Darunavir-TL - instructions for use, dose, side effects, contraindications

Active substance:	400.0 mg	600.0 mg
Darunavir ethanolate	433.64 mg	650.46 mg
in terms of darunavir	400.00 mg	600.00 mg
Excipients:
Microcrystalline cellulose	310.36 mg	465.54 mg
Crospovidone	40.00 mg	60.00 mg
Silica colloidal dioxide	8.00 mg	12.00 mg
Magnesium stearate	8.00 mg	12.00 mg
Film Sheath:
Opadrai II 85F93377 (orange) [polyvinyl alcohol 40.0%, titanium dioxide 22.5%, macrogol 20.2%, talc 14.8%, aluminum varnish based on the sunset sunset yellow (E110) 2.5%]	32.00 mg	-
Opadrai II 85F13962 (orange) [polyvinyl alcohol - 40.0%, macrogol - 20.2%, titanium dioxide - 19.5%, talc - 14.8%, aluminum varnish based on the sunset sunset yellow (E110) - 5.5%]	-	48.00 mg

Description:

For a dosage of 400 mg

Tablets are oval, biconvex, covered with a film coat of light orange color, two layers are visible on a cross section. The core of the tablet is white or almost white colors.

For a dosage of 600 mg

The tablets are oval, biconvex, covered with a film membrane of orange color, two layers are visible on a cross section. The core of the tablet is white or almost white.

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). Darunavir selectively inhibits splitting of polyproteins Gag-Pol HIV in viral-infected cells, preventing the formation of mature viral particles.

Darunavir strongly binds to the HIV-1 protease (K_D 4.5 x 10^-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, have been studied in healthy volunteers and in HIV-infected patients.The concentrations of darunavir in plasma were higher in patients infected with HIV-1 than in healthy individuals.

This difference can be explained by higher concentrations of sy-acid glycoprotein in patients infected with HIV-1, which leads to an increase in the amount of darunavir associated with α₁acid plasma glycoprotein. Darunavir is metabolized mainly by isoenzyme CYP3A4. Ritonavir inhibits isoenzyme 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 after 2.5-4.0 hours. The absolute bioavailability of a single dose of darunavir (600 mg) with oral administration was about 37% and increased to about 82% in the presence of ritonavir (100 mg 2 times a day). The total pharmacokinetic effect of ritonavir consisted of an approximately 14-fold increase in the concentration of darunavir in blood plasma after one oral administration of 600 mg of ritonavir 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. Consequently, darunavir should be taken with ritonavir during meals. The nature of food does not affect the concentration of darunavir in plasma.

Distribution

About 95% of darunavir binds to plasma proteins, predominantly with α₁acid 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 were identified, whose activity was 10 times less than the activity of darunavir in relation to wild-type HIV.

Excretion

After a single dose of 400 mg ¹⁴C-darunavir and 100 mg of ritonavir are about 79.5 and 13.9% 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 / hr without ritonavir and 5.9 l / h in the presence of a low dose of ritonavir.

Special patient groups

Children

The pharmacokinetics of darunavir in combination with ritonavir in children aged 6 to 18 and a body weight of at least 20 kg are 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 15 to 20 kg is comparable to pharmacokinetics in adult patients receiving a darunavir / ritonavir 600/100 mg bid 2 times a day.

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

With population pharmacokinetic analysis, slightly higher (16.8%) concentrations of darunavir in HIV-infected women were detected 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 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 a lung (Class A Child-Pugh classification) and moderate (class B according to the Child classification -Pugh) a violation of liver function were comparable to those of healthy individuals. The effect of severe liver dysfunction on the pharmacokinetics of darunavir has not been studied.

Indications:

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

Contraindications:

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

- severe hepatic insufficiency (class C according to the Child-Pugh classification);

- children under 18 years of age (for this dosage);

- simultaneous reception of darunavir in combination with ritonavir in low doses with drugs, the clearance of which is predominantly determined by the cytochrome P450 isoenzyme CYP3A4 and an increase in plasma concentration is associated with serious and / or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, alfuzosin, colchicine (in patients with renal or hepatic insufficiency), sildenafil, terfenadine, midazolam (orally), triazolam, cisapride, pimozide, ranolazine, sertindole, quetiapine, ergotamine, dihydroergotamine, ergometrine and methylergomethrin, a combination of lopinavir / ritonavir, amiodarone, beprideil, dronedaron, quinidine, lidocaine with systemic administration, simvastatin, lovastatin, ticagrelor (see also section "Interactions with other drugs");

- simultaneous reception with drugs containing rifampicin, as well as with preparations containing St. John's wort extract, because their simultaneous application can lead to a decrease in the concentration of darunavir in the plasma, and consequently - to a loss of therapeutic effect and the development of resistance.

