Kemeruwir® (KEMERUVIR®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDarunavirDarunavir
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    • Dosage form: & nbspfilm-coated tablets
    Composition:

    Each film-coated tablet contains:

    active substance: darunavir amorphous 800 mg.

    Excipients: core: giprolose low-substituted 26.67 mg, polysorbate 80 16.00 mg, crospovidone 64.00 mg, silicon colloidal dioxide 16.00 mg, PROSOLV® EASYtab SP 736.00 mg; film sheath: hypromellose E5 28.07 mg, iron dye oxide yellow 1.64 mg, macrogol 6000 5.41 mg, talc 0.859 mg, titanium dioxide 1.344 mg.

    Description:

    Oblong, biconvex tablets covered with a film membrane, from light yellow to dark yellow, with a risk on one side.

    On a cross-section a tablet of white or white with a yellowish shade of 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 HIV-1 protease. The drug selectively inhibits the cleavage of polyproteins Gag-Pol HIV in viral-infected cells, preventing the formation of full-fledged viral particles. Darunavir is strongly associated with HIV-1 protease (KD 4,5x10-12 M). 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 CYP3A. Ritonavir inhibits isoenzymes CYP3A of the liver and thereby substantially increases the concentration of darunavir in plasma.

    Suction

    After oral administration darunavir quickly absorbed in the gastrointestinal tract (GIT). The maximum concentration of darunavir in plasma in the presence of a low dose of ritonavir is achieved after 2.5-4.0 hours. The absolute bioavailability of a single dose of darunavir (600 mg) when ingested is about 37% and increases to about 82% in the presence of ritonavir (100 mg two times a day). There is a 14-fold increase in the concentration of darunavir in the plasma after a single oral intake at a dose of 600 mg 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 is 30% lower than when taken with meals. Therefore, Kemeruwir® tablets should be taken with ritonavir during meals, the nature of the food does not affect the concentration of darunavir in the plasma.

    Distribution

    About 65% of darunavir binds to plasma proteins, predominantly with an alpha-1-acid glycoprotein.

    Metabolism

    And 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. 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 (betonavir) and 5.91 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 a darunavir / ritonavir 600/100 mg bid 2 times a day.

    The pharmacokinetics of darunavir in combination with ritonavir in children aged 3 to 6 years and in masses of 10 kg to 20 kg are comparable to pharmacokinetics in adult patients receiving a darunavir / ritonavir 600/100 mg bid 2 times a day.

    Age differences

    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 HIV-infected patients with an average severity of impaired renal function (serum creatinine clearance 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 darunavir in combination with ritonavir (600/100 mg) twice daily, it was shown that the stable pharmacokinetic parameters of darunavir in patients with mild (class A on the Child-Pugh scale, n= 8) and the average severity of liver function disorders (class B on the Child-Pugh scale, n= 8) were comparable with those of healthy individuals.

    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 components of the drug;

    - simultaneous reception of a combination of darunavir / ritonavir in low doses from preparations whose clearance is predominantly determined by the cytochrome P450 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, 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, avanofil, ticagrelor (see also the section "Interaction with other medicinal products"). When using the drug darunavir and ritonavir in low doses, patients should not simultaneously use drugs containing rifampicin, as well as preparations containing extract of St. John's wort perfumed,since simultaneous administration can lead to a decrease in the concentration of darunavir in the plasma, this can lead to a loss of therapeutic effect and the development of resistance;

    - severe hepatic impairment (Child-Pugh class C);

    - Children under 18 years of age (for this dosage).

    Carefully:

    - Disorders of liver function of mild to moderate severity (class A and B on the Child-Pugh scale):

    - allergy to sulfonamides;

    - age over 65;

    - 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.

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

    It is not known whether darunavir penetrate into breast milk in humans. 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 darunavir, should refrain from breastfeeding.

    Dosing and Administration:

    Inside. Darunavir 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 initiating darunavir / ritonavir therapy.

    After initiating therapy with darunavir, patients should not change or discontinue therapy without consulting the attending physician. Patients should be instructed about taking the drug darunavir with a low dose of ritonavir no later than 30 minutes after the meal ends.

    Adult patients:

    Patients who have not previously received protease inhibitors

    Patients who previously received protease inhibitors

    Not having mutations that cause resistance to darunavir *

    Having at least 1 mutation that causes resistance to darunavir *

    800 mg 1 time per day in combination with 100 mg ritonavir, while eating.

    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, T74P, L76V, I84V and L89V

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

    However, if it is not possible to perform genotypic analyzes, patients who have not previously received protease inhibitors should take the darunavir / ritonavir combination once a day 800 mg / 100 mg, and patients who have previously received protease inhibitors are recommended to take the darunavir / ritonavir combination twice 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 darunavir / ritonavir should be used with caution in patients of this age group.

    Patients with hepatic impairment

    In patients with mild or moderate severity of liver dysfunction, dose adjustment is not required. Information on the use of the darunavir / ritonavir combination in patients with severe liver dysfunction 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 combination of darunavir / ritonavir are not required.

    Skipping the drug

    If the delay in taking the darunavir / 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 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 post-marketing period were: diarrhea, rash, nausea, vomiting and headache. The most frequent serious side effects were: acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis, fever.

    The following classification of undesirable reactions is used depending on the frequency of occurrence: very often (> 1/10), often (> 1/100, <1 10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10,000, <1/1000), very rarely (<1/10000).

    From the hemopoietic system and lymphatic system:

    Infrequent: thrombocytopenia, neutropenia, anemia, and leukopenia.

