therapy, inflammatory responses to asymptomatic or residual infections may occur. There were also autoimmune diseases (eg, Graves' disease). However, the time to onset of the disease may vary, and such diseases may begin months after initiation of therapy. Bleeding in patients with hemophilia

There was an increase in the incidence of spontaneous bleeding in patients with hemophilia receiving antiretroviral protease inhibitors.

Patients with co-infections with the hepatitis B virus and / or C

In patients with these infections, an increase in hepatic transaminase activity was more common than in patients without concomitant viral hepatitis B or C.

Overdose:

Information on acute overdose with the use of PRESIST® in combination with ritonavir in humans is limited. Healthy volunteers were taken once to 3200 mg of darunavir in the form of a solution and up to 1600 mg in the form of PRESISTA tablets in combination with ritonavir, with no adverse effects noted.

The specific antidote is unknown. In case of an overdose, general supportive therapy with monitoring of basic physiological parameters should be carried out. For removing nevsosavsheysya formulation shown gastric lavage or enema. Can be applied Activated carbon. Darunavir predominantly binds to plasma proteins, therefore, a significant removal of the active substance by dialysis is unlikely.

Interaction:

Darunavir, used in combination with ritonavir, is an inhibitor of the isoenzymes CYP3A, CYP2D6 and P-glycoprotein. The simultaneous use of the PRESIST® / ritonavir combination and preparations that are metabolized predominantly by the CYP3A, CYP2D6 isoenzymes and carried by the P-glycoprotein may cause an increase in plasma concentrations of such drugs, which in turn may cause a prolongation or prolongation of the therapeutic effect, occurrence of side effects.

Recommendations for concurrent use with other antiretroviral drugs

Integrase inhibitors

Dolutegravir

The combination of PRESIST® / ritonavir (600/100 mg twice daily) did not have a clinically significant effect on the concentration of dolutegravir in plasma. Comparison of the results of studies with retrospective pharmacokinetic data showed that dolutegravir does not have a clinically significant effect on the pharmacokinetics of darunavir. With the simultaneous use of the PRESIST® / ritonavir and dolutegravir combination, dose adjustment is not required.

Elvitegravir

With the simultaneous use of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and elvitegravir, the dose of elvitegravir should be 150 mg once daily.

Pharmacokinetic data and recommendations for dosing when using other doses of darunavir, as well as when used with the combination of elvitegravir / cobicystate, are absent. Therefore, simultaneous use of the PRESIST® / ritonavir combination at doses other than 600/100 mg twice daily and elvitegravir is not recommended.

It is not recommended simultaneous use of the PRESIS® / ritonavir and elvitegravir combinationin the presence of a co-bicystate.

Raltegravir

Based on the results of several clinical studies, it is suggested that raltegravir can cause a slight decrease in the concentration of darunavir in blood plasma. At present, the effect of raltegravir on the concentration of darunavir in blood plasma does not seem clinically significant. It is not necessary to correct the dosage of PRESISTA® when combined with a low dose of ritonavir and raltegravir.

Nucleoside / nucleotide reverse transcriptase inhibitors

Didanosine

The combination of PRESIS® / ritonavir (600/100 mg twice daily) simultaneously with didanosine can be used without dose adjustment. Didanosine it is recommended to use on an empty stomach, it can be taken 1 hour before or 2 hours after the PRESIS® / ritonavir, which is taken with food.

Tenofovir

The results of the study of the interaction between tenofovir (tenofovir disoproxil fumarate 300 mg / day) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that the concentration of tenofovir in plasma increased by 22%. This change is not clinically significant.With the simultaneous use of tenofovir and darunavir, the renal excretion of both drugs did not change. Tenofovir had no significant effect on the concentration of darunavir in plasma. With the simultaneous use of the PRESISTA® / ritonavir combination and tenofovir, dose adjustment is not required.

Other nucleoside reverse transcriptase inhibitors

Other nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) are eliminated mainly by the kidneys, and therefore the probability of their interaction with the darunavir / ritonavir combination is negligible.

Non-nucleoside reverse transcriptase inhibitors

Delavirdine

The simultaneous use of the PRESIST® / ritonavir and delavirdine combination may increase the concentration of darunavir and delavirdine due to inhibition of the CYP3A isoenzyme. Suitable doses of the PRESIS® / ritonavir and delavirdine combination are not established. The simultaneous use of the PRESIST® / ritonavir and delavirdine combination is not recommended.

Etravirine

When studying the interaction of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and etravirine, it was founda decrease in the concentration of etravirine by 37% and no significant changes in the concentration of darunavir. Thus, the combination of PRESIS® / ritonavir can simultaneously be administered with 200 mg of etravirine 2 times a day without changing the dose.

Efavirenz

A study was made of the interaction between the darunavir / ritonavir combination (300 mg / 100 mg twice daily) and efavirenz (600 mg once daily). In the presence of efavirenz, the concentration of darunavir in plasma was decreased by 13%. On the other hand, plasma concentration of efavirenz increased by 21% when used concomitantly with the darunavir / ritonavir combination. This interaction is not clinically relevant, and therefore the combination of PRESIS® / ritonavir and efavirenz can be used simultaneously without correction of the doses of the drugs.