Carefully:

- In patients with impaired liver function of mild and moderate severity (classes A and B according to the Child-Pugh classification);

- in patients with allergy to sulfonamides;

- in elderly patients.

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.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 associated with exposure to darunavir, HIV-infected women receiving darunavir, should refrain from breastfeeding.

Dosing and Administration:

Inside. Patients should be instructed to take darunavir with a low dose of ritonavir no later than 30 minutes after eating.

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.

After initiation of therapy with Darunavir-TL, patients should not change or discontinue therapy without consulting the attending physician.

Adult patients

Patients who have not previously received HIV protease inhibitors	Patients who previously received HIV protease inhibitors
	not having mutations that cause resistance to darunavir *	have at least 1 mutation that causes resistance to darunavir *
800 mg once a day in combination with 100 mg of ritonavir, while eating	800 mg once a day in combination with 100 mg of ritonavir, while eating	600 mg twice a day in combination with 100 mg of ritonavir, while eating

* Mutations causing resistance to darunavir: VIII, V32I, L33F, I47V, I50V, I54M, I54L, T74R, L76V, I84V and L89V.

For patients who have previously received HIV protease inhibitors, genotypic assays are recommended. However, if it is impossible for such assays patients not previously treated with HIV protease inhibitors, it is recommended to take a combination of darunavir / r 1 times a day in a dose of 800/100 mg, and patients previously treated with protease inhibitors - 2 times a day in a dose of 600/100 mg .

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

Skipping darunavir in combination with ritonavir

If reception of darunavir in combination with ritonavir assigned one time per day and late in the reception is less than 12 hours, the missed dose should be taken as soon as possible with food and resume normal dosing regimen; if the delay in the reception was more than 12 hours, the missed dose should not be taken; the next dose is taken at the usual time.

If taking darunavir in combination with ritonavir is prescribed 2 times a day and the delay in admission is less than 6 hours, the missed dose should be taken as soon as possible with food and resume the usual dosing regimen. If the delay in admission is more than 6 hours, the missed dose should not be taken; the next dose is taken at the usual time.

Special patient groups

Elderly patients

Information on use in elderly patients is limited, so darunavir in combination with ritonavir in patients of this age group should be used with caution.

Patients with hepatic impairment

Darunavir is metabolized by the hepatic system. In patients with mild to moderate liver function disorder (Child-Pugh classes A and B), dose adjustment is not required, but caution is necessary. The combination of darunavir / ritonavir in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) is contraindicated.

Patients with impaired renal function

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

Side effects:

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

The most frequent serious side effects were: acute renal insufficiency, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis and fever.

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

Side effects noted in clinical trials and during the postgraduate experience with darunavir are given in accordance with the classification MedDRA: very frequent (≥1 / 10), frequent (≥1 / 100, <1/10), infrequent (≥1 / 1000 and <1/100), rare (≥1 / 10,000 and <1/1000) and very rare (<1/10 000).

Side effects observed during clinical trials and post-marketing period when using darunavir in combination with ritonavir

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

Description of some side effects

Rash. In clinical studies, mainly a mild to moderate rash was observed.The rash most often manifested itself during the first 4 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, a rash, regardless of its cause, was more likely to occur with treatment regimens containing darunavir and raltegravir, than when taking only darunavir or only raltegravir. The rash caused by taking the drug appeared with a similar frequency. The rash that developed in clinical trials was mild and moderate, which did not lead to discontinuation of therapy.

Lipodystrophy. Combined antiretroviral therapy (ARVT) causes fat redistribution (lipodystrophy) in patients with HIV. Lipodystrophy was manifested by 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 ARVT causes metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

Disturbances from the musculoskeletal tissue. Increased activity of creatine phosphokinase, myalgia, myositis and rhabdomyolysis (rarely) were observed with the use of protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors. Osteonecrosis has been reported, especially in patients with recognized risk factors, with HIV infection at a late stage or for a long time receiving combined ARVT. The incidence of osteonecrosis is unknown.

Syndrome of restoration of immunity. In patients with HIV infection and severe immunodeficiency at the onset of combined ARVT, 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 develop 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 drugs from the protease inhibitor group.

