Darunavir - instructions for use, dose, side effects, contraindications - Medicinal reference TALKDRUGS

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Active substanceDarunavirDarunavir

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Heterose Labs Limited India

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BIOCAD, CJSC Russia

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Profarm, LLC Russia

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TECHNOLOGY OF DRUGS, LTD. Russia

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FARMASINTEZ, JSC (Irkutsk) Russia

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FARMASINTEZ, JSC (Irkutsk) Russia

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Johnson & Johnson, LLC Russia

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Johnson & Johnson, LLC Russia

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Johnson & Johnson, LLC Russia

Dosage form: & nbsptfilm-covered laths

Composition:

Darunavir, 75 mg

1 A film coated tablet contains:

active substance: darunavir ethanolate 81.31 mg (equivalent to darunavir 75.0 mg); Excipients: cellulose microcrystalline 72.00 mg, crospovidone 3.12 mg, silicon dioxide colloid 3.50 mg, magnesium stearate 1.00 mg;

shell: film coating 6.25 mg, which includes polyvinyl alcohol 40.0%, titanium dioxide (E171) 25.00%, macrogol 20.20%, talc 14.80%.

Darunavir, 150 mg

1 A film coated tablet contains:

active substance: darunavir ethanolate 162.62 mg (equivalent to darunavir 150.0 mg);

Excipients: cellulose microcrystalline 144.00 mg, crospovidone 6.24 mg, silicon colloidal dioxide 7.00 mg, magnesium stearate 2.00 mg;

shell: film coating 12.50 mg, which includes polyvinyl alcohol 40.0%, titanium dioxide (E171) 25.00%, macrogol 20.20%, talc 14.80%.

Darunavir, 300 mg

1 A film coated tablet contains:

active substance: darunavir ethanolate 325.24 mg (equivalent to darunavir 300.0 mg);

Excipients: cellulose microcrystalline 288.00 mg, crospovidone 12.48 mg, silicon colloidal dioxide 14.00 mg, magnesium stearate 4.00 mg;

shell: film coating 25.00 mg, which includes polyvinyl alcohol 40.0%, titanium dioxide (E171) 21.50%, macrogol 20.20%, talc 14.80%, dye-based aluminum dye sunset yellow (E110) 2.40%, iron dye oxide yellow 0.66 %, aluminum lacquer based on indigocarmine (E132) 0.44%.

Darunavir, 400 mg

1 A film coated tablet contains:

active substance: darunavir ethanolate 433.65 mg (equivalent to darunavir 400.0 mg);

Excipients: cellulose microcrystalline 384,00 mg, crospovidone 16.64 mg, silicon dioxide colloidal 18.67 mg, magnesium stearate 5.33 mg;

shell: film coating 33,33 mg, which includes polyvinyl alcohol 40,0%, titanium dioxide (E171) 11,10%, macrogol 20,20%, tal%, lacquer aluminum based on the dye sunset yellow (E110) 8.40%, lacquer aluminum based on the dye red charming (E129) 5.50%.

Darunavir, 600 mg

1 A film coated tablet contains:

active substance: darunavir ethanolate 650.48 mg (equivalent to darunavir 600.0 mg);

Excipients: cellulose microcrystalline 576.00 mg, crospovidone 24.96 mg, silicon dioxide colloid 28.00 mg, magnesium stearate 8.00 mg;

shell: film coating 50.00 mg, which includes polyvinyl alcohol 40.0%, titanium dioxide (E171) 21.50%, macrogol 20.20%, talc 14.80%, dye-based aluminum dye sunset yellow (E110) 2.40%, iron dye oxide yellow 0.66 %, aluminum lacquer based on indigocarmine (E132) 0.44%.

Description:

75 mg: biconvex tablets capsular shaped, covered with a film shell of white color. On a cross-section of a tablet of white or almost white color.

150 mg: biconvex tablets capsular shaped, covered with a film shell of white color. On a cross-section of a tablet of white or almost white color.

300 mg: biconvex tablets capsular shaped, covered with a film shell of light orange color. On a cross-section of a tablet of white or almost white color.

400 mg: biconvex tablets capsular shaped, covered with a film shell of orange color.On a cross-section of a tablet of white or almost white color.

600 mg: biconvex tablets capsular shaped, covered with a film shell of light orange color. On a cross-section of a tablet of white or almost white color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.10 Darunavir

Pharmacodynamics:

Darunavir is an inhibitor of dimerization and catalytic activity of the protease of human immunodeficiency virus type 1 (HIV-1). The drug selectively inhibits the cleavage of polyproteins Gag-Pol HIV in viral-infected cells, preventing the formation of full-fledged viral particles. Darunavir strongly binds to HIV-1 protease (K_D4,5 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, 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 sy-acid glycoprotein in patients infected with HIV-1. As a consequence, large amounts of darunavir bind to the w-acid plasma glycoprotein. Darunavir intensively metabolized in the liver mainly by isoenzymes CYP3A. Ritonavir inhibits isoenzymes CYP3A in the liver and, thereby, significantly increases the concentration of darunavir in plasma.

Suction

After oral administration darunavir quickly absorbed from the gastrointestinal tract. Maximum concentration (FROM_m_Oh) darunavir in plasma in the presence of a low dose of ritonavir is achieved in 2.5 to 4.0 hours. The absolute bioavailability of darunavir when ingested in a single dose of 600 mg was about 37% and increased to about 82% in the presence of ritonavir (100 mg 2 times / day ). The overall pharmacokinetic effect of ritonavir consisted in an approximately 14-fold increase in the concentration of darunavir in plasma after one ingestion of 600 mg of darunavir in combination with ritonavir (100 mg 2 times / day). When taking an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir was 30% lower than when taken with meals. Therefore, darunavir tablets should be taken with ritonavir while eating.The nature of the food did not affect the concentration of darunavir in the plasma.