Nevirapine

The results of the study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and nevirapine (200 mg twice daily) showed that the plasma concentrations of darunavir did not depend on the presence of nevirapine. However, with simultaneous use with the darunavir / ritonavir combination, nevirapine plasma concentration increased by 27% (compared with the control).This interaction is considered clinically insignificant, and therefore the combination of darunavir / ritonavir and nevirapine can be used simultaneously without changing their doses.

Rilpivirine

The results of the study of the interaction between the PRESIST® / ritonavir combination (800 mg / 100 mg once daily) with rilpivirin (150 mg once daily) showed no clinically significant effect on the concentration of darunavir.

The concentration of rilpivirin increased by 130% when used concomitantly with the PRESIST® / ritonavir combination. This interaction is considered clinically insignificant, and therefore the combination of PRESIS® / ritonavir and rilpivirine can be used simultaneously without changing their doses.

Protease Inhibitors

Ritonavir

In general, the effect of improving the pharmacokinetics of darunavir ritonavir was manifested in the fact that the concentrations of darunavir in plasma increased approximately 14-fold after taking one dose of darunavir (600 mg) and 100 mg of ritonavir twice a day. Therefore, the drug PRESISTA® should be used in combination with a low dose of ritonavir to increase the bioavailability of darunavir.

The combination of lopinavir / ritonavir

The results of research on the interaction betweena combination of darunavir / ritonavir (1200 mg / 100 mg twice daily) or 1200 mg of darunavir without ritonavir and a combination of lopinavir / ritonavir (400 mg / 100 mg twice daily or 533 mg / 133.3 mg twice daily) In the presence of lopinavir / ritonavir, the concentration of darunavir in plasma decreased by 40%. It is not recommended to use the combination of lopinavir / ritonavir simultaneously with the PRESIS® / ritonavir.

Saquinavir

The study of the interaction of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily) showed that the concentration of darunavir in plasma decreased by 26% in the presence of saquinavir and ritonavir; on the other hand, the combination of darunavir / ritonavir did not affect the concentration of saquinavir in plasma. It is not recommended to apply saquinavir simultaneously with the drug PRESISE® regardless of the use of a small additional dose of ritonavir.

Atazanavir

The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and atazanavir (300 mg once daily) showed no significant change in the concentrations of darunavir and atazanavir in plasma when administered concomitantly. Atazanavir can be used concomitantly with the darunavir / ritonavir combination.

Indinavir

In a study of the interaction between darunavir / ritonavir (400 mg / 100 mg twice daily) and indinavir (800 mg twice daily), the concentration of darunavir in plasma increased by 24% in the presence of indinavir and ritonavir; In the presence of the darunavir / ritonavir combination, plasma concentrations of indinavir increased by 23%. When used in conjunction with the PRESISTA® / ritonavir combination, the dose of indinavir in patients who do not tolerate it can be reduced from 800 mg twice daily to 600 mg twice daily.

Other protease inhibitors

Until now, the interaction between the PRESIST® / ritonavir combination and protease inhibitors in addition to lopinavir, saquinavir, atazanavir and indinavir has not been studied, and therefore, protease inhibitors not listed here should not be used concomitantly with the darunavir / ritonavir combination.

CCR5 receptor antagonists

With the simultaneous use of the PRESIST® / ritonavir combination maraviroc should be administered at a dosage of 150 mg 2 times a day. In the study of the interaction between the combinationdarunavir / ritonavir (600 mg / 100 mg twice daily) and maraviroc (150 mg twice daily) the concentration of maraviroc increased by 305%. The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.

Recommendations for simultaneous use with preparations of other classes

Drugs that reduce the acidity of gastric juice

Antacid preparations (aluminum / magnesium hydroxide, calcium carbonate)

No interaction between the PRESIS® / ritonavir combination and antacid preparations is expected. The combination of PRESIS® / ritonavir and antacid preparations can be applied simultaneously without dose adjustment.

H₂-gistaminovyh receptors blockers (cimetidine, famotidine, nisatidine, ranitidine)

The simultaneous use of ranitidine (150 mg twice daily) and the PRESISTA® / ritonavir combination (400/100 mg twice daily) had no effect on the concentration of darunavir in plasma. Combination PRESIS® / ritonavir and antagonists H₂-receptors can be used simultaneously without dose adjustment.

Proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

The simultaneous use of omeprazole (20 mg per day) and the PRESISTA® / ritonavir combination (400/100 mg twice daily) had no effect on the concentration of darunavir in plasma.The combination of PRESIS® / ritonavir and proton pump inhibitors can be applied simultaneously without dose adjustment.

Antagonists of alpha1-adrenergic receptors (alfuzosin)

The concentration of alfuzosin in plasma can be increased when used concomitantly with the PRESIST® / ritonavir combination. The simultaneous use of alfuzosin and the PRESIST® / ritonavir combination is contraindicated.