Patients with co-infections with the hepatitis B virus and / or C. In patients with these infections, an increase in hepatic transaminase activity was more common than in patients without concomitant hepatitis B and / or C.

Overdose:

Information on acute overdose when taking darunavir 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 tablets in combination with ritonavir, with no adverse effects noted.

Treatment. The specific antidote is unknown. In case of an overdose, general supportive therapy with monitoring of basic physiological parameters should be carried out. With appropriate indications for the withdrawal of non-sucking drug, it is necessary to induce vomiting. You can also apply Activated carbon. Darunavir predominantly binds to plasma proteins, therefore, a significant removal of the active substance by dialysis is unlikely.

Interaction:

Drugs affecting the profile of darunavir in combination with ritonavir

Darunavir, used in combination with ritonavir, is an inhibitor of isoenzymes CYP3A, CYP2D6 and P-glycoprotein.Simultaneous application toamalgamations darunavir / ritonavir and drugs that are metabolized predominantly isoenzymes CYP3A, CYP2D6 and transferred by P-glycoprotein, can cause an increase in the concentrations of such drugs in the plasma, which, in turn, may be the reason for the enhancement or prolongation of the therapeutic effect, as well as the cause of side effects.

The combination of darunavir / ritonavir is contraindicated to be applied simultaneously 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 astemizole, alfuzosin, colchicine, sildenafil, terfenadine, midazolam (orally), triazolam, cisapride, pimozide, ranolazine, sertindole, quetiapine, ergotamine, dihydroergotamine, ergometrine and methylergometrine, combination lopinavir / ritonavir, amiodarone, beprideil, dronedaron, quinidine, lidocaine (with systemic administration), simvastatin, lovastatin, ticagrelor.

Rifampicin is a strong inducer of enzymes CYP450.The combination of darunavir / ritonavir can 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 darunavir.

The combination of darunavir / ritonavir should not be used concomitantly with drugs containing extract of St. John's wort perfumed (Hypericum perforatum), as this may be accompanied by a significant decrease in the concentration of darunavir in the plasma, as a result of which the therapeutic effect of darunavir may disappear.

Recommendations for concurrent use with other antiretroviral drugs

HIV integrase inhibitors

Dolutegravir

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

Elvitegravir

When a combination of darunavir / ritonavir (600/100 mg twice daily) and elvitegravir is used, the dose of elvitegravir should be 150 mg once daily. Pharmacokinetic data and recommendations for dosing when other darunavir doses are not available. Therefore, simultaneous use of the darunavir / ritonavir combination at doses other than 600/100 mg twice daily and elvitegravir is not recommended.

Raltegravir

Based on the results of several clinical studies, it is suggested that raltegravir can cause a slight decrease in the concentration of darunavir in blood plasma. At present, the effect of raltegravir on the concentration of darunavir in blood plasma does not seem clinically significant. When combined with a low dose of ritonavir and raltegravir, dose adjustment of darunavir is not required.

Nucleoside reverse transcriptase inhibitors (NRTIs)

Didanosine

The combination of darunavir / ritonavir (600/100 mg twice daily) simultaneously with didanosine can be used without dose adjustment. 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 (300/100 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 simultaneous application of a combination of darunavir / ritonavir and tenofovir, dose adjustment is not required.

Other NRTIs

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

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz

A study was made of the interaction between the darunavir / ritonavir combination (300/100 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 concentration of efavirenz in plasma with its simultaneous use with the darunavir / ritonavir combination increased by 21%. 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.

Etravirine

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

Nevirapine

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

Rilpivirine

In studies of the interaction between darunavir / ritonavir (800/100 mg once daily) with rilpivirin (150 mg once a day), there is no clinically significant effect on the concentration of darunavir. The concentration of rilpivirin when used concomitantly with the darunavir / ritonavir combination increased by 130%. This interaction is considered clinically insignificant, and therefore the combination of darunavir / ritonavir and rilpivirine can be used simultaneously without changing their doses.

Protease Inhibitors (MP)

Ritonavir

In general, the effect of improving the pharmacokinetics of darunavir ritonavir was manifested in the fact that the concentrations of darunavir in plasma after taking a single dose of darunavir (600 mg) and 100 mg of ritonavir twice daily increased by about 14 times. Therefore, the drug Darunavir-TL should be used in combination with a low dose of ritonavir to increase the bioavailability of darunavir.

