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

PREMISES SMCC HD90 (the composition includes microcrystalline cellulose, colloidal silicon dioxide anhydrous), crospovidone, silicon dioxide colloidal anhydrous, magnesium stearate.

Sheath:

coloring agent Opadrai II white 85F18422 (the composition includes partially hydrolyzed polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc).

Description:

Tablets 75 mg: white, capsular tablets, covered with a film sheath, engraved on one side of the "75", and on the other - "TMS". On the break the tablets are white or almost white in color.

Tablets of 150 mg: white, oval tablets covered with a film sheath, engraved on one side of the "150", and on the other - "TMS". On the break the tablets are 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 (KD 4.5 x 10^-12 mol / l). Darunavir resistant to 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, were 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,and therefore large amounts of darunavir bind to the alpha 1-acid plasma glycoprotein.

Darunavir is metabolized mainly by isoenzymes CYP3A4. Ritonavir inhibits isoenzymes CYP3A4 of the liver and thereby substantially increases the concentration of darunavir in plasma.

Absorption

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 total pharmacokinetic effect of ritonavir was 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, PRESIS® tablets 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 alpha1-acid glycoprotein.

Metabolism

In experiments in vitro on human liver microsomes it was shown that darunavir is subjected primarily to oxidative metabolism. Darunavir is intensively metabolized 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. In humans, at least 3 oxidative metabolites of darunavir have been identified; 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. On 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 5.91 l / h in the presence of a low dose of ritonavir.

Special 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 PRESIS® / ritonavir 600/100 mg twice daily.

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in the pharmacokinetic parameters of darunavir in the 18-75 age group (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 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 the study with. using several doses of PRESIS®. in combination with ritonavir (600/100 mg) twice a day, it was shown that stable pharmacokineticallye paramedarunavir in patients with mild 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 adults and children aged 6 years and with a body weight of 20 kg or more, previously receiving antiretroviral therapy (in combination with low-dose ritonavir and other antiretroviral drugs).

Contraindications:

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

- aboutsimultaneous reception with drugs, the clearance of which is predominantly determined by the isoenzyme 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, sildenafil (in the case of pulmonary arterial hypertension therapy), terfenadine, midazolam, triazolam, cisapride, pimozide, preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergomethrin) (see also the section "Interactions with other drugs");

- odesa timely reception with preparations of St. John's wort, perforated rifampicin, a combination of lopinavir / ritonavir (see also section "Interactions with other drugs");

- PAcute insufficiency (Child-Pugh class C);

- dUp to 6 years of age.

Carefully:

- In patients with impaired hepatic function (Child-Pugh classes A and B);

- in patients with allergy to sulfonamides;

- in patients over the age of 65;

- while concomitantly taking medications that are highly binding to the alpha1-acid glycoprotein;

- in patients with chronic hepatitis (including chronic viral hepatitis B and C);

- in patients with hemophilia.

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.

A combination of PRESIS® / ritonavir can be given to pregnant women women only in those cases when the expected benefit of its application to 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 in 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 PRESISTA® 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 preparations. The possibility of prescribing ritonavir should be considered before PRESISTA® / ritonavir therapy begins.

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

Adult patients:

Dosages of 75 mg and 150 mg are designed for use in children's practice. In adults to reach therapeutic doses of dosage data require receiving a large number of tablets, that on one hand makes them difficult to swallow, the other - may cause allergic reaction due to increased revenues auxiliary substances contained in the tablets, so they should be used only when the unavailability of other dosages .

Patients who previously received protease inhibitors

The recommended dose of PRESIST® is 600 mg twice a day in combination with 100 mg of ritonavir twice a day; a combination is taken during a meal. The type of food does not affect the absorption of darunavir.

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

Children

Patients 6 to 18 years old who received antiretroviral therapy before

The recommended dose of PRESIS® / ritonavir for children 6 to 18 years of age and body weight of at least 20 kg depends on body weight (see table below) and should not exceed the recommended dose for adult patients (600/100 mg twice daily). PREZIST® tablets should be taken with ritonavir 2 times a day during meals. The type of food does not affect the absorption of darunavir.