Antianginal agents (ranolazine)

The concentration of ranolazine in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination due to inhibition of CYP3A isoenzymes. The simultaneous use of ranolazine and the combination of PRESIS® / ritonavir is contraindicated.

Antiarrhythmic drugs (bepripid, disopyramide, dronedaron, mexiletine, system lidocaine, quinidine, amiodarone, flecainide, propafenone)

The combination of PRESIS® / ritonavir can increase serum concentrations of these antiarrhythmic agents. With the simultaneous use of this combination and listed antiarrhythmic agents, it is recommended that care be taken and, if possible, monitoring the concentrations of these agents in the plasma.Contraindicated simultaneous use of the PRESIST® / ritonavir combination with amiodarone, bepridil, dronedarone, quinidine and lidocaine in systemic administration.

Digoxin

In all studies on the interaction of the PRESIST® / ritonavir combination (600/100 mg twice daily) and a single dose of digoxin (0.4 mg), an increase in the final concentration of digoxin in plasma by 77% was demonstrated. It is recommended that a minimum dose of digoxin be initially prescribed and that its serum concentration be measured to obtain the desired clinical effect when used concomitantly with the PRESISTA / ritonavir combination.

Anticoagulants

Apixaban, dabigatran, rivaroxaban

With simultaneous use of the PRESISTA® / ritonavir combination and the anticoagulants listed above, the concentration of anticoagulant in the plasma may increase due to inhibition of the isoenzyme CYP3A or P-glycoprotein. The recommended dose of apixaban when used concomitantly with the PRESIST® / ritonavir combination is 2.5 mg 2 times a day. Combination PRESIS® / ritonavir and dabigatran should be used with caution and should not be used in patients with severe renal diseaseinsufficiency. It is not recommended to simultaneously use the PRESISTA® / ritonavir combination and rivaroxaban.

Warfarin

The combination of PRESIS® / ritonavir can affect the concentrations of warfarin in the plasma. With the simultaneous use of warfarin and this combination it is recommended to monitor the international normalized relationship.

Anticonvulsant drugs (phenobarbital, phenytoin and carbamazepine)

Phenobarbital and phenytoin are inducers of CYP450 enzymes. The combination of PRESIS® / ritonavir is not recommended in combination with these drugs, as this can cause a significant reduction in the concentration of darunavir in the plasma and, consequently, a decrease in its therapeutic effect.

The study of the interaction between the PRESIST® / ritonavir combination (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the concentration of darunavir does not change in this case, while the concentration of ritonavir decreases by 49%. The concentration of carbamazepine is increased by 45%. A dose change for the PRESIS® / ritonavir combination is not required. If it is necessary to simultaneously use the PRESIST® / ritonavir and carbamazepine combination,patients should be observed in connection with the possibility of side effects of carbamazepine. Carbamazepine concentrations should be measured, and its doses should be adjusted in accordance with clinical manifestations. Thus, doses of carbamazepine can be reduced by 25-50% when combined with a PRESISTA / ritonavir combination.

Antihistamines

Astemizole, terfenadine

With the simultaneous use of these antihistamines with the PRESISTA® / ritonavir combination, the concentration of antihistamines in the plasma may increase. The simultaneous use of the PRESIST® / ritonavir combination with astemizole and terfenadine is contraindicated.

Anti-malarial drugs

When investigating the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and the combination of artemether / lumefantrine (80/480 mg, 6 doses taken at 0, 8, 24, 36, 48 and 60 hours) an increase in the concentration of lumefantrine by 2.75 times, while the concentration of darunavir did not change. The concentration of artemether and its active metabolite, dihydroartemisinin, decreased by 16% and 18%, respectively.The combination of PRESIST® and artemether / lumefantrine can be used without dose adjustment. However, due to the increased concentration of lumefantrine, this combination should be used with caution.

Antidepressants

Paroxetine and sertraline

The study of the interaction between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and the PRESISTA® / ritonavir combination (400 mg / 100 mg twice daily) showed that the concentration of darunavir in plasma was independent of the presence sertraline or paroxetine. On the other hand, in the presence of the PRESIST® / ritonavir combination, plasma concentrations of sertraline and paroxetine decreased by 49 and 39%, respectively. In cases where selective serotonin reuptake inhibitors must be used concomitantly with PRESISTA® and ritonavir, the dose of these inhibitors must be carefully selected based on the clinical evaluation of the antidepressant effect. In addition, in patients receiving a stable dose of sertraline or paroxetine, which are started to be treated with the PRESISTA® / ritonavir combination, it is necessary to carefully monitor the severity of the underlying effect of the antidepressant.

Amitriptyline, imipramine, nortriptyline, trazodone, desipramine

The combined use of PRESIST® / ritonavir with the above antidepressants can cause an increase in the antidepressant concentration in the plasma due to inhibition of the CYP2D6 and / or CYP3A4 isoenzymes. This can cause side effects such as nausea, dizziness, lowering blood pressure, fainting. If necessary, the combined use of these drugs and the PRESISTA / ritonavir combination is recommended to conduct clinical monitoring of the patient's condition, it may be necessary to adjust the dose of antidepressant.