The combination of lopinavir / ritonavir

The results of the study of the interaction between the darunavir / ritonavir combination (1200/100 mg twice daily) or 1200 mg of darunavir without ritonavir and the combination of lopinavir / ritonavir (400/100 mg twice daily or 533 / 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%. The simultaneous use of a combination of darunavir / ritonavir and lopinavir / ritonavir is contraindicated.

Saquinavir

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

Atazanavir

Investigation of the interaction between the darunavir / ritonavir combination (400/100 mg 2 times a day) and atazanavir (300 mg once a day) showed no significant changes in the concentrations of darunavir and atazanavir in plasma when they are used simultaneously. Atazanavir can be used concomitantly with the darunavir / ritonavir combination.

Indinavir

In a study of the interaction between the darunavir / ritonavir combination (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, the concentration of indinavir in plasma increased by 23%.When used 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 a day to 600 mg twice a day.

Other PIs

To date, the interaction between the combination of darunavir / ritonavir and IP (in addition to lopinavir, saquinavir, atazanavir and indinavir) was not studied, therefore, it is not recommended to use the IP not listed here simultaneously with the darunavir / ritonavir combination.

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 by 305%. The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.

Preparations, depressing breathing

When a combination of darunavir / ritonavir and respiratory depression is combined, it is necessary to monitor the patient because of the risk of prolonged delay or stopping of breathing, which may require a reduction in the dose of alfentanil.

Recommendations for simultaneous use with preparations of other classes

Antiarrhythmic drugs (bepripid, disopyramide. dronedarone, mexiletine, systemic lidocaine, quinidine, amiodarone, flecainide, propafenone, ranolazine)

The combination of darunavir / ritonavir can increase serum concentrations of these antiarrhythmic agents. With the simultaneous use of this combination and listed antiarrhythmic drugs, it is recommended to be cautious and, if possible, monitor the concentrations of these agents in the plasma. The simultaneous use of the darunavir / ritonavir combination with amiodarone, bepridil, dronedarone, quinidine, ranolazine, and lidocaine in its systemic administration is contraindicated.

Digoxin

In all studies on the interaction of darunavir / 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 by 77% was demonstrated. It is recommended that a minimum dose of digoxin be initially prescribed and its serum concentration measured to obtain the desired clinical effect when used concomitantly with the darunavir / ritonavir combination.

Anticoagulants (apixaban, dabigatran, rivaroxaban, warfarin)

Simultaneous use of the darunavir / ritonavir combination and the above anticoagulants is not recommended.

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.

Anticonvulsant drugs (phenobarbital phenytoin and carbamazepine)

Phenobarbital and phenytoin are inducers of enzymes CYP450. The combination of darunavir / ritonavir is not recommended in combination with these drugs, as this can cause a 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 (600/100 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 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 apply the combination simultaneouslydarunavir / ritonavir and carbamazepine patients should be observed in connection with the potential for side effects of carbamazepine. Carbamazepine concentrations should be measured and its dosage adjusted according to clinical manifestations. Thus, doses of carbamazepine can be reduced by 25-50% when combined with a combination of darunavir / ritonavir.

Antihistamines

Astemizole, terfenadine

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

Anti-malarial drugs

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

Antidepressants

Paroxetine and sertraline

The study of the interaction between paroxetine (20 mg once a day) or sertraline (50 mg once daily) and darunavir / ritonavir (400/100 mg twice daily) showed that the concentration of darunavir in plasma did not depend on the presence of sertraline or paroxetine. On the other hand, in the presence of the darunavir / ritonavir combination, the concentrations of sertraline and paroxetine in plasma decreased by 49 and 39%, respectively. In cases where selective serotonin reuptake inhibitors should be used concomitantly with the drug Darunavir-TL and ritonavir, the dose of these inhibitors must be carefully selected 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 / ritonavir combination, should carefully monitor the severity of the underlying effect of the antidepressant.

Amitriptyline, imipramine, nortriptyline, trazodone, desipramine

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

Sedatives / hypnotics (buspirone, clorazepate, diazepam, estazolam, flurazepam. midazolam, triazolam, zolpidem)

The combined use of the darunavir / ritonavir combination with these sedative / hypnotic drugs may increase their plasma concentration due to inhibition of the isoenzyme CYP3A4. When combined, clinical monitoring is recommended and the possibility of reducing the dose of a sedative / hypnotic drug should be considered.