The recommended dose of PRESIS® and ritonavir tablets for patients 6 to 18 years of age, previously receiving antiretroviral therapy
Body weight (kg)	Dose
≥ 20 kg - <30 kg	375 mg of PRESIS® / 50 mg of ritonavir 2 times a day
≥ 30 kg - <40 kg	450 mg of PRESIS® / 60 mg of ritonavir 2 times a day
≥ 40 kg	600 mg PRESIS® / 100 mg ritonavir 2 times a day

If a dose of PRESIS® and / or ritonavir is missed within 6 hours after the usual intake time, the prescribed dose of PRESIS® and / or ritonavir should be taken as soon as possible. In the event that after the usual time of taking the drug more than 6 hours, it is recommended to adhere to the established scheme of taking the drug.These recommendations are based on a 15-hour half-life of darunavir in the presence of ritonavir and the prescribed mode of taking the drug every 12 hours.

Patients with hepatic impairment

In patients with mild or moderate impairment of 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.

Side effects:

The most frequent side effects (≥2%) of moderate or severe degree (2 or more degrees) are diarrhea, hypertriglyceridemia, rash, nausea, hypercholesterolemia and headache. The most frequent side effects of severe degree (3-4 degrees) are an increase in the activity of "liver" and pancreatic enzymes.

2.6% of patients discontinued therapy due to side effects.

Information on the side effects of adult patients who had previously received antiretroviral therapy with 600/100 mg PRESIS® / ritonavir 2 times a day is given below.

Undesirable side effects are grouped by organs and frequency of occurrence. The frequency was defined as: very often ≥10%, often - 1-10%, infrequently - 0,1-1%.

From the hemopoietic system and lymphatic system:

Infrequent: thrombocytopenia, neutropenia, anemia, increased number of eosinophils, and leukopenia.

From the cardiovascular system:

Heoften: myocardial infarction, angina pectoris, lengthening interatala QT, sinusoidal bradycardia, tachycardia, palpitations, increased blood pressure, "hot flashes" of blood.

On the part of the respiratory system:

Infrequently: shortness of breath, cough, nosebleeds, rhinorrhea, choking in the throat.

On the part of the digestive system:

Very often: diarrhea;

Often: nausea, vomiting, abdominal pain, increased amylase activity, dyspepsia, bloating, flatulence;

Infrequently: pancreatitis, gastritis, gastroesophageal reflux, stomatitis, incl. aphthous, bloody vomiting, dry mouth, discomfort in the gastrointestinal tract, constipation, increased lipase activity, belching, impaired oral sensitivity, cheilitis, dry lips, plaque in the tongue.

From the hepatobiliary system:

Often: increased activity of alanine aminotransferase and aspartate aminotransferase;

Infrequently: hepatitis, incl. cytolytic, hepatic artery stenosis, hepatomegaly, increased activity of transaminase, alkaline phosphatase, gamma-glutamyltransferase, an increase in bilirubin in the blood.

From the nervous system:

Often: headache, peripheral neuropathy, dizziness;

Infrequent: fainting, cramping, apathy, paresthesia, hypesthesia, agevzia, dysgeusia, impaired concentration, memory impairment, drowsiness, sleep phases disturbance.

Mental disorders:

Often: insomnia;

Infrequently: depression, confusion, disorientation, anxiety, mood swings, sleep disorders, unusual dreams, nightmarish dreams, decreased libido.

From the urinary system:

Infrequent: renal failure (including acute), nephrolithiasis, increased creatinine concentration, decreased creatinine clearance, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria.

From the side of the organ of vision:

Infrequent: decreased vision, conjunctival hyperemia, dry eyes.

From the organ of hearing:

Infrequently: vertigo.

From the immune system:

Infrequently: a syndrome of immune reactivation.

From the endocrine system:

Infrequently: hypothyroidism, an increase in the production of stimulating hormones of the thyroid gland.

From the skin and soft tissues:

Often: an eruption (including macular, maculopapular, papular, erythematous and itchy), itching;

Infrequent: generalized rash, dermatitis, incl. allergic, face swelling, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, seborrheic dermatitis, dry skin, changes in the pigmentation of the nails.

It was revealed in the postmarketing period: toxic epidermal necrolysis.

From the osteomuscular system and connective tissue:

Infrequently: myalgia, muscle spasms, muscle weakness, arthritis, arthralgia, rigidity of muscles, joint stiffness, pain in the extremities, osteoporosis, increased activity of creatinine phosphokinase.

It was revealed in the postmarketing period: osteonecrosis.

On the part of the reproductive system and mammary glands:

Infrequently: erectile dysfunction, gynecomastia.