Distribution

The binding of darunavir to plasma proteins (mainly with si-acid glycoprotein) is about 95%.

Metabolism

In experiments in vitro on human liver microsomes it was shown that darunavir is subjected primarily to oxidative metabolism. Darunavir is extensively metabolized in the liver by the enzyme system P450, 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. whose activity against wild-type HIV was less than 1/10 of that of darunavir itself.

Excretion

After a single dose ¹⁴C-darunavir in a dose of 400 mg and ritonavir at a dose of 100 mg of about 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 (T₁_/₂) of darunavir was about 15 hours when taken in combination with ritonavir. The clearance of darunavir after intravenous administration at a dose of 150 mg was 32.8 l / hr without ritonavir and 5.91 l / h in the presence of a low dose of ritonavir.

Pharmacokinetics in special patient groups

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. Twelve 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 have not been studied,but population pharmacokinetic analysis demonstrated no significant change in the pharmacokinetic parameters of darunavir in patients with moderate renal impairment (creatinine clearance (CK) of 30-60 ml / min, n = 20).

Patients with hepatic impairment

Darunavir is metabolized and excreted mainly by the liver. Studies in patients with impaired liver function were not performed. In a study using darunavir in several doses in combination with ritonavir (600/100 mg) 2 times / day, it was shown that the stable pharmacokinetic parameters of darunavir in patients with a lung (class A in Child-Pugh, n = 8) and moderate impairment of liver function (Child-Pugh class B, n = 8) were comparable with those of healthy individuals. The effect of severe liver function abnormalities on the pharmacokinetics of darunavir has not been studied.

Children

The pharmacokinetics of darunavir in combination with ritonavir in children aged from 6 up to 18 years and weight not less than 20 kg is comparable to pharmacokinetics in adult patients receiving darunavir / ritonavir 600/100 mg 2 times a day.

Pregnancy

When taking a combination of darunavir / ritonavir in a dose of 600/100 mg 2 times a day or 800/100 mg 1 once a day in the combination of antiretroviral therapy, the concentrations of darunavir and ritonavir in blood plasma were lower when taken during pregnancy compared with those during admission to the postpartum period. However, the pharmacokinetic parameters of unbound (active) darunavir have been reduced to a lesser degree, since during pregnancy there is an increase in the concentration of the free fraction of darunavir in comparison with that in the postpartum period.

In women who received darunavir / ritonavir at a dose of 600/100 mg twice daily for the second trimester of pregnancy, the mean FROM_m_Oh, AUC_12h (area under the concentration-time curve for 12 hours after taking the drug) and Cmin (the minimum concentration of darunavir in plasma) of darunavir was 28%, 24% and 17%, respectively, compared with the values of these indicators in the postpartum period. During the 3rd trimester of pregnancy FROM_m_Oh, AUC_12h and C_min darunavir were respectively 19% and 17% lower and 2% higher than those in the postpartum period.

In women receiving a combination of darunavir / ritonavir at a dose of 800/100 mg once daily for 2th trimester of pregnancy, mean values FROM_m_Oh, AUC_12h and C_min darunavir were respectively 34%, 34% and 32% lower compared to the values of these indicators in the postpartum period. During the 3rd trimester of pregnancy FROM_m_Oh, AUC_12h and C_min darunavir were 31%, 35% and 50%, respectively, compared with the values of these indicators in the postpartum period.

Indications:

Treatment of HIV infection in adult patients and children aged from 6 years and with a body weight 20 kg and more (in combination with low-dose ritonavir and other antiretroviral drugs).

Contraindications:

- Hypersensitivity to darunavir or to any auxiliary substance that is part of the drug.

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

- Severe hepatic insufficiency (Child-Pugh class C).

- Children age up to 6 years and a body weight of up to 20 kg (for dosages of 75 mg, 150 mg, 300 mg, 600 mg).

- Children under 18 years of age (for a dosage of 400 mg).

Carefully:

- In patients with impaired hepatic and mild liver function (Child-Pugh class A and B).

- In patients with allergies to sulfonamides.

- In patients who during pregnancy and in the puerperium are simultaneously taking drugs that can reduce the concentration of darunavir in the blood plasma.

- In elderly patients (from 65 years and older).

Pregnancy and lactation:

Full-fledged studies in pregnant women to assess the effect of darunavir on the outcome of pregnancy was not conducted. Studies in animals have not revealed darunavir's toxic activity or negative impact on reproductive function and fertility. In studies in rats darunavir did not affect the ability to reproduce and fertility. To monitor the effect on the fetus and the body of the mother, a Register of cases of taking antiretroviral drugs during pregnancywww.apregistry.com). This register is a voluntary prospective observational study to collect and evaluate data on the effect of antiretroviral drugs on the outcome of pregnancy. Data on the use of darunavir in the first trimester of pregnancy are sufficient to assess its effect on the increased risk of congenital fetal defects.

By now it is shown that darunavir does not increase the risk of birth defects.