Sedatives / hypnotics

Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldiem

The combined use of PRESIST® / ritonavir with these sedatives / hypnotics may increase their plasma concentrations due to the inhibition of CYP3A isoenzymes. When combined, clinical monitoring is recommended and the possibility of reducing the dose of a sedative / hypnotic drug should be considered. When combined with parenterally administered midazolam,conduct thorough clinical monitoring and take urgent measures in the event of respiratory depression or prolonged sedation. Consider the possibility of reducing the dose of parenterally administered midazolam, especially if more than one dose of midazolam is used. The use of PRESIS® / ritonavir with oral midazolam or triazolam is contraindicated.

Neuroleptics

Pimozide

With the simultaneous use of the PRESISTA® / ritonavir and pimozide combination, it is possible to increase the concentration of pimozide in the plasma by inhibiting the isoenzymes CYP3A and CYP2D6. The simultaneous use of pimozide and the combination of PRESIS® / ritonavir is contraindicated.

Sertindole

Simultaneous use of sertindole and PRESIST® / ritonavir combination is contraindicated.

Risperidone, thiorizadine

In the combined use of risperidone or thiorizadine with the PRESISTA® / ritonavir combination, their plasma concentrations may increase, resulting in a reduction in the dosage of risperidone and thiorizadine when combined.

Quetiapine

When quetiapine is combined with the PRESISTA® / ritonavir combination, the concentration of quetiapine in plasma can be increased by inhibiting the CYP3A isoenzyme with PRESISTA®.The simultaneous use of the PRESIST® / ritonavir and quetiapine combination is contraindicated, as this may lead to an increase in toxicity associated with quetiapine. An increase in the concentration of quetiapine in the blood plasma can lead to coma.

Colchicine

When colchicine is used together with the PRESISTA® / ritonavir combination, colchicine concentration in the plasma may increase. The following scheme for changing the dose of colchicine is recommended. For the treatment of gout exacerbations for patients receiving the PRESISTA® / ritonavir combination, the recommended dose of colchicine is 0.6 mg, followed by 0.3 mg after 1 hour. The course of treatment should be repeated no earlier than 3 days later. For the prevention of exacerbations for patients receiving the PRESISTA® / ritonavir combination, the recommended dose of colchicine is 0.3 mg every other day or every other day. For the treatment of familial Mediterranean fever for patients receiving the PREZIST® / ritonavir combination, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg twice daily). Patients with reduced renal or hepatic function colchicine when combined with PRESIS® / ritonavir is contraindicated.

Blocks of "slow" calcium channels (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

Plasma concentrations of "slow" calcium channel blockers may increase with simultaneous use with the PRESISTA® / ritonavir combination by inhibiting the CYP3A and / or CYP2D6 isoenzymes. In such cases it is necessary to closely monitor the condition of patients.

Clarithromycin

The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and clarithromycin (500 mg twice daily) showed that the concentration of clarithromycin in the plasma increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function, it is recommended to reduce the dose of clarithromycin.

Dexamethasone (for systemic use)

Dexamethasone when injected into the bloodstream induces the CYP3A isoenzyme in the liver, which leads to a decrease in the plasma concentration of darunavir. This can lead to a decrease in its therapeutic effect. It is advisable to use caution when using concomitant dexamethasone and darunavir.

Boszentan

With the simultaneous use of bosentan and the PRESISTA® / ritonavir combination, the concentration of bosentan in plasma may increase. Patients who receive the PRESIS® / ritonavir combination for a minimum of 10 days are advised to take the initial dose of bosentan 62.5 mg every other day or every other day, depending on individual tolerability. For patients receiving bosentan and initiating therapy with the PRESIS® / ritonavir combination, it is recommended to cancel bosentan at least 36 hours prior to the PRESIS® / ritonavir therapy. At least 10 days after initiation of PRESISTA® / ritonavir therapy, bosentan should be taken at a dosage of 62.5 mg every other day or every other day, depending on individual tolerability.

Fluticasone, budesonide, prednisone

With simultaneous use of systemic or inhaled / nasal budesonide, fluticasone or prednisone and PRESISTA® / ritonavir combination, plasma glucocorticosteroid concentrations may increase.

Simultaneous use may increase the risk of systemic effects of corticosteroid drugs, including Cushing's syndrome and suppression of adrenal function.If both prednisone and the PRESISTA® / ritonavir combination are used concomitantly, clinical monitoring should be performed. Alternative treatment options should be considered, especially for long-term use.

Antiviral drugs of direct action

NS3-4A inhibitors of hepatitis C protease

Boceprevir

In a study on the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and bocepreviram (800 mg 3 times daily), the concentration of darunavir decreased by 44%, and the concentration of bocetrevir decreased by 32%. Therefore, it is not recommended to use the PRESIS® / ritonavir combination with bocetrevir.