Metabolic disorders and eating disorders:

Often: lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridemia, hypercholesterolemia, hyperlipidemia;

Infrequent: diabetes mellitus, gout, anorexia, decreased appetite, weight loss, weight gain, hyperglycemia, insulin resistance, decreased high-density lipoprotein concentrations, increased appetite, polydipsia, increased blood lactate dehydrogenase activity.

Violations of a general nature:

Often: asthenia, fatigue;

Infrequent: increased body temperature, pain in the chest, peripheral edema, a feeling of malaise, chills, a feeling of heat, irritability, pain, abnormal dryness of the skin.

Other violations:

Infrequent: herpes simplex.

The frequency, type and severity of side effects with PRESIS® in children and adolescents are comparable to those in adult patients.

Side effects of combined antiretroviral therapy

In HIV-infected patients, combined antiretroviral therapy may be accompanied by a redistribution of adipose tissue (lipodystrophy). This redistribution includes loss of peripheral and facial subcutaneous fat tissue, an increase in the amount of intra-abdominal and visceral fat, hypertrophy of the mammary glands and fat accumulation in the dorso-cervical region (formation of the fatty hump).

Combined antiretroviral therapy can also cause the following metabolic disorders: hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

In HIV-infected patients with severe immunodeficiency during the initial combined antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections may occur.

In patients receiving protease inhibitors, especially in combination with non-nucleoside reverse transcriptase inhibitors, the activity of creatine phosphokinase may increase, myositis and, rarely, rhabdomyolysis may occur.

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

In HIV-infected patients with concomitant hepatitis B and / or hepatitis C virus infection, treatment with the PRESIST® / ritonavir combination is not associated with a higher incidence of side effects and laboratory changes (compared with HIV-infected patients without hepatitis B and / or hepatitis C) . The pharmacokinetics of darunavir and ritonavir in patients with concomitant hepatitis B and / or C infections was similar tosuch in patients with HIV monoinfection, with the exception of an increase in the activity of liver enzymes.

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 and ritonavir are inhibitors of the isoenzyme CYP3A4. Simultaneous use of the PRESIST® / ritonavir combination and drugs that are metabolized predominantly by isoenzyme CYP3A4, can cause an increase in the concentration of such drugs in the plasma, which, in its queue, may be the reason for the enhancement or prolongation of the therapeutic effect, as well as the cause of the occurrence of side effects.

The combination of PRESIS® / ritonavir should not be used concomitantly with drugs whose clearance is largely determined by the isoenzyme CYP3A4 and elevated concentrations of which in the plasma can cause serious and / or life-threatening side effects (narrow therapeutic range). These drugs include amiodarone, beprideil, quinidine, system lidocaine, astemizole, alfuzosin, sildenafil (in the case of pulmonary arterial hypertension therapy), terfenadine, oral midazolam, triazolam, cisapride, prmozide, sertindole, simvastatin, lovastatin and ergot alkaloids (for example, ergotamine, dihydroergotamine, ergometrine and methylergomethrin). Rifampicin is a powerful inducer of cytochrome isoenzymes CYP450. The combination of PRESIS® / ritonavir should not be used concomitantly with rifampicin, since in such cases the concentration of darunavir in plasma can be significantly reduced. A consequence of this may be the loss of the therapeutic effect of PRESISTA®.

The combination of PRESIS® / ritonavir should not be used concomitantly with preparations containing St. John's wort extract (perforated (Hypericum perforatum), as this may be accompanied by a significant decrease in the concentration of darunavir in plasma, so that the therapeutic effect of PRESIST® can disappear.

Recommendations for concurrent use with other antiretroviral drugs

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.

As 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 PRESIS® / ritonavir 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 combination of darunavir / ritonavir is negligible.

Non-nucleoside reverse transcriptase inhibitors

Etravirine

When studying the interaction of the PRESISTA® / ritonavir combination (600/100 mg twice daily) and etravirine, a decrease in the concentration of etravirin by 37% was found and no significant changes in the concentration of darunavir were observed. However, 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, the plasma concentration of efavirenz increased by 21% when it was used concomitantly with the darunavir / ritonavir combination.This interaction is not clinically relevant, and therefore 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.

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 preparation PRESISTA® should be used in combination with a low dose of ritonavir.

The combination of lopinavir / ritonavir

The results of the study of the interaction between the darunavir / ritonavir combination (1200 mg / 100 mg twice daily) or 1200 mg of darunavir without ritonavir and the combination of lopinavir / ritonavir (400 mg / 100 mg twice daily or 533 mg / 133.3 mg twice daily) showed that in the presence of a combination 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 increased by 26% in the presence of saquinavir and ritonavir; on the other hand, the combination of darunavir / ritonavir did not affect concentration of saquinavir in plasma. It is not recommended to apply saquinavir simultaneously with the drug PRESIS®, 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 simultaneously. 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 administered in combination 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.