When combined with midazolam, administered parenterally,should be carefully monitored and take urgent measures in the event of respiratory depression or prolonged sedation. It is necessary to consider the possibility of reducing the dose of parenterally administered midazolam, especially if more than one dose of midazolam is used. The use of a combination of darunavir / ritonavir with oral midazolam or triazolam is contraindicated.

Neuroleptics

Quetiapine

When quetiapine is combined with a darunavir / ritonavir combination, the concentration of quetiapine in plasma can be increased by inhibiting the isoenzyme CYP3A4 darunavir. The simultaneous use of the darunavir / ritonavir and quetiapine combination is contraindicated, as this may lead to an increase in toxicity associated with quetiapine. An increase in the concentration of quetiapine in the blood plasma can lead to coma.

Pimozide, sertindole, perphenazine, risperidone, thioridazine

With the simultaneous use of the darunavir / ritonavir and pimozide combination, an increase in plasma pimozide concentration due to inhibition of isozymes CYP3A4 and CYP2D6. The simultaneous use of pimozide and the combination of darunavir / ritonavir is contraindicated.

The simultaneous use of sertindole and the combination of darunavir / ritonavir is contraindicated.

In the combined use of risperidone or thioridazine with the darunavir / ritonavir combination, the concentrations of risperidone and thioridazine in the plasma may increase, resulting in a reduction in the dose of neuroleptics when combined.

Antidotal agent colchicine

When colchicine is used together with darunavir / ritonavir, the concentration of colchicine in plasma can increase. The following scheme for changing the dose of colchicine is recommended. For the treatment of gout exacerbations in patients receiving the darunavir / ritonavir combination, the recommended dose of colchicine is 0.6 mg followed by 0.3 mg after 1 h. The course of treatment should be repeated no earlier than 3 days later. For the prevention of exacerbations in patients receiving the darunavir / 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 in patients receiving the darunavir / ritonavir combination, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg 2 times a day).Patients with reduced kidney or liver function are contraindicated in the appointment of colchicine when combined with a combination of darunavir / ritonavir.

Blockers of slow calcium channels

Concentrations in the plasma of slow calcium channel blockers (eg, amlodipine, verapamil, felodipine, nifedipine, nicardipine, diltiazem) may increase with simultaneous use with a combination of darunavir / ritonavir. In such cases it is necessary to closely monitor the condition of patients.

Antibiotic clarithromycin

The study of the interaction between the darunavir / ritonavir combination (400/100 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 did not change. In patients with impaired renal function, it is recommended to reduce the dose of clarithromycin.

Corticosteroids

Dexamethasone

Dexamethasone when injected into the bloodstream induces isoenzyme CYP3A4 in the liver, which leads to a decrease in the concentration of darunavir in plasma. 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 combination of darunavir / ritonavir, the concentration of bosentan in plasma may increase. In patients receiving the darunavir / ritonavir combination for at least 10 days, the recommended initial dosage of bosentan is 62.5 mg every other day or every other day, depending on individual tolerability. For patients receiving bosentan and initiating therapy with a combination of darunavir / ritonavir, it is recommended to cancel bosentan at least 36 hours prior to the initiation of therapy with darunavir and ritonavir. At least 10 days after initiation of therapy with darunavir / ritonavir, bosentan should be taken at a dose of 62.5 mg every other day or every other day, depending on individual tolerability.

Fluticasone, budesonide. prednisolone

With the simultaneous use of systemic or inhaled / nasal budesonide, fluticasone or prednisolone and darunavir / ritonavir combinations, plasma glucocorticosteroid concentrations may increase. Simultaneous use may increase the risk of systemic effects of corticosteroid drugs, including Cushing's syndrome and suppression of adrenal function.If both prednisolone and the combination of darunavir / ritonavir are used concomitantly, clinical monitoring should be performed. Alternative treatment options should be considered, especially for long-term use.

Antiviral drugs of direct action

Inhibitors NS3-4A-protease of hepatitis C

Boceprevir

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

Telaprevir

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

Symeprevir

In clinical studies of the interaction of darunavir / ritonavir and simeprevir, the concentration of simeprevir in the plasma increased 2.59 times, the concentration of darunavir 1.18 times.Not recommended at the same time simeprevir and a combination of darunavir / ritonavir.