Telaprevir

In studies of the interaction between the PRESISTA® / ritonavir combination (600 mg / 100 mg twice daily) with telaprevir (750 mg every 8 hours), the concentration of darunavir decreased by 40%, and the concentration of bodyprevir decreased by 35%. The simultaneous administration of the PRESIS® / ritonavir combination by telaprevir is not recommended.

Symeprevir

With the simultaneous use of simeprevir and PRESISTA® / ritonavir (800/100 mg / day), concentrations of darunavir and simeprevir in plasma were increased by inhibition of CYP3A isoenzymes.In clinical studies of the interaction of the PRESISTA® / ritonavir and simeprevir combination, the concentration of the simeprevir in the plasma increased 2.59 times, the concentration of darunavir increased 1.18 times. Not recommended at the same time simeprevir and a combination of PRESIS® / ritonavir.

Herbal preparations

Preparations containing St. John's wort extract

Extract of St. John's wort reduces the concentration of darunavir and ritonavir in blood plasma (induction of liver enzymes). The combination of PRESIS® / ritonavir should not be used in conjunction with preparations containing St. John's wort extract. In case the patient began taking medications containing St. John's wort extract, stop them and, if possible, check the virus titres. The concentration of darunavir (as well as the concentration of ritonavir) may increase after discontinuation of drugs containing St. John's wort extract. This effect can persist for two weeks after the withdrawal of preparations containing St. John's wort extract.

Inhibitors of HMG-CoA reductase (atorvastatin, lovastatin, Pitavastatin, pravastatin, rosuvastatin, simvastatin)

In the metabolism of statins, such as simvastatin and lovastatin, the CYP3A isoenzymes play an important role, so their plasma concentrations can increase significantly when used concomitantly with the PRESISTA / ritonavir combination. Elevated concentrations of statins can cause myopathy, including rhabdomyolysis. The use of the PRESIST® / ritonavir combination with lovastatin or simvastatin is contraindicated.

The study of the interaction between atorvastatin (10 mg once daily) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that in this situation the concentration of atorvastatin in plasma was only 15% lower than with monotherapy with atorvastatin ( 40 mg once daily). If it is necessary to simultaneously use atorvastatin and a combination of darunavir / ritonavir, it is recommended to start with a dose of atorvastatin 10 mg once daily. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy.

The combination of darunavir / ritonavir (600 mg / 100 mg twice daily) increased the concentration of pravastatin in plasma after taking one dose of this drug (40 mg) by about 80%, but only in a part of the patients.If it is necessary to use pravastatin together with PRESISTA® / ritonavir combination, it is recommended to start taking pravastatin from the lowest possible doses and increase the dose until the clinical effect appears, controlling the manifestation of side effects of the drug.

Investigation of the interaction between the PRESIS® / ritonavir combination (600 mg / 100 mg) with rosuvastatin (10 mg) revealed an increase in the concentration of rosuvastatin. If it is necessary to simultaneously use rosuvastatin and PRESISTA® / ritonavir combination, it is recommended to start with the lowest dose of rosuvastatin, gradually increasing the dose to obtain a clinical effect, constantly monitoring the safety of therapy. Investigation of the interaction between the PRESIST® / ritonavir combination (800/100 mg / day) and Pitavastatin (4 mg / day) revealed a decrease in plasma pentavastatin concentration, which is not considered clinically significant. The combination of PRESIS® / ritonavir and Pitavastatin can be used simultaneously without dose adjustment.

Inhalation beta-adrenomimetics (salmeterol)

Simultaneous application of salmeterol and PRESISTA® / ritonavir combination is not recommended, becausemay increase the risk of side effects of salmeterol from the cardiovascular system, incl. lengthening of the QT interval, palpitations and sinus tachycardia.

Immunosuppressants (ciclosporin, tacrolimus, sirolimus)

Concentrations in the plasma of cyclosporine, tacrolimus and sirolimus may increase when these drugs are used simultaneously with the PRESISTA / ritonavir combination. In these situations, it is recommended to monitor the concentration of immunosuppressive agents in plasma. Simultaneous use of the PRESIS® / ritonavir and everolimus combination is not recommended.

Ketoconazole, itraconazole, posaconazole, clotrimazole and voriconazole

Ketoconazole, itraconazole, posaconazole, clotrimazole and voriconazole are strong inhibitors of the isoenzyme CYP3A, and some of them are also its substrates. Systemic use of these antifungal drugs concomitantly with the combination of PRESISTA® / ritonavir can lead to an increase in darunavir plasma concentrations. On the other hand, this combination can increase plasma concentrations of some of these antifungal agents.This was confirmed by a study of the interaction between ketoconazole (200 mg twice daily) and a combination of darunavir / ritonavir (400 mg / 100 mg twice daily) in which concentrations of ketoconazole and darunavir increased 212% and 42%, respectively. If a darunavir / ritonavir combination is required simultaneously with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg. With the simultaneous use of the PRESISTA® / ritonavir combination and posaconazole, clinical monitoring of the patient's condition is recommended. Concentrations of voriconazole in plasma may decrease when combined with darunavir / ritonavir. Voriconazole should not be used concomitantly with darunavir / ritonavir, concurrent use is only possible if the potential benefits of using voriconazole exceed the potential risk.