    Rarely: eosinophilia.

    From the cardiovascular system:

    Infrequently: tachycardia, increased blood pressure, "hot flashes", angina pectoris, lengthening of the interval QT, myocardial infarction.

    Rarely: sinus bradycardia, palpitation.

    On the part of the respiratory system:

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

    Rarely: rhinorrhea.

    On the part of the digestive system:

    Very often: diarrhea.

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

    Infrequent: pancreatitis, gastritis, gastroesophageal reflux, aphthous stomatitis, urge for vomiting, dryness of the oral mucosa, abdominal discomfort, constipation, increased lipase activity, eructation, impaired oral sensitivity.

    Rarely: stomatitis, vomiting with blood, xylitol, dryness of the mucous membrane of the lips, plaque on the tongue.

    From the hepatobiliary system:

    Often: increased activity of alanine aminotransferase.

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

    From the nervous system:

    Often: headache, peripheral neuropathy, dizziness.

    Infrequently: apathy, paresthesia, hypesthesia, dysgeusia, impaired concentration, memory impairment, retardation, drowsiness.

    Rarely: fainting, seizures, sleep phases, agesia.

    Mental disorders:

    Often: insomnia.

    Infrequent: depression, anxiety, disorientation, sleep disorders, unusual dreams, nightmarish dreams, decreased libido.

    Rarely: confusion, change of mood, anxiety.

    From the side moexcel system:

    Infrequent: acute renal failure, nephrolithiasis, increased concentration of creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria.

    Rarely: decreased creatinine clearance.

    From the side of the organ of vision:

    Infrequent: conjunctival hyperemia, dryness of the cornea and conjunctiva of the eyes.

    Rarely: impaired vision.

    From the organ of hearing:

    Infrequently: vertigo.

    From the immune system:

    Infrequently: a syndrome of restoration of immunity.

    From the endocrine system:

    Infrequently: hypothyroidism, increased concentration of thyroid-stimulating hormone in the blood.

    From the skin and soft tissues:

    Often: a rash (macular, maculopapular, papular, erythematous and itchy), itching. Infrequent: generalized rash, allergic dermatitis, angioedema, hives, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, changes in the pigmentation of the nails.

    Rarely: drug rash with eosinophilia and systemic manifestations (DRESSsyndrome), Stevens-Johnson syndrome, erythema multiforme, skin lesions, xeroderma, dermatitis, seborrheic dermatitis.

    It was revealed in the postmarketing period: toxic epidermal necrolysis, acute generalized exanthematous pustulosis.

    From the osteomuscular system and connective tissue:

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

    On the part of the reproductive system and mammary glands:

    Infrequently: erectile dysfunction, gynecomastia.

    Disorders from the metabolism and nutrition:

    Often: diabetes, lipodystrophy (incl.lipogypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridemia, hypercholesterolemia, hyperlipidemia

    Infrequent: 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.

    Rarely: chills, poor health, xerosis of the skin.

    Infectious and parasitic diseases:

    Infrequently: herpetic infection.

    Opiesome side effectsyesstvia

    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 with a rash,regardless of its cause, more often occurred with the admission of treatment regimens containing the drug darunavir and raltegravir, than when taking the drug darunavir without raltegravir or raltegravir without the drug darunavir. 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 nucleotide 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 of viral hepatitis B 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:

    Data on acute overdose when taking darunavir in combination with ritonavir in humans are limited. Healthy volunteers took only once to 3200 mg darunavir in the form of a solution and up to 1600 mg in the form of tablets in combination with ritonavir, with no side 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. To remove non-sucking drug shows gastric lavage or cleansing enema. You can apply Activated carbon. Darunavir to a large extent binds to plasma proteins, so it is not removed in significant quantities by dialysis.

    Interaction:

    Drugs for HIV treatment

    Nucleoside / nucleotide reverse transcriptase inhibitors

    Didanosine

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

    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. Regular monitoring of renal function is necessary. Tenofovir had no significant effect on the concentration of darunavir in plasma. With simultaneous application of a combination of darunavir / ritonavir and tenofovir, dose adjustment is not required.

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

    Non-nucleoside reverse transcriptase inhibitors

    Delavirdine

    The simultaneous use of the darunavir / ritonavir and delavirdine combination may lead to an increase in the concentration of darunavir and delavirdine in the blood due to inhibition of isoenzymes CYP3A. Adequate doses of drugs with combined use are not established (in terms of safety and efficacy). It is not recommended simultaneous use of the combination of darunavir / ritonavir and delavirdine.

    Etravirine

    When studying the interaction of the darunavir / ritonavir combination (600/100 mg 2 times a day) and etravirine, a decrease in the concentration of etravirin by 37% and no significant changes in the concentration of darunavir were observed. The combination of darunavir / ritonavir can be given concomitantly with etravirine at a dose of 200 mg 2 times a day without dose adjustment.

    Efavirenz

    A study was made of the interaction between the darunavir / ritonavir combination (300/100 mg twice daily) and efavirenz (600 mg once daily). However, in the presence of efavirenz there was a decrease in the concentration of darunavir in plasma by 13%. The concentration of efavirenz in the blood plasma increased by 21% with its simultaneous use with a combination of darunavir / ritonavir. This interaction is not clinically relevant, so the combination of darunavir / 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 (400/100 mg twice daily) and nevirapine (200 mg twice daily) showed that darunavir plasma concentrations 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, so the combination of darunavir / ritonavir and nevirapine can be used simultaneously without correction of the doses of the drugs.