Receptor antagonists CCR5

With the simultaneous use of the PRESIST® / ritonavir combination maraviroc should be given in a dose of 150 mg 2 times a day. In a study of the interaction between a combination of darunavir / ritonavir (600 mg / 100 mg twice daily) and maraviroc (150 mg twice daily) AUC Maraviroc increased to 305%.The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.

Recommendations for simultaneous use with preparations of other classes

Antiarrhythmic drugs (beprideal, systemic lidocaine, quinidine, amiodarone, flecainide, propafenone)

The combination of PRESIS® / ritonavir can increase serum concentrations of bepridil, lidocaine, quinidine, amiodarone, flecainide and propafenone. 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.

Digoxin

In all studies on the interaction of PRESIST® / ritonavir (600/100 mg twice daily) and a single dose of digoxin (0.4 mg), an increase in the final concentration of digoxin in plasma was shown to be 77%. 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 concurrently administered with PRESISTA® / ritonavir.

Anticoagulants

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

Panticonvulsants (phenobarbital, phenytoin and carbamazepine)

Phenobarbital and phenytoin are inducers of cytochrome isoenzymes CYP450. 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 in this case does not change, while the concentration of ritonavir is reduced by 49%. The concentration of carbamazepine is increased by 45%. Dose changes for PRESIS® / ritonavir are not required. If it is necessary to prescribe simultaneously PRESISTA® / ritonavir and carbamazepine, the patient should be under the constant supervision of medical personnel in connection with the possible occurrence 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 PRESISTA® / ritonavir.

Antidepressants (trazodone, desipramine)

The combined use of PRESIST® / ritonavir with trazodone and desipramine may increase the concentration of trazodone and desipramine in plasma. This can cause side effects such as nausea, dizziness, lowering blood pressure, fainting. If necessary, the combined use of these drugs and PRESISTA / ritonavir should be used with caution and consider the use of smaller doses of trazodone and desipramine.

Benzodiazepines (milazolam parenteral)

The combined use of PRESIST® / ritonavir with parenterally administered midazolam may increase the concentration of midazolam in the plasma. When combined, careful clinical monitoring should be carried out and urgent measures taken in the event of respiratory depression or prolonged sedation.Consider the possibility of reducing the dose of midazolam, especially in the case of prolonged therapy.

The use of PRESIS® / ritonavir with oral midazolam is contraindicated.

Neuroleptics (risperidone, thiorazadine)

With the combined use of neuroleptics with PRESISTE / ritonavir, their plasma concentrations may increase, resulting in the simultaneous use of lower doses of antipsychotics.

Colchicine

When the colchicine is used together with PRESISTA® / ritonavir, will increaseьConcentrationacolchicine in plasma. The following is recommendeddose change of colchicine. For the treatment of gout exacerbations for patients receiving the PRESISTA® / ritonavir combination, the recommended dose of colchicine is 0.6 mg (1 tablet) and 0.3 mg (1/2 tablet) 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 PRESISTA® / 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 should not be prescribed colchicine when combined with PRESIS® / ritonavir.

Blocks of "slow" calcium channels

Concentrations in the plasma of slow calcium channel blockers (eg, felodipine, nifedipine, nicardipine) may increase with simultaneous use with a PRESISTA / ritonavir combination. In such situations 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

Dexamethasone when injected into the bloodstream induces isoenzyme CYP3A4 in the liver, which leads to a decrease in the concentration in the plasma 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 novice PRESISTA® / ritonavir therapy, it is recommended to cancel bosentan at least 36 hours prior to the PRESIS® / ritonavir therapy. At least 10 days after the start of PRESISTA® / ritonavir therapy, bosentan should be taken at a dose of 62.5 mg every other day or every other day, depending on individual tolerability.

Fluticasone, budesonide

With simultaneous use of inhaled fluticasone and PRESISTA® / ritonavir combination, the concentration of fluticasone in plasma can increase. A similar interaction can be observed with the use of other corticosteroids metabolized by the isoenzyme CYP3A4, for example, budesonide. It is advisable to use drugs that are alternative to fluticasone, not which areI substrate of isoenzyme CYP3A4 (eg, beclomethasone).