Care should be taken with co-administration of clotrimazole and the combination of darunavir / ritonavir, and it is also recommended that the patient be constantly monitored.

Beta-blockers (carvedilol, metoprolol, timolol)

The combined use of beta-blockers and the PRESISTA® / ritonavir combination may lead to an increase in the concentration of beta-blockers due to inhibition of the CYP2D6 isoenzyme. If both of these drugs and the PRESISTA / ritonavir combination are used concomitantly, care should be taken and clinical monitoring carefully conducted, and a dose reduction of beta-blockers may also be required.

Methadone

In a study of the effect of the PRESIST® / ritonavir combination (600/100 mg twice daily) on stable maintenance therapy with methadone, a 16% decrease in the concentration of R-methadone in plasma was shown. Based on pharmacokinetic and clinical results, correction of the dose of methadone during the initiation of PRESISTA® / ritonavir therapy is not required. However, it is recommended to conduct clinical monitoring, as in some patients maintenance therapy requires correction.

Buprenorphine / naloxone

The results of the study of the interaction between the PRESISTA® / ritonavir and buprenorphine / naloxone combination demonstrated the lack of influence of the PRESISTA® / ritonavir combination on the concentration of buprenorphine when combined.

The concentration of the active metabolite of buprenorphine - norbuprenorphine increased by 46%. Correction of the dose of buprenorphine was not required. When co-administration of the PRESIST® / ritonavir and buprenorphine combination, careful clinical monitoring is recommended.

Estrogen-containing oral contraceptives

The results of the study on the interaction between the PRESISTA® / ritonavir combination (600/100 mg twice daily) and ethinyl estradiol and norethisterone indicate that the constant plasma concentrations of ethinylestradiol and norethisterone are reduced by 44% and 14%, respectively. Therefore, it is recommended to use alternative non-hormonal methods of contraception.

Inhibitors of phosphodiesterase type 5 (PDE-5)

In the treatment of erectile dysfunction (avanafil, sildenafil, tadalafil, vardenafil)

One study examined sildenafil concentrations after taking one dose of this drug (100 mg), and after taking 25 mg of sildenafil concomitantly with the darunavir / ritonavir combination (400 mg / 100 mg twice daily). The concentrations of sildenafil were similar in both situations.Caution should be exercised while using PDE-5 inhibitors for the treatment of erectile dysfunction and the PRESISTA / ritonavir combination. If it is necessary to use PRESIST® and ritonavir simultaneously with sildenafil, vardenafil or tadalafil, a single dose of sildenafil should not exceed 25 mg within 48 hours, a single dose of vardenafil should not be more than 2.5 mg within 72 hours, and a single dose of tadalafil should not exceed 10 mg for 72 hours. The simultaneous use of the PRESIS® / ritonavir and avanafil combination is not recommended.

In the treatment of pulmonary arterial hypertension (sildenafil, tadalafil)

A safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension with concomitant use with the PRESIST® / ritonavir combination is not established. There is an increased risk of side effects of sildenafil (including visual impairment, arterial hypotension, prolonged erection and fainting). Thus, the simultaneous use of the PRESIST® / ritonavir and sildenafil combination in the treatment of pulmonary arterial hypertension is contraindicated.For the treatment of pulmonary arterial hypertension, tadalafil, when used concomitantly with the PRESISTA / ritonavir combination, requires a change in the dose of tadalafil. For patients receiving the PRESISTA® / ritonavir combination for at least one week, the initial dose of tadalafil should be 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerability. For patients receiving tadalafil and initiating therapy with the PRESIS® / ritonavir combination, you should cancel tadalafil at least 24 hours before the start of therapy with the PRESISTA® / ritonavir combination and simultaneous use of tadalafil should be avoided during the initiation of therapy with the PRESISTA® / ritonavir combination. 1 week after the start of therapy with the PRESISTA® / ritonavir combination, tadalafil should be resumed at a dose of 20 mg once daily with a possible increase to 40 mg once daily on the basis of individual tolerability.

Anti-TB drugs

Rifabutin

Rifabutin is a substrate of CYP450 enzymes. In the study of the interaction of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and rifabutin (150 mg every other day), an increase in the concentration of darunavir by 57% was observed.Based on the safety profile of the PRESISTA® / ritonavir combination, increasing the concentration of darunavir in the presence of rifabutin does not require dose adjustment for PRESIST® / ritonavir. Interaction studies showed comparable concentrations with 300 mg rifabutin once daily and 150 mg every other day in combination with PRESISTA® / ritonavir (600/100 mg twice daily), as well as an increase in the concentration of the active metabolite 25-O-deacetyltrifabutin. When using this combination, patients need to reduce the dose of rifabutin by 75% of the usual dose of 300 mg per day (eg, 150 mg every other day) and increased control of the side effects of rifabutin.