    Rilpivirine

    The results of the study of the interaction between darunavir / ritonavir (800/100 mg once daily) and rilpivirin (150 mg once daily) did not show a clinically significant effect on plasma darunavir concentrations. The concentration of rilpivirin increased by 130% when used concomitantly with the darunavir / ritonavir combination. This interaction is considered clinically insignificant, so the combination of darunavir / ritonavir and rilpivirine can be used simultaneously without changing the doses of the drugs.

    Protease Inhibitors

    Ritonavir

    In general, the effect of optimizing the pharmacokinetics of darunavir ritonavir was manifested in Tom, that the concentrations of darunavir in plasma increased approximately 14-fold after taking a single dose of darunavir (600 mg) and 100 mg of ritonavir 2 times at day. Consequently, Kemeruwir® should be used in combination with a low dose of ritonavir.

    The combination of lopinavir / ritonavir

    With simultaneous application, a decrease in the effect was observed (AUC) of darunavir by 40%. Adequate doses of drugs with combined use are not established. Therefore, the simultaneous administration of a combination of darunavir with ritonavir and a combination of lopinavir / ritonavir is contraindicated.

    Saquinavir

    A study of the interaction of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily), and ritonavir (100 mg twice daily) showed that in the presence of saquinavir and ritonavir, a decrease in AUC, a minimum and maximum concentration of darunavir by 26 %, 42% and 17%, respectively. However, the combination of darunavir / ritonavir did not have a significant effect on saquinavir concentrations in plasma. It is not recommended simultaneous use of the combination of darunavir / ritonavir and saquinavir.

    Atazanavir

    When investigating the interaction between a combinationdarunavir / ritonavir (400/100 mg twice daily) and atazanavir (300 mg once a day) showed no significant changes in the concentrations of darunavir and atazanavir in plasma when administered concomitantly. Atazanavir can be used concomitantly with a combination of darunavir / ritonavir.

    Indinavir

    In a study of the interaction between darunavir / ritonavir (400/100 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 a darunavir / 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

    To date, the interaction between the darunavir / ritonavir combination and protease inhibitors in addition to lopinavir, saquinavir, atazanavir and indinavir has not been studied so that the protease inhibitors listed above are not recommended use simultaneously with a combination of darunavir / ritonavir.

    Receptor antagonists CCR5

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

    Integrase inhibitors

    Dolutegravir

    With the simultaneous use of dolutegravir with a combination of darunavir / ritonavir (600/100 mg 2 times a day) there are no clinically significant deviations in the pharmacokinetic parameters of darunavir / ritonavir. Correction of the dose is not required.

    Elvitegravir

    When the darunavir / ritonavir combination (600/100 mg 2 times a day) and elvitegravir are used concomitantly, the dose of elvitegravir should be 150 mg once a day. Pharmacokinetic data and recommendations for dosing when using other doses of darunavir, as well as when using the combination of darunavir / ritonavir with the combination of elvitegravil / cobicystate, are absent. Therefore, the use of a combination of darunavir / ritonavir in doses other than 600/100 mg 2 times a day, along with elvitegravir, is not recommended.It is not recommended to use the darunavir / ritonavir combination simultaneously with elvitegravir in the presence of a co-bicystate.

    Raltegravir

    In some clinical studies, it has been established that raltegravir can cause a slight decrease in the concentration of darunavir in blood plasma. The effect of raltegravir on the concentration of darunavir in blood plasma does not seem clinically significant. No dose adjustment is required darunavir when combined with low-dose ritonavir and raltegravir.

    Other medicines

    Antiarrhythmic drugs (amiodarone, befriended, quinidine, lidocaine for systemic use, flecainide, propafenone)

    The combination of darunavir / ritonavir can increase plasma concentrations of bepristil, lidocaine (with systemic administration), quinidine, amiodarone, flecainide, propafenone. These antiarrhythmic drugs are contraindicated for joint use with darunavir in combination with ritonavir in connection with the possible development of life-threatening cardiac arrhythmias.

    Digoxin

    In all studies of the interaction of darunavir / ritonavir (600/100 mg twice daily) and digoxin in a single dose (400 μg), 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 its serum concentration determined in order to obtain the desired clinical effect when given concomitantly with the darunavir / ritonavir combination.

    Dysopyramide, mexiletine

    It is expected that a combination of darunavir / ritonavir may increase concentrations of these antiarrhythmic drugs in the blood plasma (by inhibiting the CYP3A isoenzymes). With the simultaneous use of these drugs with darunavir in combination with ritonavir, care should be taken to monitor the therapeutic concentration of these antiarrhythmic drugs.

    Dronedarone, ranolazine

    Simultaneous administration of the darunavir / ritonavir combination with these drugs is contraindicated.

    Anticoagulants

    Warfarin

    The combination of darunavir / 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 (MBUT).

    Apixaban, dabigatran ethoxylate, rivaroxaban

    The application has not been studied.Simultaneous administration of the darunavir / ritonavir combination may increase anticoagulant concentrations (inhibition of the isoenzyme CYP3A). Joint use is not recommended.

    Tikagrelor

    The combined use of darunavir and ticagrelor may increase the concentration of anticoagulant. The simultaneous administration of darunavir with ticagrelor is contraindicated. It is recommended that other agents that inhibit platelet aggregation be used that are not affected by inhibition or induction of the isoenzyme CYP3A4 (for example, prasugrel).