The combination of darunavir / ritonavir in co-administration with baseline therapy was evaluated in a clinical trial involving 34 pregnant women during the second and third trimesters of pregnancy. Pharmacokinetic data showed that the concentrations of darunavir and ritonavir during pregnancy were lower than in the puerperium (6-12 weeks). The virologic response persisted in both groups throughout the study. There was no vertical transmission of the virus from mother to infant in 29 patients taking antiretroviral therapy until delivery. The combination of darunavir / ritonavir was well tolerated during admission during pregnancy and in the postpartum period. The safety profile in this study was comparable to that of adult patients infected with HIV and taking the darunavir / ritonavir combination.

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

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

Dosing and Administration:

The drug is intended for oral administration.

Darunavir should always be prescribed in combination with 100 mg ritonavir as a means of improving its pharmacokinetic characteristics, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before starting therapy with the darunavir / ritonavir combination.

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

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

Dosages of 75 mg and 150 mg are designed to achieve therapeutic doses, these dosages require the intake of a large number of tablets, which on one hand makes it difficult to swallow,on the other hand, can cause allergic reactions due to increased intake of excipients contained in tablets, so they should only be used when other dosages are not available.

Adult patients:

Patients who have not previously received protease inhibitors:

The recommended dose of darunavir is 800 mg once daily in combination with 100 mg of ritonavir 1 once a day; a combination is taken during a meal.

Patients who previously received protease inhibitors:

- not having mutations that cause resistance to darunavir * (with a plasma level of HIV-1 RNA <100,000 copies / ml and quantity Cd4+ cells ≥100 X 10⁶/ l):

The recommended dose of darunavir is 800 mg once daily in combination with 100 mg ritonavir 1 once a day; a combination is taken during a meal.

- Having at least 1 mutation that causes resistance to darunavir*:

The recommended dose of darunavir is 600 mg twice daily in combination with 100 mg of ritonavir 2 once a day; a combination is taken during a meal.

* Mutations causing resistance to darunavir: VIII, V32I, L33F, I47V, I50V, I54M, I54L, T74R, 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 1 once a day 800 mg/100 mg, and patients who previously received protease inhibitors are recommended to take the darunavir / ritonavir combination 2 once 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 impaired renal function. In patients with impaired renal function, dose changes in the combination of darunavir / ritonavir are not required.

Patients with impaired hepatic function. In patients with mild to moderate liver failure (class A and B by Child-Pugh), dose adjustment is not required, but caution should be exercised when using the darunavir / ritonavir combination in these patients. Information on the use of combination therapy darunavir / ritonavir in severe violations of liver function is absent. Therefore, it is not possible to give specific recommendations for dosing.The combination of darunavir / ritonavir in patients with severe hepatic impairment (Child-Pugh class C) is contraindicated.

The admission of the darunavir / ritonavir combination, depending on the mode of administration (1 or 2 times a day)

If the darunavir / ritonavir combination is prescribed once a day and the delay in admission is less than 12 hours, then the missed dose should be taken as soon as possible with food and resume the usual dosing regimen; if the delay in the reception was more than 12 hours, then the missed dose should not be taken, and the next dose is taken at the usual time. If the darunavir / ritonavir combination is prescribed 2 Once a day, and the delay in admission was 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 the reception was not more than 6 hours, then the missed dose should not be taken, and the next dose is taken at the usual time.

Children:

Patients 6 to 18 years old who received antiretroviral therapy earlier

The recommended dose of darunavir / ritonavir for children aged 6 up to 18 years of age and a body weight of at least 20 kg depends on the body weight (table 1) and should not exceed 600/100 mg 2 times a day. Darunavir tablets should be taken with ritonavir 2 times a day during meals (Table 1). The type of food does not affect the absorption of darunavir.

Table 1. Recommended dose of darunavir and ritonavir for patients aged from 6 up to 18 years of age who had previously received antiretroviral therapy

Body weight (kg)	Dose
≥ 20 kg - <30 kg	Darunavir 375 mg / ritonavir 50 mg twice daily
≥ 30 kg - <40 kg	Darunavir 450 mg / ritonavir 60 mg twice daily
≥ 40 kg	Darunavir 600 mg / ritonavir 100 mg twice daily

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

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 failure, myocardial infarction, inflammatory immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis and fever.

Side-effects are shown in Table 2 in accordance with the system-organ classification and with the frequency distribution of occurrence. In each frequency group, side effects are presented in order of decreasing severity.

The frequency of side effects is defined as follows: very often (≥ 1/10 cases), often (≥ 1/100 and <1/10 cases) infrequently (≥ 1/1000 and <1/100 cases), rarely (≥ 1/10000 and <1/1000 cases) and frequency is unknown (it is not possible to estimate the frequency from the available data).