Preparations from the group of statins

In the metabolism of statins, such as simvastatin, rosuvastine and lovastatin, an important role is played by the isoenzyme CYP3A4, therefore their plasma concentrations can be significantly increased with simultaneous use with the PRESIST® / ritonavir combination. Elevated concentrations of statins can cause myopathy, including rhabdomyolysis. Given this, it is not recommended to use the PRESISTA® / ritonavir combination with lovastatin, rosuvastin, or simvastatin.

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 simultaneous use of atorvastatin and a combination of darunavir / ritonavir it is recommended to start with a dose of atorvastatin 10 mg once a day. 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 pravastatin and PRESISTA® / ritonavir are to be used together, it is recommended that pravastatin should be taken from the lowest possible doses and that doses be increased until the clinical effect appears, controlling the manifestation of the side effects of the drug.

Blockers H₂-gistaminovyh receptors and inhibitors proton pumps

The use of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) along with the combination of darunavir / ritonavir (400 mg / 100 mg twice daily) did not affect the concentration of darunavir in plasma. Given these data, the PRESISTA® / ritonavir combination can be used concomitantly with H blockers₂receptors and proton pump inhibitors without changing the dose of any of these drugs.

Inhalation beta-adrenomimetics (salmeterol)

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

Immunosuppressive drugs (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.

Ketoconazole, itraconazole and voriconazole

Ketoconazole, itraconazole and voriconazole are potent inhibitors of the isoenzyme CYP3A4, as well as its substrates. Systemic use of ketoconazole, itraconazole, and voriconazole concurrently with the PRESISTA® / ritonavir combination may lead to an increase in darunavir concentrations in plasmae. On the other hand, this combination can beet increase concentrations in plasma ketoconazole or itraconazole. 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 combination is required, darunavir / ritonavir concurrently with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg.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.

Clotrimazole

The interaction of the PRESIST® / ritonavir combination with clotrimazole has not been studied. With the simultaneous use of clotrimazole and darunavir, and low doses of ritonavir, there may be an increase in the concentration of darunavir in plasma. With the simultaneous use of the PRESISTA® / ritonavir and clotrimazole combination, care should be taken and clinical monitoring performed.

Beta-blockers (metoprolol, timolol)

The combined use of beta-blockers and the PRESISTA® / ritonavir combination may lead to an increase in the concentration of beta-blockers. 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 PRESIS® / ritonavir combination (600/100 mg twice daily) on stable maintenance therapy with methadone, a 16% decrease in concentration Rin the plasma. 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 absence of PRESIST® / ritonavir's influence on the concentration of buprenorphine when combined. The concentration of active metabolite of buprenorphine of norbuprenorphine increased by 46%. Correction of the dose of buprenorphine was not required. With the joint administration of PRESIS® / ritonavir and buprenorphine, careful clinical monitoring is recommended.

Estrogen-containing oral contraceptives

The results of the study on the interaction between the PRESIST® / ritonavir combination (600/100 mg twice daily) and ethinyl estradiol and butRwith etisteroneflow aboutm, that a constant concentration in the plasma 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)

When treating erectile dysfunction

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 PRESIS® 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 within 72 hours.

In the treatment of pulmonary arterial hypertension

A safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension has not been established. There is an increased risk of side effects of sildenafil (including visual impairment, lower blood pressure, prolonged erections 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 on the basis of 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.

Rifabutin

Rifabutin is a substrate of cytochrome isoenzymes CYP450. In an investigation of PRESIST® / ritonavir (600/100 mg twice daily) and rifabutin (150 mg every other day), there was an increase in darunavir concentration by 57%. Based on the PRESISTA® / ritonavir safety profile, an increase in 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), and увelycheeConclusioneactive metabolite 25-ABOUT-desacetyltrifabutin. When The appointment of such a combination requires patients to reduce the dose of rifabutin by 75% of the usual dose of 300 mg per day and an increased control of the side effects of rifabutin.

Selective serotonin reuptake inhibitors

A study of the interaction between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and a combination of PRESISTA® / ritonavir (400 mg / 100 mg twice daily) showed that the concentration of darunavir in plasma did not depend on presence of 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 are to be used concomitantly with PRESISTA® and ritonavir, the dose of these inhibitors must be carefully selected based on the clinical evaluation antidepressant effect. In addition, patients receiving a stable dose of sertraline or paroxetine, who are being treated with the PRESISTA / ritonavir combination, should carefully monitor the severity of the underlying antidepressant effect.