    Antifungal means

    Fluconazole, postazonazole

    Joint application has not been studied. The combination of darunavir / ritonavir can increase the concentration of antifungal drugs in blood plasma (inhibition of P-glycoproteins), and posaconazole or fluconazole can increase the concentration of darunavir. Caution should be exercised when co-prescribing drugs and conduct clinical monitoring.

    Ketoconazole, itraconazole and voriconazole

    Ketoconazole, itraconazole and voriconazole are strong inhibitors of the isoenzyme CYP3A4, as well as its substrates.Care should be taken when co-prescribing drugs. Systemic use of ketoconazole, itraconazole, and voriconazole concomitantly with the combination of darunavir / ritonavir can lead to an increase in darunavir plasma concentrations. On the other hand, this combination can increase plasma concentrations of 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 the concentrations of ketoconazole and darunavir increased by 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. 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. With simultaneous use, it is recommended that care be taken andclinical monitoring.

    Anticonvulsant drugs (phenobarbital, phenytoin and carbamazepine)

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

    The study of the interaction between the darunavir / ritonavir combination (600 mg / 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%. Dose changes for the darunavir / ritonavir combination are not required. If it is necessary to simultaneously prescribe a combination of darunavir / ritonavir and carbamazepine, patients should be monitored for possible side effects of carbamazepine. It is necessary to monitor the concentration of carbamazepine in the blood plasma and adjust its dose in accordance with clinical manifestations.Thus, doses of carbamazepine can be reduced by 25-50% when given concomitantly with the darunavir / ritonavir combination.

    Antidepressants (trazodone, desipramine)

    With the simultaneous use of darunavir / ritonavir with trazodone and desipramine, an increase in the concentration of trazodone and desipramine in plasma is possible. This can cause side effects such as nausea, dizziness, arterial hypotension, fainting. Care should be taken if joint use of these drugs and the combination of darunavir / ritonavir is required, and the use of trazodone and desipramine in smaller doses should be considered.

    Benzodiazepines

    Midazolam

    Simultaneous use of the darunavir / ritonavir combination with parenterally administered midazolam may increase the concentration of midazolam in the plasma. Simultaneous use of the darunavir / ritonavir combination and intravenous midazolam should be carried out in intensive care units or in the intensive care unit for the purpose of timely clinical monitoring and adequate treatment in the event of respiratory depression and / or prolonged sedation.Consider the possibility of reducing the dose of midazolam, especially in the case of prolonged therapy. The use of a combination of darunavir / ritonavir with oral midazolam is contraindicated.

    Triazolam

    Contraindicated simultaneous appointment of a combination of darunavir / ritonavir with triazolam.

    Amitriptyline, imipramine, nortriptyline

    Simultaneous use of the darunavir / ritopavir combination with these antidepressants may lead to an increase in the concentration of antidepressants due to inhibition by the isoenzyme CYP2D6 and CYP3A. Clinical monitoring is recommended with simultaneous prescription of a combination of darunavir / ritonavir with these antidepressants. You may need to adjust the dose of antidepressants.

    Antipsychotics

    Risperidone, thioridazine

    When these neuroleptics are combined with the darunavir / ritonavir combination, their concentrations in the plasma may increase, so with simultaneous use, the doses of antipsychotics (neuroleptics) should be reduced.

    Pimozide

    Darunavir / ritopavir may increase the exposure of pimozide and lengthen the interval QT. Pimozide is contraindicated in patients taking the darunavir / ritopavir combination because of the high risk of life-threatening cardiac rhythm disturbances (see "Contraindications").

    Sertindole

    With the simultaneous use of darunavir / ritonavir and sertindole, an increase in the serotindol concentration in the plasma is possible. therefore sertindole it is contraindicated to apply simultaneously with a combination of darunavir / ritonavir because of the potential danger of lengthening the interval QT and development of cardiac arrhythmias (see the section "Contraindications").

    Quetiapine

    When used simultaneously with darunavir in combination with ritonavir, the concentration of quetiapine in plasma may be increased (by inhibiting the isoenzyme CYP3A). And the association with the possible increased toxic effects of quetiapine and the risk of coma development concomitant administration of quetiapine and combination darunavirritonavir is contraindicated.

    Perphenazine

    Joint application has not been studied. It is expected that the combination darunavirritonavir can increase the concentration of perphenazine in the blood plasma (due to inhibition of the isoenzyme CYP2D6 and P-glycoprotein).It may be necessary to reduce the dose of perphenazine when given concomitantly with a combination of darunavir / ritonavir.

    Anti-malarial drugs

    When investigating the interaction between the darunavir / 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) AUC lumefantrine by 2.75 times, while the effect of darunavir did not change. AUC Artemether and its active metabolite dihydroartemisinin decreased by 16% and 18% respectively. Combination of artemether / lumefantrine and darunavir can be used without dose adjustment. However, due to the increased exposure to lumefantrine, this combination should be used with caution.

    Colchicine

    Patients with normal kidney and liver function are advised to reduce colchicine dose or to stop colchicine treatment if a darunavir / ritonavir combination is required. Patients with renal or hepatic insufficiency are contraindicated in the appointment of colchicine with a combination of darunavir / ritonavir.

    Blockers of slow calcium channels

    Amlodipine, diltiazem, verapamil

    Joint use with these drugs has not been studied. It is expected that the combination of darunavir / ritonavir may lead to an increase in the concentration of amlodipine, diltiazem, verapamil in blood plasma (by inhibition CYP3A4, CYP2D6). Clinical monitoring of the therapeutic effects and adverse events is recommended while concomitant administration of these drugs.