Herbal preparations

Preparations containing St. John's wort extract

Extract of St. John's wort reduces the concentration of darunavir and ritonavir in blood plasma (induction of liver enzymes). The combination of darunavir / ritonavir should not be used in conjunction with preparations containing St. John's wort extract. In the event that the patient began taking medications containing St. John's wort extract, stop taking them and, if possible, check the virus titres. The concentration of darunavir (as well as the concentration of ritonavir) may increase after discontinuation of drugs containing St. John's wort extract. This effect can persist for 2 weeks after the withdrawal of preparations containing St. John's wort extract.

Preparations from the group of statins (atorvastatin, lovastatin, Pitavastatin, pravastatin, rosuvastatin, simvastatin)

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

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 use pravastatin together with darunavir / ritonavir combination, it is recommended to start taking pravastatin from the lowest possible doses and to increase doses before the appearance of a clinical effect,controlling the manifestations of side effects of the drug.

In an investigation of the interaction between the darunavir / ritonavir combination (600/100 mg) with rosuvastatin (10 mg), an increase in rosuvastatin concentration was found. If it is necessary to simultaneously use rosuvastatin and a combination of darunavir / ritonavir, it is recommended to start with the lowest dose of rosuvastatin, gradually increasing it to obtain a clinical effect and controlling the safety of therapy.

Blockers H₂-gistaminovyh receptors (ranitidine)

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

Inhaled β-adrenomimetics (salmeterol)

The simultaneous use of salmeterol and the combination of darunavir / ritonavir is not recommended, since the risk of side effects of salmeterol from the side of the cardiovascular system may increase, including the lengthening of the interval QT, heart palpitations and sinus tachycardia.

Immunosuppressants (cyclosporine, tacrolimus, sirolimus, everolimus)

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 immunosuppressants in plasma. Simultaneous use of the combination of darunavir / ritonavir and everolimus is not recommended.

Antifungal drugs (ketoconazole. itraconazole, posaconazole, clotrimazole and voriconazole)

Ketoconazole, itraconazole, posaconazole, clotrimazole and voriconazole are strong inhibitors of the isoenzyme CYP3A4, and some of them - also its substrates.

Systemic use of these antifungal drugs concomitantly with the combination of darunavir / ritonavir can lead to an increase in the concentrations of darunavir in plasma. On the other hand, this combination can increase plasma concentrations of some of these antifungal agents. This was confirmed in a study of the interaction between ketoconazole (200 mg twice daily) and a combination of darunavir / ritonavir (400/100 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. With the simultaneous use of the darunavir / ritonavir combination and posaconazole, clinical monitoring of the patient's condition is recommended. Concentrations of voriconazole in plasma may decrease when combined with darunavir / ritonavir. Voriconazole Do not use this combination at the same time; simultaneous application is possible only if the potential benefit from using voriconazole exceeds the potential risk.

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

β-adrenoblockers (carvedilol, metoprolol, timolol)

Joint use of β-blockers and the combination of darunavir / ritonavir can lead to an increase in the concentration of β-blockers due to inhibition of the isoenzyme CYP2D6. With simultaneous use of these drugs and the combination of darunavir / ritonavir, care should be taken and careful clinical monitoring should be carried out,Also, a reduction in the doses of β-blockers may be required.

Narcotic analgesics Methadone

In a study of the effect of a combination of darunavir / ritonavir (600/100 mg twice daily) on stable maintenance therapy with methadone, a decrease in the concentration of 11-methadone in plasma by 16% was shown. Based on the results of pharmacokinetic and clinical studies, it is shown that dose adjustment of methadone at the beginning of therapy with the darunavir / ritonavir combination 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 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%. A dose adjustment 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 (600/100 mg twice daily) and ethinyl estradiol and norethisterone indicate that the constant plasma concentrations of ethinyl estradiol 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

when treating erectile dysfunction (avanafil, sildenafil, tadalafil, vardenafil)

In one study, sildenafil concentrations were studied after taking one dose of this drug (100 mg), and also 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 should be exercised when using phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction and the combination of darunavir / ritonavir. if it is necessary to use darunavir 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 2.5 mg for 72 hours,and a single dose of tadalafil is 10 mg for 72 hours. The simultaneous use of darunavir / ritonavir and avanafil is not recommended.