Rifampicin and rifapentin

Rifampicin and rifapentin are inducers of CYP3A isoenzymes and cause a significant decrease in darunavir concentrations, which may cause a loss of the therapeutic effect of PRESIST®. In attempts to compensate for this decrease in concentrations by increasing the dose of other protease inhibitors taken with a low dose of ritonavir, liver reactions (increased activity of liver enzymes) were observed. The combined use of rifampicin and PRESISTA® / ritonavir is contraindicated.The combined use of rifapentin and PRESISTA® / ritonavir combination is not recommended.

Antineoplastic agents (dasatinib, everolimus, nilotinib, vinblastine, vincristine)

With the simultaneous use of the PRESIST® / ritonavir combination and antitumor drugs, an increase in plasma concentrations in the plasma is expected due to inhibition of CYP3A isoenzymes, which can cause unwanted reactions, usually associated with the administration of these drugs. It is advisable to use caution when using the PRESIST® / ritonavir combination and antineoplastic agents simultaneously. It is not recommended simultaneous use of everolimus and PRESIST® / ritonavir combination.

Ergot alkaloids (ergotamine, ergometrine, dihydroergotamine, methylergomethrin)

The concentration of ergot alkaloids in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination. The simultaneous use of ergot alkaloids and the combination of PRESIS® / ritonavir is contraindicated.

Cisapride

The concentration of cisapride in plasma may increase with simultaneous use with the PRESIST® / ritonavir combination.Simultaneous use of cisapride and PRESIS® / ritonavir combination is contraindicated.

Special instructions:

Patients should be informed that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV, including sexual transmission. Patients should explain the need for appropriate precautions.

Elderly patients: information on treatment with the PRESIS® / ritonavir combination of patients 65 years of age or older is very limited, caution should be exercised in treating such patients with PRESIS® because they are more likely to have liver dysfunction and are more likely to have comorbidities or take combination therapy.

Absolute bioavailability after a single dose of 600 mg of darunavir was approximately 37% and increased to about 82% after taking darunavir in combination with 100 mg of ritonavir twice a day. The overall effect of improving the pharmacokinetics of darunavir with ritonavir was approximately 14-fold increase in the concentration of darunavir in plasma after taking one dose of this drug (600 mg) in combination with 100 mg of ritonavir twice a day.Thus, the preparation PRESISTA® must be taken only in combination with a low dose of ritonavir as a pharmacokinetic enhancer. An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma and therefore a dose of ritonavir is not recommended to be increased.

PRESIS® tablets contain yellow dye "sunset sunset" (E110) and therefore can cause allergic reactions.

Severe skin reactions

In 0.4% of patients with PRESIS®, severe skin reactions were detected, which may be accompanied by fever and / or an increase in hepatic transaminase activity. The Stevens-Johnson syndrome was rarely recorded (<0.1%). In the post-marketing period, toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic manifestations) and acute generalized exanthematous pustulosis were recorded very rarely (<0.01%). If there are signs or symptoms of severe skin reactions (severe rash or rash, accompanied by fever, general malaise, fatigue, pain in the muscles or joints, blisters,lesions of the oral cavity, conjunctivitis, hepatitis and / or eosinophilia, etc.), the drug PRESIS® should be immediately discontinued.

A rash (of all types) was observed in 10.3% of patients taking PRESIST®. The rash was mostly mild or moderate, and was often observed during the first four weeks of treatment and decreased with continued therapy. In 0.5% of cases, the rash caused the withdrawal of the PRESIS® / ritonavir combination.

Rashes were more common in patients taking both raltegravir and a combination of PRESIS® / ritonavir compared to patients who received separately raltegravir or a combination of PRESIS® / ritonavir. The rash, the occurrence of which was associated with taking the drug, occurred with the same frequency in all three groups. The rash was of mild or moderate severity and did not limit therapy. The rash was not the reason for the abolition of therapy.

Darunavir contains a sulfonamide group. The use of PRESIS® in patients with allergies to sulfonamides should be done with caution. In clinical trials of the PRESISTA® / ritonavir combination, the incidence and incidence of rash were the same in patients, regardless of the history of allergy to sulfonamides.

Patients with concomitant diseases

Patients with liver disease

Data on the use of the PRESIST® / ritonavir combination in patients with severe liver dysfunction are not available; therefore, it is not possible to give specific recommendations for dosing. Based on the data that stable pharmacokinetic parameters in the use of darunavir in patients with mild to moderate degree of impaired liver function (Child-Pugh class A and B) are comparable with those of healthy individuals, dose adjustment for patients with mild to moderate liver function disorder class A and B by Child-Pugh) is not required.

Hepatotoxicity

When using the PRESISTA® / ritonavir combination, it is possible to develop hepatitis caused by the use of medications (eg, acute hepatitis, cytolytic hepatitis). Hepatitis was observed in 0.5% of patients receiving PRESIST® / ritonavir combination therapy. In patients with impaired hepatic function, incl. with chronic active hepatitis B or C, there is an increased risk of developing serious side effects from the liver.