Table 2. Frequency of adverse effects with darunavir

System-Organic grade Frequency Category	Side effects
Infectious and parasitic diseases
Infrequently	Herpetic infection.
Violations of the blood and lymphatic system
Infrequently	Thrombocytopenia, neutropenia, anemia, and leukopenia.
Rarely	Eosinophilia.
Immune system disorders
Infrequently	Syndrome of restoration of immunity, (medicinal) hypersensitivity.
Disorders from the endocrine system
Infrequently	Hypothyroidism, increased concentration of thyroid-stimulating hormone in the blood.
Disorders from the metabolism and nutrition
Often	Lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia.
Infrequently	Gout, anorexia, decreased appetite, weight loss, weight gain, hyperglycemia, insulin resistance, lower high-density lipoprotein concentrations, increased appetite, polydipsia, increased lactate dehydrogenase activity in the blood.
Disorders of the psyche
Often	Insomnia.
Infrequently	Depression, disorientation, anxiety, sleep disorders, pathological dreams, nightmares, decreased libido.
Rarely	Confusion, change of mood, anxiety.
Disturbances from the nervous system
Often	Headache, peripheral neuropathy, dizziness.
Infrequently	Drowsiness, 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, dryness of the mucous membrane of the eyes.
Rarely	Visual impairment.
Hearing and balance disorders
Infrequently	Vestibular dizziness.
Heart Disease
Infrequently	Myocardial infarction, angina pectoris, augmentation of the tooth QT on the electrocardiogram, tachycardia.
Rarely	Acute myocardial infarction, sinus bradycardia, palpitation.
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, pain in the abdomen, increased activity of amylase in the blood, indigestion, bloating, flatulence.
Infrequently	Pancreatitis, gastritis, gastroesophageal reflux, aphthous stomatitis, desires for vomiting, dryness of the oral mucosa, discomfort in the abdomen, constipation, increased lipase activity, eructation, impaired sensitivity in the oral cavity.
Rarely	Stomatitis, vomiting with blood, cheilitis, dryness of the mucous membrane of the lips, plaque on the tongue.
Disturbances from the liver and bile ducts
Often	Increased activity of alanine aminotransferase.
Infrequently	Hepatitis, cytolytic hepatitis, steatosis of the liver, hepatomegaly, increased transaminase activity, increased activity of aspartate aminotransferase, 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, papular, erythematous and itchy), itching.
Infrequently	Angioedema, generalized rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, pigmentation of nails.
Rarely	Drug rash with eosinophilia and systemic manifestations (DRESSsyndrome), Stevens-Johnson syndrome, erythema multiforme, dermatitis, seborrheic dermatitis, skin lesions, xeroderma.
Frequency unknown	Toxic epidermal necrolysis, acute generalized exentematous 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, xerosis of the skin.

Description of some side effects

Rash

In clinical studies, mainly a mild to moderate rash was observed. The rash usually appeared during the first four weeks of therapy and disappeared with continued use of the drug. When developing severe skin reactions, see the section "Special instructions". In clinical trials in patients previously treated with a rash,regardless of its cause, more often occurred with the admission of treatment regimens containing darunavir and raltegravir, than when taking darunavir without raltegravir or raltegravir without 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 nucleoside reverse transcriptase inhibitors. Osteonecrosis has been reported, especially in patients with recognized risk factors, with HIV disease at a later stage or for a long time receiving combined antiretroviral therapy. The incidence of osteonecrosis is unknown.

Immunodeficiency Syndrome

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

Bleeding in patients with hemophilia

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

Patients with co-infections of viral hepatitis AT and / or C

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

Overdose:

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

The specific antidote is unknown. In case of an overdose, general supportive therapy with monitoring of basic physiological parameters should be carried out. To remove non-absorbed drug shows gastric lavage or cleansing enema. Can be applied Activated carbon. Darunavir predominantly binds to plasma proteins, so a significant removal of the active substance by dialysis is unlikely

Interaction:

Darunavir, used in combination with ritonavir, is an inhibitor of the isoenzyme CYP3A, CYP2D6 and P-glycoprotein. The simultaneous use of the darunavir / ritonavir combination and drugs that are predominantly metabolized by isoenzymes CYP3A, CYP2D6 and transferred by P-glycoprotein, the concentration of such drugs in the plasma can drop out, 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 combined use of the darunavir / ritonavir combination with drugs whose clearance is largely dependent on the isoenzyme CYP3A, and an increase in the systemic level of which can be accompanied by the development of serious and / or life-threatening phenomena (narrow therapeutic range).

The general pharmacokinetic enhancing effect of ritonavir was an increase in the systemic level of darunavir by approximately 14 times with a single dose of darunavir 600 mg in combination with ritonavir at a dose of 100 mg twice a day. In this way, darunavir should be used in combination with only low doses of ritonavir as a pharmacokinetic "enhancer".

In a clinical study using a mixture of drugs metabolized by cytochromes CYP2C9, CYP2C19 and CYP2D6, there was an increase in activity CYP2C9 and CYP2C19 and inhibition of activity CYP2D6 in the presence of a combination of darunavir / ritonavir, which may be due to the presence of a low dose of ritonavir. The combined use of darunavir and ritonavir with drugs metabolized predominantly by isoenzyme CYP2D6 (eg, flecainide, propafenone, metoprolol) may increase the concentration of these drugs in the plasma, which can cause an increase or prolongation of their therapeutic effect and undesirable reactions. The combined use of darunavir and ritonavir with drugs that are predominantly metabolized CYP2C9 (e.g., warfarin) and isoenzyme CYP2C19 (for example, methadone), can lead to a decrease in the systemic level of these drugs, which can cause a decrease or decrease in their therapeutic effect.

Although the effect on CYP2C8 studied only in vitro, the combined use of the darunavir / ritonavir combination with drugs that are predominantly metabolized CYP2C8 (for example, paclitaxel, rosiglitazone, repaglinide), can lead to a decrease in the systemic level of these drugs, which can cause a decrease or decrease in their therapeutic effect.

Drugs affecting the concentration of darunavir / ritonavir

The metabolism of darunavir and ritonavir isoenzyme participates CYP3A. Drugs that induce isoenzyme activity CYP3A, presumably will strengthen clearance of darunavir and ritonavir, causing a decrease in the concentration of these drugs in the plasma (for example, it concerns rifampicin, St. John's wort and lopinavir). The combined use of darunavir and ritonavir with other isozyme inhibitory drugs CYP3A, can reduce the clearance of darunavir and ritonavir and increase their plasma concentration (for example, it concerns indinavir, systemic azoles, in particular ketoconazole and clotrimazole). These interactions are described in the table below.