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

a safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension while concomitant use with a combination of darunavir / ritonavir is not 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. for the therapy of pulmonary arterial hypertension with tadalafil while simultaneous application with the combination of darunavir / ritonavir, the dose of tadalafil is required. In patients receiving the darunavir / ritonavir combination for at least 1 week, the initial dose of tadalafil should be 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerability. in patients receiving tadalafil and initiating therapy with a combination of darunavir / ritonavir, should be canceled tadalafil at least 24 hours before the initiation of therapy with the darunavir / ritonavir combination and avoid simultaneous use of tadalafil at the start of therapy with the darunavir / ritonavir combination. 1 week after initiation of therapy with the darunavir / 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.

proton pump inhibitors (esomeprazole. lansoprazole. omeprazole. pantoprazole, rabeprazole)

The simultaneous use of omeprazole (20 mg / day) and the combination of darunavir / ritonavir (400/100 mg twice daily) did not affect the concentration of darunavir in plasma. the combination of darunavir / ritonavir and proton pump inhibitors can be applied simultaneously without dose adjustment.

Panti-tuberculosis drugs

rifabutin

Rifabutin is an enzyme substrate cyp450. In the study of the interaction of the darunavir / ritonavir combination (600/100 mg twice daily) and rifabutin (150 mg every other day), an increase in the concentration of darunavir by 57% was observed.taking into account the safety profile of the darunavir / ritonavir combination, an increase in the concentration of darunavir in the presence of rifabutin does not require a dose adjustment for the darunavir / ritonavir combination. study of the interaction showed comparable concentrations with 300 mg rifabutin once a day and 150 mg every other day in combination with darunavir / ritonavir (600/100 mg twice daily), as well as an increase in the concentration of the active metabolite 25-0-deacetyltrifabutin. when using this combination, a reduction in the dose of rifabutin by 75% from the usual dose of 300 mg / day (eg, 150 mg every other day) and increased control of the side effects of rifabutin.

rifampicin and rifapentin

rifampicin and rifapentin are strong inducers of isoenzyme cyp3a4 and cause a significant decrease in the concentrations of darunavir, which may cause a loss of therapeutic effect of the drug darunavir-t. In attempts to compensate for this reduction in concentration by increasing the dose of other protease inhibitors taken with a low dose of ritonavir, liver reactions (increased activity of liver enzymes) were observed.the combined use of rifampicin and the combination of darunavir / ritonavir is not recommended.

antiplatelet drugs

with the simultaneous use of a combination of darunavir / ritonavir leads to increased exposure to ticagrelor. The simultaneous use of ticagrelor and the combination of darunavir / ritonavir is contraindicated.

simultaneous use of other antiplatelet drugs and darunavir / ritonavir combination is possible without dose adjustment.

antitumor drugs (dasatinib. everolimus. nilotinib. vinblastine, vincristine)

when the combination of darunavir / ritonavir and these antineoplastic agents are simultaneously applied, an increase in plasma concentration in the plasma is expected due to inhibition of the isoenzyme cyp3a4, which can cause unwanted reactions, usually associated with the taking of these drugs. caution should be exercised when using a combination of darunavir / ritonavir and antineoplastic agents. The simultaneous use of everolimus and the combination of darunavir / ritonavir is not recommended.

drugs, reducing the acidity of gastric juice

antacid preparations (aluminum / magnesium hydroxide, calcium carbonate)

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

antagonists α₁-adrenoceptors (alfuzosin)

the plasma concentration of alfuzosin may increase with simultaneous use with the darunavir / ritonavir combination. simultaneous use of alfuzosin and the combination of darunavir / ritonavir is contraindicated.

antianginal agents (ranolazine)

the concentration of ranolazine in plasma can be increased by simultaneous use with the darunavir / ritonavir combination due to inhibition of the isoenzyme cyp3a4. The simultaneous use of ranolazine and the combination of darunavir / ritonavir is contraindicated.

preparations of ergot alkaloids (ergotamine, dihydroergotamine, methylergomethrin)

the concentration of alkaloids of ergot in the plasma may increase with simultaneous use with a combination of darunavir / ritonavir. simultaneous application of ergot alkaloids and the combination of darunavir / ritonavir is contraindicated.

cisapride

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

Special instructions:

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

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

Absolute bioavailability after a single dose of 600 mg of darunavir is approximately 37% and increases to approximately 82% after taking darunavir in combination with 100 mg of ritonavir 2 times a day. The overall effect of improving the pharmacokinetics of darunavir ritonavir is expressed in approximately 14-foldincreasing the concentration of darunavir in plasma after taking one dose of this drug (600 mg) in combination with 100 mg of ritonavir 2 times a day. In this way, darunavir It should be taken only in combination with a low dose of ritonavir as a pharmacokinetic enhancer. An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma, and therefore a dose of ritonavir is not recommended. Darunavir-TL tablets contain aluminum lacquer based on the sunset sunset yellow (E110) and therefore can cause allergic reactions.