    Felodipine, nifedipine, nicardipine

    Concentrations in the plasma of felodipine, nifedipine, nicardipine may increase with simultaneous use with a combination of darunavir / ritonavir. In such situations careful monitoring of the patients' condition is necessary.

    Clarithromycin

    FROM use caution clarithromycin in the combination of darunavir / ritonavir. To select a dose for patients with renal failure, read the instructions for the use of clarithromycin.

    Boszentan

    Joint application has not been studied. The simultaneous administration of bosentan and the combination of darunavir / ritonavir can increase the concentration of bosentan in blood plasma. Expected that bosentan reduces the concentration of darunavir and / or ritonavir in the blood plasma (due to the induction of isoenzymes CYP3A). When concomitant administration with darunavir and a low dose of ritonavir should monitor the patient's tolerability of bosentan.

    Dexamethasone

    Dexamethasone induces isoenzyme upon entering the systemic circulation CYP3A4 in the liver and, consequently, reduces the concentration in the plasma of darunavir. This can lead to a decrease in the therapeutic effect of darunavir. It is advisable to use caution when using concomitant dexamethasone and darunavir.

    Fluticasone propionate, budesonide

    With the simultaneous use of inhalation fluticasone propionate and the combination of darunavir / ritonavir, an increase in the concentration of fluticasone propionate in the blood plasma is possible. A similar interaction can be observed with the use of other glucocorticosteroids metabolized by isoenzyme CYP3A4, for example budesonide. It is advisable to use drugs alternative to fluticasone propionate, which are not a substrate of isoenzyme CYP3A4 (e.g., beclomethasone). In the event of cessation of glucocorticosteroid therapy, a gradual dose reduction should be performed over a long period.Simultaneous application is possible provided that the expected benefit exceeds the possible risk.

    Prednisone

    Joint application has not been studied. The combination of darunavir / ritonavir may increase prednisone plasma concentrations (due to inhibition of isoenzymes CYP3A). Simultaneous use of darunavir with a low dose of ritonavir and prednisone may increase the risk of systemic effects of prednisone, including Cushing's syndrome and suppression of adrenal cortex function. Clinical monitoring is recommended with concomitant administration of darunavir in combination with ritonavir and glucocorticosteroids.

    Antiviral drugs of direct action

    NS inhibitors 3-4 A proteins of hepatitis C

    Boceprevir

    In the study of the interaction between the darunavir / ritonavir combination (600/100 mg twice daily) and bocepreviram (800 mg 3 times daily), the effect of darunavir decreased by 44%, The effect of boceprevir decreased by 32%. Therefore, it is not recommended to use the combination of darunavir / ritonavir concomitantly with boceprevirov.

    Telaprevir

    In studies of the interaction between the darunavir / ritonavir combination (600/100 mg twice daily) and telaprevir (750 mg every 8 hours), the effect of darunavir decreased by 40%, and the effect of bodyprevir decreased by 35%.It is not recommended to use the combination of darunavir / ritonavir concurrently with telaprevir.

    Symeprevir

    The dose of simeprevir in the study of drug interaction was 50 mg when taken concomitantly with darunavir / ritonavir compared with 150 mg in the monotherapy group of simeprevir. The concentration of simeprevir increased by 159%, and the concentration of darunavir increased by 18%. Thus, simultaneous administration of a combination of darunavir / ritonavir with simeprevir is not recommended.

    Preparations from the group of statins

    In the metabolism of statins, such as simvastatin, rosuvastatin and lovastatin, an important role is played by the isoenzyme CYP3A4, therefore their concentrations in plasma can increase significantly when applied simultaneously with the darunavir / ritonavir combination. Statins in high concentrations can cause myopathy, including rhabdomyolysis. It is contraindicated to use a combination of darunavir / ritonavir concomitantly with lovastatin or simvastatin.

    The study of the interaction between atorvastatin (10 mg once a day) and the combination of darunavir / ritonavir (300/100 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 a day).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 a day. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy.

    The combination of darunavir / ritonavir (600/100 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 co-prescribe pravastatin and a combination of darunavir / ritonavir, it is recommended to start taking pravastatin from the lowest possible doses with a subsequent increase to the appearance of a clinical effect, controlling the manifestation of the side effects of the drug. Investigation of the interaction between rosuvastatin (10 mg) and the combination of darunavir / ritonavir (600/100 mg) revealed an increase in the concentration of rosuvastatin. If a rosuvastatin and a combination of darunavir / ritonavir are required, rosuvastatin should be taken with the lowest dose. Then the dose of rosuvastatin can be gradually increased until the appearance of a clinical effect, constantly monitoring the safety of therapy.

    Antagonists of histamine H2-receptor and proton pump inhibitors

    The use of omeprazole (20 mg once a day) or ranitidine (150 mg twice daily) along with the combination of darunavir / ritonavir (400/100 mg twice daily) had no effect on the concentration of darunavir in plasma. Given this, a combination of darunavir / ritonavir can be used concomitantly with histamine H antagonists2receptors and proton pump inhibitors without changing the dose of any of these drugs.

    Inhalation beta-adrenomimetics (salmeterol)

    The simultaneous use of salmeterol and the combination of darunavir / ritonavir 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.

    Immunosuppressants (ciclosporin, tacrolimus, sirolimus)

    Concentrations in the plasma of cyclosporine, tacrolimus and sirolimus may increase when these drugs are used concomitantly with the darunavir / ritonavir combination.