It is necessary to monitor appropriate laboratory parameters before prescribing PRESISTA® / ritonavir combination therapy and during treatment.Consideration should be given to monitoring the increase in AST / ALT activity in patients with chronic hepatitis, cirrhosis, or in patients who have experienced increased transaminase activity prior to initiation of therapy, and especially during the first few months of combination therapy with the PRESISTA / ritonavir combination. In case of liver function abnormalities or worsening of their severity (including a clinically significant increase in the activity of hepatic enzymes and / or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, tenderness in palpation of the liver, hepatomegaly) should be considered the possibility of interrupting or canceling therapy with the PRESIS® / ritonavir combination.

Patients with kidney disease

Kidneys play an insignificant role in the clearance of darunavir, and therefore in patients with kidney disease, the overall clearance of darunavir is practically not reduced. Darunavir and ritonavir have a high degree of binding to plasma proteins, and therefore hemodialysis or peritoneal dialysis does not play a significant role in removing these drugs from the body.

Patients with hemophilia

There are reports of increased bleeding, including spontaneous cutaneous hematomas and hemarthrosis, in patients with haemophilia type A and B treated with protease inhibitors. Some of these patients were receiving coagulation factor VIII. In more than half of the cases described, treatment with protease inhibitors continued without interruption or was resumed after a temporary suspension. It was suggested a causal relationship between the treatment of protease inhibitors and increased bleeding in patients with hemophilia, but the mechanism of such a connection is not established.

Patients with hemophilia receiving the PRESIS® / ritonavir combination should be informed of the possibility of increased bleeding.

Diabetes mellitus / hyperglycemia

Patients receiving antiretroviral therapy, including protease inhibitors, have described newly diagnosed cases of diabetes mellitus, hyperglycemia, or worsening of the course of an already existing diabetes mellitus. In some of these patients, hyperglycemia was severe and in some cases was accompanied by ketoacidosis. Many patients had concomitant diseases, some of which required treatment with drugs,contributing to the development of diabetes mellitus or hyperglycemia.

Redistribution of fat and metabolic disorders

Combined antiretroviral therapy can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. At present, there are no data on the long-term consequences of this phenomenon, and its mechanism is largely unclear. A hypothesis has been made about the relationship between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors.

The increased risk of lipodystrophy is associated with factors such as old age, as well as with long-term therapy with antiretroviral drugs and the associated metabolic disorders. In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to physical signs of fat redistribution.

It is recommended to measure the content of serum lipids and fasting blood glucose. Disorders of lipid metabolism should be treated with appropriate drugs.

Osteonecrosis

Despite the multifactorial etiology (use of glucocorticosteroid hormones, alcohol consumption, severe immunosuppression, increased body mass index), cases of osteonecrosis have been noted, especially in patients with advanced HIV disease and / or in patients receiving long-term combined antiretroviral therapy.

Patients should be informed of the need to visit the doctor immediately if joint pain, joint stiffness or movement difficulties occur.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, an inflammatory response of the body to asymptomatic or residual opportunistic infections may occur, which can lead to serious clinical complications or worsening of symptoms. Typically, such reactions are observed in the first weeks or months of combined antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumonia caused by Pneumocystis jiroveci. It is necessary to determine the severity of any symptoms of inflammation and to conduct appropriate therapy. Autoimmune diseases (such as Graves' disease) have also been noted in the occurrence of an inflammatory immune system recovery syndrome. However, the time to onset of the disease may vary, and such diseases may begin months after initiation of therapy.

Interaction with other drugs

Darunavir and ritonavir are inhibitors of isoenzymes CYP3A and CYP2D6, as well as inhibitors of P-glycoprotein. Simultaneous use of a combination PREZISTA® / ritonavir and other drugs that are metabolized by CYP3A isozymes predominantly, CYP2D6 and transferred to the P-glycoprotein may increase the concentration of drugs in plasma, thus may increase or lengthen their therapeutic and side effects. Darunavir is metabolized by the CYP3A isoenzyme.

Simultaneous administration of drugs inducing CYP3A activity may increase the clearance of darunavir, resulting in a decrease in the concentration of darunavir in plasma. Simultaneous administration of darunavir with CYP3A inhibitors can reduce the clearance of darunavir,as a result of which the concentration of darunavir in plasma will increase.

Effect on the ability to drive transp. cf. and fur:

There have been no studies to study the effect of the PRESISTA® / ritonavir combination on the ability to drive vehicles and mechanisms. However, it is necessary to take into account the fact that dizziness was observed in some patients during treatment, including the PRESIS® / ritonavir combination. When dizziness occurs, you should refrain from performing these activities.

Form release / dosage:Tablets, film-coated, 800 mg.

Packaging:

For 30 tablets in a bottle of high-density polyethylene, covered with aluminum film, lid, protected from accidental opening by children.

Each bottle, along with instructions for medical use, is placed in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002329

Date of registration:13.12.2013

Date of cancellation:2018-12-13

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

PHARMSTANDART-UFIM VITAMIN FACTORY, OJSC Russia

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp28.12.2015

Illustrated instructions

Instructions

Presista® (Prezista®)