Table of drug interactions

The interactions between the darunavir / ritonavir combination and antiretroviral and other drugs are given in the table below (not defined as "N / A"). The direction of the arrow for each pharmacokinetics parameter is based on a 90% confidence interval for the average geometric ratio that can be in the range (↔), below (↓) or above (↑) of the range of 80-125%.

A number of interaction studies (indicated by # in the table below) were performed using darunavir doses below recommended or with a different regimen of therapy.Effects on co-administered drugs can thus be underestimated, and as a consequence, clinical safety monitoring can be indicated.

The drug, used in conjunction with the darunavir / ritonavir combination

Interaction

Change in Geometric Mean (%)

Recommendations for joint use

ANTIRETROVIRAL PREPARATIONS FOR TREATMENT OF HIV INFECTION

Integrase inhibitors

Dolutegravir

AUC dolutegravir ↓ 32%

FROM_24hdolutegravir 38%

FROM_max dolutegravir ↓ 11%

darunavir ↔ *

* Based on comparisons between studies using historical pharmacokinetics data

The combination of darunavir / ritonavir and dolutegravir can be used without dose adjustment.

Elvigegravir

AUC of elvitegravir ↔

C_min elvitegrewra ↔

FROM_max elvitegrewra ↔

AUC of darunavir ↔

C_min darunavir 17%

FROM_max darunavira ↔

When darunavir is used together with low doses of ritonavir (600/100 mg twice daily) in combination with elvitegravir, the dose of elvitegravir should be 150 mg once daily.

Pharmacokinetics and dosage recommendations for other doses of darunavir or for combination with elvitegravir / co-bicystate have not been established.Thus, the combined use of the darunavir / ritonavir combination at any dose other than 600/100 mg twice daily, in combination with elvitegravir is not recommended.

The combined use of darunavir / ritonavir and elvitegravir with cobicystate is not recommended.

Raltegravir

As a result of some clinical studies, it was suggested that raltegravir can cause a moderate decrease in the concentration of darunavir in plasma.

It is currently assumed that the effect of raltegravir on the concentration of darunavir in plasma is not clinically significant.

The combination of darunavir / ritonavir and raltegravir can be used without dose adjustment.

Nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs)

Didanosine

400 mg once a day

AUC didanosine ↓ 9%

C_minDidanosine H / O

FROM_max didanosine ↓ 16%

AUC of darunavir ↔

C_min darunavira ↔

FROM_maxdarunavira ↔

The combination of darunavir / ritonavir and didanosine can be used without dose adjustment.

Didanosine should be taken on an empty stomach, so it should be taken 1 hour before or 2 hours after taking the darunavir / ritonavir combination with food.

Tenofovir disoproxil fumarate

300 mg once a day

AUC of tenofovir ↑ 22%

C_min tenofovir ↑ 37%

FROM_max tenofovir ↑ 24%

^#AUC of darunavir ↑ 21%

^#C_min darunavir ↑ 24%

^#FROM_maxdarunavir ↑ 16%

(↑ concentrations of tenofovir due to influence on mediated MDR-1 transport in the renal tubules)

When the darunavir / ritonavir combination with tenofovir is combined, monitoring of renal function can be shown, especially in patients with systemic or renal diseases, or with the use of nephrotoxic drugs.

Abacavir

Emtricitabine

Lamivudine

Stavudine

Zidovudine

Not studied. Based on the ways of elimination of other NRTIs (zidovudine, emgricitabine, stavudine, lamivudine), which are excreted mainly by the kidneys, and abacavir, in the metabolism of which CYP450 does not participate, no interactions between these drugs and the darunavir / ritonavir combination are expected.

The combination of darunavir / ritonavir and can be used with these NRTIs without dose adjustment.

Non-nucleoside / non-nucleotide reverse transcriptase inhibitors (NNRTIs)

Efavirenz

600 mg once a day

AUC of efavirenz ↑ 21%

C_minefavirenz ↑ 17%

FROM_max efavirenz ↑ 15%

^#AUC of darunavir ↓ 13%

^#C_min darunavir ↓ 31%

^#FROM_max darunavir ↓ 15%

(↑ concentration of efavirenz due to inhibition of CYP3A)

(↓ concentrations of darunavir due to induction of CYP3A)

When using the combination of darunavir / ritonavir in combination with efavirenz, a clinical monitoring of the central nervous system toxicity associated with an increased concentration of efavirenz may be required.

The use of efavirenz in combination with a combination of darunavir / ritonavir in a dose of 800/100 mg once a day can lead to a suboptimal value of C_mindarunavir. If efavirenz should be taken in combination with a combination of darunavir / ritonavir, you should use the 600/100 mg regimen 2 times a day.

Etravirine

100 mg twice daily

AEC etravirine ↓ 37%

C_minetravirine ↓ 49%

FROM_max etravirine ↓ 32%

AUC of darunavir ↑ 15%

C_min darunavira ↔

FROM_max darunavira ↔

The combination of darunavir / ritonavir with etravirine 200 mg 2 times a day can be used without dose adjustment.