    In these situations it is recommended to monitor the concentration of immunosuppressant in plasma.

    Clotrimazole

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

    Beta-blockers

    Metoprolol, timolol

    With the simultaneous use of darunavir / ritonavir with metoprolol and timolol, an increase in the concentration of beta-blockers is possible. With the simultaneous use of these drugs and the combination of darunavir / ritonavir, caution should be exercised and careful clinical monitoring should be carried out, and a dose reduction of beta-blockers may also be required.

    Carvedilol

    Joint application has not been studied. It is expected that the combination of darunavir / ritonavir increases carvedilol concentrations in the blood plasma (by inhibiting the isoenzyme CYP2D6). It is recommended to conduct thorough clinical monitoring while concomitantly prescribing a combination of darunavir / ritonavir and carvedilol. Consider the possibility of reducing the dose of the beta-blocker.

    Methadone

    In a study of the effect of the darunavir / ritonavir combination (600 mg / 100 mg 2 times per day), a 16% decrease in the concentration of stable methadone maintenance therapy Rin the plasma. Based on the pharmacokinetic and clinical results of methadone dose adjustment during the initiation of therapy, the darunavir / ritonavir combination is not required. However, it is recommended that clinical monitoring be carried out. in some patients, maintenance therapy requires correction.

    Buprenorphine / naloxone

    The results of the study of the interaction of the darunavir / ritonavir combination with buprenorphine / naloxone showed no effect of the darunavir / ritonavir combination on the buprenorphine concentration when combined. The concentration of the active metabolite of buprenorphine - norbuprenorphine increased by 46%. Correction of the dose of buprenorphine was not required. When a combination of darunavir / ritonavir and buprenorphine is administered together, careful clinical monitoring is recommended.

    Estrogen-containing oral contraceptives

    The results of the study on the interaction between the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and ethinyl estradiol and norethisterone indicate that the equilibrium concentration (Css) in the plasma of ethinylestradiol and norethisterone is reduced by 44% and 14%, respectively. When using the darunavir / ritonavir combination, it is recommended to use alternative non-hormonal methods of contraception.

    Inhibitors of phosphodiesterase type 5 (PDE-5)

    When treating erectile dysfunction

    In one study, sildenafil concentrations were studied after taking one dose of this drug (100 mg), and after taking 25 mg of sildenafil concomitantly with a combination of darunavir / ritonavir (400/100 mg twice daily). The concentrations of sildenafil were similar in both situations. Caution is required when concurrent use of PDE-5 inhibitors for the treatment of erectile dysfunction and the combination of darunavir / ritonavir. If a darunavir / ritonavir combination is required, together 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 exceed 2.5 mg within 72 hours, and a single dose of tadalafil should not exceed 10 mg for 72 hours.

    Avanafil

    Contraindicated simultaneous administration of avanafil and combination darunavirritonavir.

    In the treatment of pulmonary arterial hypertensionnisia

    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, arterial hypotension, prolonged erection and fainting). Thus, simultaneous use of the combination of darunavir / ritonavir and sildenafil in the treatment of pulmonary arterial hypertension is contraindicated. It is not recommended simultaneous administration of tadalafil for the treatment of pulmonary arterial hypertension with a combination of darunavir / ritonavir.

    Selective serotonin reuptake inhibitors

    The study of the interaction between paroxetine (20 mg once a day) or sertraline (50 mg once a day) and a combination of darunavir / ritonavir (400/100 mg twice daily) showed that the concentration of darunavir in plasma was not dependent on the presence of sertraline or paroxetine. On the other hand, in the presence of the darunavir / ritonavir combination, plasma concentrations of sertraline and paroxetine decreased by 49% and 39%, respectively. If simultaneous use with a darunavir / ritonavir combination is necessarycarefully select the dose of selective serotonin reuptake inhibitors based on the clinical evaluation of the antidepressant effect. In addition, patients receiving a stable dose of sertraline or paroxetine, who are being treated with the darunavir / ritopavir combination, should carefully monitor the severity of the underlying effect of the antidepressant.

    Sedatives / hypnotics

    Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem

    Joint application has not been studied. Sedatives / hypnotics are mainly metabolized by isozymes CYP3A. Simultaneous reception with a combination of darunavir / ritonavir can cause a significant increase in the concentrations of these drugs in the blood. Clinical monitoring is recommended while concomitantly prescribing a combination of darunavir / ritonavir with these sedatives / hypnotics. A reduction in the dose of sedatives / hypnotics should be considered.

    Painkillers

    Alfentanil

    Joint application has not been studied. Metabolism of alfentanil is mediated by isoenzyme CYP3A and, in this connection, can be inhibited when combined with a darunavir / ritonavir combination. With the simultaneous administration of alfentanil and the combination of darunavir / ritonavir, a reduction in the dose of alfentanil may be required. Clinical monitoring is required because of the risk of developing prolonged or delayed respiratory depression.

    Anti-TB drugs

    Rifampicin, rifapentin

    Joint application has not been studied. Rifapentin and rifampicin are powerful isoenzyme inducers CYP3A. It has been found that these preparations significantly reduce the concentrations of other protease inhibitors, which can lead to virological inefficiency and development of resistance (due to induction by the isoenzyme of the system CYP450). Attempts to compensate for a decrease in the concentrations of other protease inhibitors in combination with a low dose of ritonavir by increasing the dose often led to the development of adverse reactions to rifampicin from the side of the liver. The simultaneous administration of rifapentin and the combination of darunavir / ritonavir is not recommended. The simultaneous use of rifampicin combination and the combination of darunavir / ritonavir is contraindicated.