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 hepatic transaminase activity. Stevens-Johnson syndrome was rarely recorded (<0.1% of cases). In the post-marketing period, toxic epidermal necrolysis, DRESS-syndrome (drug rash with eosinophilia and systemic manifestations) and acute generalized exanthematous pustulosis were recorded very rarely (<0.0% of cases).If severe skin reactions occur (severe rash or rash accompanied by fever, general malaise, fatigue, pain in the muscles or joints, blisters, oral cavity, conjunctivitis, hepatitis and / or eosinophilia, etc.), the drug Darunavir-TL must 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 4 weeks of treatment and decreased with continued therapy. 0.5% cases of 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 with patients receiving separately raltegravir or 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.The use of drug Darunavir-TL in patients with allergies to sulfonamides should be done with caution. In clinical studies of the darunavir / ritonavir combination, the extent and incidence of rash were the same in patients, regardless of the history of allergy to sulfanilamides.

Patients with concomitant diseases

Patients with liver disease

Data on the use of the darunavir / ritonavir combination in patients with severe liver dysfunction are not available; therefore, it is not possible to give specific recommendations for dosing. Based on the data that stable pharmacokinetic parameters in the application of darunavir in patients with impaired liver function of mild and moderate severity (classes A and B according to the Child-Pugh classification) are comparable with those of healthy individuals, dose adjustment for such patients is not required, but take caution when taking it. The combination of darunavir / ritonavir in patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) is contraindicated.

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 combination therapy with darunavir / ritonavir. In patients with impaired hepatic function, including 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 therapy and during treatment. Consideration should be given to monitoring the increase in activity of aspartate or alanine aminotransferase in patients with chronic hepatitis, cirrhosis, or in patients who have experienced increased transaminase activity prior to initiation of therapy, and especially during the first few months of combination therapy with the darunavir / ritonavir combination. In cases of liver function abnormalities or worsening of their severity (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) should consider the possibility of interrupting or canceling therapy with a combination of darunavir / ritonavir.

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 taking 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 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 ARVT, including protease inhibitors, described for the first time identified 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 ARVT can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. At present, there are no data on the long-term consequences of this phenomenon, and its mechanism is largely unclear. A hypothesis has been made about the relationship between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy is associated with factors such as elderly age,as well as with long-term therapy with antiretroviral drugs and concomitant metabolic disorders. In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to physical signs of fat tissue redistribution. It is recommended to measure the content of serum lipids and fasting blood glucose. Disorders of lipid metabolism should be treated with appropriate drugs.

Osteonecrosis

Despite the multifactorial etiology (use of glucocorticosteroids, alcohol consumption, severe immunosuppression, increased body mass index), cases of osteonecrosis have been noted, especially in patients with HIV infection at a late stage and / or in patients receiving long-term combined ARVT. Patients should be informed of the need to visit the doctor immediately if joint pain, joint stiffness or movement difficulties occur.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency at the onset of combined ARVT, an inflammatory response of the body to asymptomatic orresidual opportunistic infections, which can lead to serious clinical complications or worsening of symptoms. Typically, such reactions are observed in the first weeks or months of combined ARV therapy. Examples include cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumonia caused by Pneumocystis (carinii) jirovecii. 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 event of the recovery of the immune system. However, the time to onset of the disease may vary, and such diseases may begin months after initiation of therapy.

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

Studies to study the effect of the darunavir / ritonavir combination on the ability to drive vehicles and mechanisms have not been conducted. However, it is necessary to take into account the fact that dizziness was observed in some patients during treatment, including the taking of the darunavir / ritonavir combination.When dizziness occurs, you should refrain from performing these activities.

Form release / dosage:

Film coated tablets, 400 mg and 600 mg.

Packaging:

On 60 tablets in a jar for medicines from plastic (from polyethylene or polypropylene), ukuporennuju a cover from plastic (from polyethylene or polypropylene). Free space in the bank is filled with cotton wool with a hygroscopic or sterile cotton ball.

Each bank along with the instruction for use is placed in a pack of cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003578

Date of registration:19.04.2016

Expiration Date:19.04.2021

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp19.03.2017

Illustrated instructions

Instructions

Darunavir-TL (Darunavir-TL)