Nevirapine

200 mg twice daily

AUC of nevirapine ↑ 27%

C_min nevirapine ↑ 47%

FROM_max nevirapine ↑ 18%

^#darunavir: concentrations corresponded to historical data

(↑ nevirapine concentration due to inhibition of CYP3A)

The combination of darunavir / ritonavir with nevirapine can be used without dose adjustment.

Rilpivirine

150 mg once a day

AUC of rilpivirin ↑ 130%

FROM_min rilpivirine ↑ 178%

FROM_max rilpivirin ↑ 79%

AUC of darunavir ↔

C_min darunavira ↓ 11%

FROM_max darunavira ↔

The combination of darunavir / ritonavir with rilpivirin can be used without dose adjustment.

HIV protease inhibitors without additional low-dose ritonavir

**

Atazanavir

300 mg once a day

AUC atazanavir ↔

C_min atazanavir ↑ 52%

FROM_max atazanavir ↓ 11%

^#AUC of darunavir ↔

^#C_min darunavira ↔

^#FROM_max darunavira ↔

Atazanavir: a comparison of atazanavir / ritonavir 300/100 mg once a day and atazanavir 300 mg once a day in combination with darunavir / ritonavir 400/100 mg 2 times a day.

Darunavir: A comparison of darunavir / ritonavir 400/100 mg 2 times a day with darunavir / ritonavir 400/100 mg 2 times a day in combination with atazanavir 300 mg once daily

The combination of darunavir / ritonavir and atazanavir can be used without dose adjustment.

Indinavir

800 mg twice daily

AUC of indinavir ↑ 23%

C_min indinavir ↑ 125%

FROM_max indinavir ↔

^#AUC of darunavir ↑ 24%

^#C_min darunavir ↑ 44%

^#FROM_max darunavir ↑ 11%

Indinavir: A comparison of indinavir / ritonavir 800/100 mg twice daily with indinavir / darunavir / ritonavir 800/400/100 mg twice daily.

Darunavir: A comparison of darunavir / ritonavir 400/100 mg 2 per day with darunavir / ritonavir 400/100 mg in combination with indinavir 800 mg twice daily.

When used in conjunction with the darunavir / ritonavir combination, it may be necessary to adjust the dose of indinavir from 800 mg 2 times a day to 600 mg twice a day in case of intolerance.

Saquinavir

1 000 mg 2 times a day

^#AUC of darunavir ↓ 26%

^#C_min darunavir ↓ 42%

^#FROM_max darunavir ↓ 17%

AUC of saquinavir ↓ 6%

C_min saquinavir ↓ 18%

FROM_max saquinavir ↓ 6%

Saquinavir: Comparison of saquinavir / ritonavir1000 / 100 mg twice daily and saquinavir / darunavir / ritonavir a 1000/400/100 mg twice daily.

Darunavir: A comparison of darunavir / ritonavir 400/100 mg 2 times a day and darunavir / ritonavir 400/100 mg in combination with saquinavir 1000 mg twice daily.

The combination of darunavir / ritonavir is not recommended with saquinavir.

HIV protease inhibitors - in combination with low doses of ritonavir **

Lopinavir / ritonavir

400/100 mg twice daily

AUC of lopinavir ↑ 9%

C_min lopinavir ↑ 23%

FROM_max lopinavir ↓ 2%

AUC of darunavir ↓ 38% *

C_min darunavira ↓ 51% *

FROM_max darunavir ↓ 21% *

Due to a decrease in the concentration (AUC) of darunavir by 40%, suitable doses of this combination have not been established.

Thus, the combined use of the darunavir / ritonavir combination with a combination drug including lopinavir / ritonavir is contraindicated.

Lopinavir / ritonavir

533 / 133.3 mg twice daily

AUC of lopinavir ↔

C_min lopinavir ↑ 13%

FROM_max lopinavir ↑ 11%

AUC of darunavir ↓ 41%

C_min darunavira ↓ 55%

FROM_max darunavir ↓ 21%

* based on non-normalized dose values

CCR5 RECEPTOR ANTAGONISTS

Maraviroc

150 mg twice daily

AUC of maraviroc ↑ 305%

C_min maraviroc N / O

FROM_max maraviroc ↑ 129% Concentrations of darunavir and ritonavir were consistent with historical data.

When used in conjunction with a combination of darunavir / ritonavir, the dose of maraviroc should be 150 mg twice daily.

ANESTHETICS

Alfentanil

Not studied. In the metabolism of alfentanil is involved the isozyme CYP3A, as a result, it can be inhibited by darunavir, used with low doses of ritonavir.

When the joint application skombinatsiey darunavir / ritonavir may require dose reduction alfentanil and risk monitoring prolonged or delayed respiratory depression.

ANTIANGINAL / ANTIARITHMIC MEANS

Disopyramide

Flecainide

Mexiletin

Propafenone

Not studied. It is assumed that darunavir will increase the concentration of these antiarrhythmic drugs in plasma (inhibition of the isoenzyme CYP3A).

Precautions are necessary, in addition, it is recommended to monitor the therapeutic concentration (if available) of these antiarrhythmic drugs when combined with the darunavir / ritonavir combination

Amiodarone

Bepridil

Dronedaron

Lidocaine (systemically)

Quinidine

Ranolazine

Contraindicated the use of darunavir / ritonavir combination with amiodarone, bepridilom, dronedarone, lidocaine (systemically), quinidine or ranolazinom.