    Rifabutin

    Rifabutin is an inducer and substrate of isoenzymes CYP450. When studying the interaction of the darunavir / ritonavir combination (600/100 mg twice daily) and rifabutin (150 mg every other day), there was an increase in the concentration of darunavir by 57%. FROM Considering the safety profile of darunavir in combination with ritonavir while concomitantly prescribing darunavir / ritonavir and rifabutin combinations, dose adjustment for the darunavir / ritonavir combination is not required. It was found that when rifabutin is used at a dose of 150 mg every other day in combination with a darunavir / ritonavir combination (600/100 mg twice daily), rifabutin concentrations comparable to those of rifabutin 300 mg once daily without the combination of darunavir / lopinavir, while the concentrations of the active metabolite 25-O-deacetyltrifabutin are increased. With the simultaneous administration of the darunavir / ritonavir and rifabutin combination, a 75% reduction in the dose of rifabutin from a normal dose of 300 mg per day and careful monitoring of the side effects of rifabutin are required.

    Antineoplastic agents

    Dasatinib, nilotinib, vinblastine, vincristine

    Concentrations of these drugs may increase with simultaneous administration with a combination of darunavir / ritonavir,which increases the risk of developing unwanted phenomena, usually due to the intake of these drugs. It is recommended that one of these antineoplastic agents be given with caution at the same time as darunavir in combination with ritonavir.

    Everolimus

    The simultaneous administration of everolimus with the darunavir / ritonavir combination is not recommended.

    Vegetable preparations

    St. John's wort perforated

    Joint application has not been studied. It is expected that St. John's wort reduces the concentration of darunavir or ritonavir in the blood plasma (due to the induction of isoenzymes of the system CYP450). The combination of darunavir / ritonavir should not be used concomitantly with preparations with a St. John's wort. If the patient is already taking St. John's wort, stop taking it and, if possible, check the level of the viral load. When discontinuing treatment with St. John's wort, an increase in the concentration of darunavir (as well as ritonavir) is possible, and therefore a dose adjustment may be necessary. Effect of inducing action on isoenzyme CYP3A may persist for at least 2 weeks after stopping the intake of St. John's wort preparations. therefore darunavir in combination with ritonavir it is recommended to appoint 2 weeks after stopping the intake of St. John's wort preparations.

    Drugs that may affect the effects of darunavir in combination with ritonavir

    Darunavir and ritonavir metabolized by isoenzymes CYP3A. Drugs that induce isozyme activity CYP3A, can increase the clearance of darunavir and ritonavir, leading to a decrease in the concentrations of these drugs in the blood and, consequently, the loss of darunavir therapeutic efficacy and development of resistance. Contraindicated simultaneous use of darunavir in combination with ritonavir with the following inducers of isoenzymes CYP3A: rifampicin, St. John's wort and lopinavir.

    Simultaneous reception of darunavir and ritonavir with other drugs that inhibit isoenzymes CYP3A, can reduce the clearance of darunavir and ritonavir, which can lead to an increase in the concentrations of darunavir and ritonavir in the blood plasma. It is not recommended simultaneous administration with potent inhibitors of isoenzymes CYP3A, with joint application should be careful. These drugs include: indinavir, system azoles, such as ketoconazole and clotrimazole and etc.

    Drugs that can be exposed to darunavir in combination with ritonavir

    Darunavir and ritonavir are inhibitors of isoenzymes CYP3A, CYP2D6 and P-glycoprotein. Simultaneous reception of darunavir / ritonavir with drugs, mainly metabolized isoenzymes CYP3A and / or CYP2D6 or transported P-glycoprotein, can cause an increase in the concentration of such drugs in the plasma, which, in turn, may be the cause of the amplification or prolongation of their therapeutic effect, as well as the cause of side effects.

    Darunavir, concurrently taken with a low dose of ritonavir, should not be used in combination with drugs whose clearance depends on isoenzyme metabolism CYP3A, and increased concentrations of which can lead to serious and / or life-threatening adverse events (narrow therapeutic breadth).

    The overall effect of pharmacokinetic enhancement of ritonavir is a 14-fold increase in the concentration of darunavir with a single dose of darunavir at a dose of 600 mg in combination with ritonavir at a dose of 100 mg twice daily. In this way, darunavir can be used only in combination with ritonavir.

    Clinical study of the interaction of drugs metabolized by isoenzymes CYP2C9, CYP2C19 and CYP2D6, and the darunavir / ritonavir combination showed an increase in isoenzyme activity CYP2C9 and CYP2C19 and inhibition of isoenzyme activity CYP2D6 in the presence of darunavir / ritonavir, which may be due to the presence of ritonavir in low doses. Simultaneous reception of darunavir and ritonavir with drugs, which are mainly metabolized by isoenzyme CYP2D6 (such as flecainide, propafenone, metoprolol) can lead to an increase in the concentration of these drugs in the blood plasma, and consequently, to enhance or prolong their therapeutic effect and develop unwanted reactions. Simultaneous reception of darunavir and ritonavir and drugs, mainly metabolized by isoenzymes CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) can lead to a decrease in the concentration of such drugs in the blood, so that the therapeutic effect may be weakened or shortened.