Special instructions:

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

Elderly patients: information on treatment with the PRESIST® / ritonavir combination of patients 65 years of age and 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 receive concomitant therapy.

Absolute bioavailability after a single dose of 600 mg of darunavir was approximately 37% and increased to approximately 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. Therefore, the preparation PRESIS® should be taken only in combination with a low dose of ritonavir.

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.

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 liver transaminase activity.Stevens-Johnson syndrome was recorded rarely (<0.1%). In the postmarketing period, toxic epidermal Necrolysis was very rare (<0.01%). When there are signs or severe skin reactions (severe rash or rash, accompanied by fever, general malaise, pain in the muscles or joints, blisters, oral cavity, conjunctivitis, hepatitis and / or eosinophilia), PRESIS® should be discontinued immediately.

A rash (of all types) was observed in 10.3% of patients taking PRESIS®. 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.

Darunavir contains a sulfonamide group. Prescription of PRESIS® to patients with allergy to sulfonamides should be done with caution. In clinical trials of PRESISTA® / ritonavir, the extent and incidence of the rash were similar in patients with and without an allergy to sulfonamides.

Patients with concomitant diseases

Patients with liver disease

Data on the use of PRESIS® / ritonavir in patients with severe liver dysfunction are absent. Based on the data that stable pharmacokinetic parameters in the application of darunavir in persons with mild and moderate impairment of liver function are comparable with those of healthy individuals, dose adjustment for patients with mild or moderate liver dysfunction is not required.

Hepatotoxicity

When using the PRESIST® / ritonavir combination, hepatitis caused by the use of medications (for example, acute hepatitis, cytolytic hepatitis) is observed. 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 ACT / ALT activity in patients with chronic hepatitis, cirrhosis,who had an increased activity of transaminases before the start of therapy and, especially, during the first few months of combined PRESISTA / ritonavir therapy.

In case of liver function abnormalities or worsening of their severity (including clinically significant increase in the activity of "liver" enzymes and / or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, tenderness in palpation of the liver, hepatomegaly) should consider the possibility of interrupting or canceling PRESIS® / ritonavir therapy.

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 that there is a causal relationship between the treatment of protease inhibitors and the increase in bleeding in hemophilia patients, 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.

Hyperglycaemia

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 that promote the development of diabetes or hyperglycemia.

Redistribution of fat and metabolic disorders

Combined antiretroviral therapy may cause redistribution of adipose tissue in HIV-infected patients(lipodystrophy). 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.

Syndrome of immune reactivation

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 carinii. It is necessary to determine the severity of any symptoms of inflammation and to conduct appropriate therapy.

There have been cases of osteonecrosis, especially in patients with common risk factors, late HIV infection or long-term combined antiretroviral therapy. The frequency of osteonecrosis is unknown.

Interaction with other medicinal products

Darunavir and ritonavir are inhibitors of the isoenzyme CYP3A4. Simultaneous use of the PRESIST® / ritonavir combination and other drugs that are metabolized predominantly by isoenzyme CYP3A4, can lead to an increase in the concentration of such drugs in the plasma, so that their therapeutic and side effects may be intensified or prolonged.

Darunavir is metabolized by isoenzyme CYP3A4. Simultaneous reception of drugs that induce activity CYP3A4, can increase the clearance of darunavir, resulting in a decrease in the concentration of darunavir in plasma. Simultaneous reception of darunavir with inhibitors CYP3A4 can reduce the clearance of darunavir, resulting in an increase in the concentration of darunavir in plasma.

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

Studies on the effect of the PRESIS® / ritonavir combination on the ability to drive and move vehicles have not been conducted. However, when considering the patient's ability to drive and move vehicles, the dizziness noted in some patients receiving PRESISTA® / ritonavir combination therapy should be considered.

Form release / dosage:

Tablets coated with a film coating, 75 mg and 150 mg.

Packaging:

75 mg: on 480 tablets in a bottle of high-density polyethylene, covered with aluminum film, with a polypropylene cover, protected from accidental opening by children.

150 mg: 240 tablets per bottle of high-density polyethylene, covered with aluminum film, with polypropylene lid, protected from accidental opening by children.

Everyth The bottle along with the instruction 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:LSR-008337/10

Date of registration:18.08.2010

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

Manufacturer: & nbsp

JANSSEN-CILAG, S.p.A. Italy

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

Information update date: & nbsp29.12.2015

Illustrated instructions

Instructions

Presista® (Prezista®)