Digoxin

0.4 mg once

AUC digoxin ↑ 61%

C_min digoxin H / O

FROM_max digoxin ↑ 29%

(↑ digoxin concentrations due to probable inhibition of P-glycoprotein)

Because the digoxin is characterized by a narrow therapeutic range, in the case of the appointment of digoxin to patients receiving darunavir / ritonavir, it is initially recommended to use the minimum possible dose of digoxin.

Next, a careful titration of the dose of digoxin should be performed in order to achieve the desired clinical effect against the background of evaluationgeneral clinical condition of the patient.

ANTIBIOTICS

Clarithromycin

500 mg twice a day

AUC of clarithromycin ↑ 57%

C_min clarithromycin ↑ 174%

FROM_max clarithromycin ↑ 26%

^#AUC of darunavir ↓ 13%

^#C_min darunavir ↑ 1%

^#FROM_max darunavir ↓ 17%

Concentrations of 14-OH-clarithromycin were not detected when combined with a darunavir / ritonavir combination.

(↑ concentrations of clarithromycin due to inhibition of the CYP3A isoenzyme and possible inhibition of P-glycoprotein).

Caution is advised when sharing clarithromycin with a combination of darunavir / ritonavir

ANTICOAGULANTS

Apixaban

Dabigatran etexilate

Rivaroxaban

Not studied.

The combined use of darunavir with anticoagulants can increase their concentration (inhibition of the isoenzyme CYP3A and / or P-glycoprotein).

The use of a combination of darunavir / ritonavir with these anticoagulants is not recommended.

Warfarin

Not studied.

When combined with darunavir and low doses of ritonavir, a change in the concentration of warfarin is possible.

When combined with warfarin with a combination of darunavir / ritonavir, monitoring of internationalnormalized relationship (INR).

ANTI-TREATMENT PREPARATIONS

Phenobarbital

Phenytoin

Not studied.

Phenobarbital and phenytoin presumably will cause a decrease in the concentrations of darunavir in plasma (induction of CYP450 enzymes).

The combination of darunavir / ritonavir should not be used in combination with these drugs.

Carbamazepine

200 mg twice daily

AUC carbamazepine ↑ 45%

C_min carbamazepine ↑ 54%

FROM_max carbamazepine ↑ 43%

AUC of darunavir ↔

C_mindarunavir ↓ 15%

FROM_max darunavira ↔

No dose adjustment of the darunavir / ritonavir combination is recommended. If a combination of darunavir / ritonavir with carbamazepine is required, monitoring of potential carbamazepine-related adverse events should be avoided.

It is necessary to control the concentration of carbamazepine, in addition, titration of its dose is required in order to provide an adequate response. Based on the results obtained, the dose of carbamazepine in the presence of a combination of darunavir / ritonavir may need to be reduced by 25% -50%.

ANTI-DEPRESSANTS

Paroxetine 20 mg

1 time per day

AUC of paroxetine ↓ 39%

C_min paroxetine ↓ 37%

FROM_max paroxetine ↓ 36% *

^#AUC of darunavir ↔

^#C_min darunavira ↔

^#FROM_max darunavira ↔

In the case of combined use of antidepressants with the darunavir / ritonavir combination, the recommended approach is titration of the antidepressant dose based on the clinical evaluation of the response to this drug. In addition, patients receiving stable doses of antidepressants who start therapy with the darunavir / ritonavir combination should be monitored for an answer to antidepressants.

Sertraline

50 mg once a day

AUC sertraline ↓ 49%

C_min sertraline ↓ 49%

FROM_max sertraline ↓ 44%

^#AUC of darunavir ↔

^#C_min darunavir ↓ 6%

^#FROM_max darunavira ↔

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

The combined use of the darunavir / ritonavir combination with these antidepressants may increase the concentration of antidepressants (inhibition of CYP2D6 and / or CYP3A).

When the darunavir / ritonavir combination is used together with these antidepressants, clinical monitoring is recommended, in addition, dosage adjustment of these antidepressants may be required.

Antihypertensive drugs

Voriconazole

Not studied.

Ritonavir can reduce the concentration of voriconazole in plasma (induction of CYP450 enzymes by ritonavir).

Voriconazole should not be used in combination with a darunavir / ritonavir combination, unless voriconazole is required based on an assessment of the risk-benefit ratio.

Ketoconazole

200 mg twice daily

AUC of ketoconazole ↑ 212%

C_min ketoconazole ↑ 868%

FROM_max ketoconazole ↑ 111%

AUC of darunavir ↑ 42%

C_min darunavir ↑ 73%

FROM_max darunavir ↑ 21%

(inhibition of CYP3A)

Care must be taken, clinical monitoring is recommended.

If combined use is required, the daily dose of ketoconazole should not exceed 200 mg.

Fluconazole

Posaconazole

Not studied.

Darunavir can increase the concentration of antifungal drugs in plasma (inhibition of P-glycoprotein), posaconazole can increase the concentration of darunavir (inhibition of the isoenzyme CYP3A).

Care must be taken, clinical monitoring is recommended.

Itraconazole

Not studied.

The combined systemic use of itraconazole and darunavir in combination with low doses of ritonavir can increase the concentration of darunavir in plasma.

Simultaneously, an increase in the concentration of itraconazole in the plasma by darunavir with low doses of ritonavir (inhibition of the isoenzyme CYP3A) is possible.

Care must be taken, clinical monitoring is recommended. If combined use is required, the daily dose of itraconazole should not exceed 200 mg.

Clotrimazole

Not studied.

Joint systemic use of clotrimazole and darunavir with low doses of ritonavir can increase the concentration of darunavir in plasma. AUC_24h darunavir ↑ 33% (based on the population model of pharmacokinetics).