    Despite the fact that the effect on isoenzyme CYP2C8 was investigated only under conditions in vitro, simultaneous administration of darunavir in combination with ritonavir and drugs, mainly metabolized by isoenzyme CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) can lead to a decrease in the concentration of such drugs in the blood, so that the therapeutic effect may be weakened or shortened.

    Ritonavir is an inhibitor of P-glycoprotein transporters OATP1B1 and OATP1B3. Therefore, simultaneous reception with these substrates of transporters can lead to an increase in the concentrations of such compounds in the blood plasma (for example, dabigatran etexilate, digoxin, statins and bosentan (see section "Interaction with other drugs")).

    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.

    Information on the combination of darunavir / ritonavir in patients 65 years of age or older is very limited. Care must be taken when treating darunavir patients of this age group, because they are more likely to have liver dysfunction, they are more likely to suffer from concomitant diseases, or receive concomitant therapy.

    Absolute bioavailability after a single dose of darunavir at a dose of 600 mg is approximately 37% and increases to about 82% after taking darunavir in combination with 100 mg of ritonavir twice a day. There is a 14-fold increase in the concentration of darunavir in the plasma after taking a single dose of 600 mg in combination with ritonavir (100 mg twice a day). In this way, darunavir should be taken only in combination with a low dose of ritonavir (100 mg) 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, so a dose of ritonavir should not be increased.

    Severe skin reactions

    In 0.4% of patients with darunavir, severe skin reactions were detected, which may be accompanied by fever and / or an increase in the level of hepatic transaminases. Stevens-Johnson syndrome and DRESS-syndrome (drug rash with eosinophilia and systemic manifestations) were rarely recorded (<0.1%).

    In the postmarketing period, toxic epidermal necrolysis and acute generalized exentematous pustulosis were recorded very rarely (<0.01%). If there are signs or symptoms of severe skin reactions (rash or rash accompanied by fever, general malaise, pain in the muscles or joints, blisters, oral cavity, conjunctivitis, hepatitis and / or eosinophilia), darunavir should be discontinued immediately.

    A rash (of all types) was observed in 10.3% of patients receiving darunavir. 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 was the cause of withdrawal of the darunavir / ritonavir combination.

    Rashes were more common in patients taking both raltegravir and a combination of darunavir / ritonavir compared to patients who received separately raltegravir and a combination of darunavir / 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. In patients with allergies to sulfonamides darunavir should be used with caution. In clinical studies of the darunavir / ritonavir combination, the extent and incidence of rash were similar in patients with and without an allergy to sulfonamides in the anamnesis.

    Patients with liver disease

    Care must be taken when using the drug in patients with impaired liver function of mild and moderate severity. Data on the use of the drug for severe liver dysfunction are absent.

    Hepatotoxicity

    When using the darunavir / 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 dronavir / 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 darunavir / ritonavir combination and during treatment. Consider monitoring the increase in activity ACT and ALT in patients with chronic hepatitis, liver 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 darunavir / ritonavir. If symptoms of liver function disorders or their progression are detected (including a clinically significant increase in hepatic enzyme activity and / or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, tenderness in palpation of the liver, hepatomegaly), consider the possibility interruption or withdrawal of therapy with a combination of darunavir / ritonavir.

    Patients with kidney disease

    Kidneys play an insignificant role in the clearance of darunavir, so in patients with kidney disease, the overall clearance of darunavir is virtually unchanged. Darunavir and ritonavir have a high degree of binding to plasma proteins,so 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 received coagulation factor VIII. In more than half of the cases described, treatment with protease inhibitors continued without interruption or resumed after suspension for some time. It has been suggested that there is a causal relationship between the treatment of protease inhibitors and increased bleeding in patients with hemophilia, but the mechanism for such a link has not been established. Patients with hemophilia receiving the darunavir / 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 current 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 mellitus or hyperglycemia.

    Redistribution of fat and metabolic disorders

    Combined antiretroviral therapy can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. 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 determine the content of lipids and fasting blood glucose. Disorders of lipid metabolism should be treated with appropriate drugs.

    Osteonecrosis

    Despite the multifactorial etiology (use of GCS, alcohol, severe immunosuppression, elevated 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 for immediate medical attention in the event of joint pain or difficulty in moving.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency, an inflammatory response of the body to asymptomatic or residual opportunistic infections may occur at the onset of combined antiretroviral therapy, which causes serious clinical complications or worsening of symptoms. Typically, such reactions are observed in the first weeks or months of combined antiretroviral therapy. Possible development of cytomegalovirus retinitis, generalized and / or local mycobacterial infection 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 of primary manifestations varied, and the disease could occur many months after the onset.

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

    Studies on the effects of darunavir / 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 clinical condition of the patient, as well as the side effects of darunavir, should be taken into account. When dizziness occurs, you should refrain from performing these activities.

    Form release / dosage:

    Tablets, film-coated, 800 mg.

    Packaging:

    Primary packaging of medicinal product.

    For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

    For 30, 60 or 120 tablets in a can of polymer with a lid pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

    Secondary packaging of medicinal product.

    For 3 or 6 contour squares, together with the instructions for use, they are placed in a pack of cardboard for consumer containers.

    On 1 bank together with instructions on application place in a pack from a cardboard for consumer tare.

    Storage conditions:

    In the original packaging of the manufacturer, at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use, after the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003327
    Date of registration:23.11.2015 / 19.05.2016
    Expiration Date:23.11.2020
    Date of cancellation:2020-11-23
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC
    Information update date: & nbsp28.12.2017
    Illustrated instructions
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