If joint use with clotrimazole is required, care must be taken, clinical monitoring is recommended.

ANTIPOGRAPHIC PREPARATIONS

Colchicine

Not studied.

The combined use of colchicine and darunavir with low doses of ritonavir can increase the concentration of colchicine.

If combination therapy is required darunavir / ritonavir, patients with normal liver function or kidney function are recommended to reduce colchicine dose or stop taking this medication.

Patients with impaired liver or kidney function should not be used colchicine in combination with a combination of darunavir / ritonavir.

ANTI-MALIGNANT MEANS

Artemether / Lumefantrine

80/480 mg,

6 doses after 0, 8, 24, 36, 48 and 60 hours

AUC Artemeter ↓ 16%

C_min artemeter ↔

FROM_max artemeter ↓ 18%

AUC of dihydroartemisinin ↓ 18%

C_min dihydroartemisinin ↔

FROM_max dihydroartemisinin ↓ 18%

AUC lumefantrine ↑ 175%

C_min lumefantrine ↑ 126%

FROM_max lumefantrine ↑ 65%

AUC of darunavir ↔

C_min darunavir ↓ 13%

FROM_max darunavira ↔

Darunavir can be used in combination with artemether / lumefantrine without dose adjustment; However, due to the increased concentration of lumefantrine, this combination should be used with caution.

ANTI-TUBERCULOSIS PREPARATIONS

Rifampicin

Rifapentin

Not studied. Rifapentin and rifampicin are powerful inducers of the CYP3A isoenzyme, they caused a marked decrease in the concentrations of other protease inhibitors, which can lead to virological inefficiency and development of resistance (induction of CYP450 enzymes). In attempts to overcome the reduction in concentration by increasing the dose of other protease inhibitors in combination with low doses of ritonavir, a high incidence of liver reactions was observed.

The use of rifapentin with a combination of darunavir / ritonavir is not recommended.

Contraindicated combined therapy with rifampicin with a combination of darunavir / ritonavir.

Rifabutin

150 mg once every 2 days

AUC *** rifabutin ↑ 55%

C_min*** Rifabutin N / O

FROM_max*** rifabutin ↔

AUC of darunavir ↑ 53%

C_min darunavir ↑ 68%

FROM_max darunavir ↑ 39%

*** the sum of the active derivatives of rifabutin (starting drug + 25-O-deacetyl metabolite)

In a study of the interaction, comparable daily systemic rifabutin concentrations were observed when administered at a dose of 300 mg once a day as monotherapy and 150 mg every other day in combination with darunavir / ritonavir (600/100 mg bid) with a tenfold increase in the daily level active metabolite (25-O-deacetyl rifabutin). In addition, the AUC of active derivatives of rifabutin (starting drug + 25-O-deacetyl metabolite) increased 1.6 times, while the value of C_maxremained comparable.

Currently, there is no data compared with the standard dose of 150 mg once a day.

(Rifabutin is an inducer and substrate of the isoenzyme CYP3A). When the combination of darunavir / ritonavir with rifabutin (150 mg every other day) was combined, there was an increase in the systemic concentration of darunavir.

Patients receiving combined therapy are recommended to reduce the dose of rifabutin by 75% of the usual dose of 300 mg / day (eg, 150 mg every other day), as well as more frequent monitoring of rifabutin-related adverse events.In case of safety problems, further increase in the interval between rifabutin administration and / or monitoring of rifabutin concentration should be considered.

It is necessary to study the official recommendations on the proper therapy of tuberculosis in HIV-infected patients.

Based on the safety profile of the darunavir / ritonavir combination, an increase in the dose of ritonavir with rifabutin therapy does not require dose adjustment of the darunavir / ritonavir combination.

Based on pharmacokinetic modeling, this dose reduction of 75% also applies to patients receiving rifabutin in a dose different from 300 mg / day.

ANTITUMOR PREPARATIONS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Not studied. It is suggested that the combination of darunavir / ritonavir will increase the concentration of these antitumor drugs in plasma (inhibition of the CYP3A isoenzyme).

When these drugs are combined with the darunavir / ritonavir combination, an increase in their concentration is possible, thus possibly increasing the adverse effects commonly observed with the use of these drugs.

Caution should be exercised when prescribing any of these antitumor drugs in combination with the darunavir / ritonavir combination.

The combined use of everolimus with a combination of darunavir / ritonavir is not recommended.

Antiplatelet drugs

Tikagrelor

Not studied.

Co-administration with a combination of darunavir / ritonavir can lead to a significant increase in ticagrelor concentration.

The concomitant use of the darunavir / ritonavir combination with ticagrelor is contraindicated.

It is recommended the use of other antiplatelet drugs, which are not affected by inhibition or induction of CYP (for example, prasugrel).

ANTIPSYCHOTIC PREPARATIONS / NEUROLEPTICS

Quetiapine

Due to inhibition of the isoenzyme CYP3A, darunavir is expected to increase the concentration of antipsychotics / antipsychotics.

The combined use of darunavir / ritonavir with quetiapine is contraindicated, since it may increase the toxicity associated with quetiapine.

An increase in quetiapine concentrations can lead to coma.

Perphenazine

Risperidone

Thioridazine

Pimozide

Sertindole

Not studied.

It is suggested that the combination of darunavir / ritonavir will increase the concentration of these antipsychotics in plasma, (inhibition of the isoenzyme CYP2D6 and / or P-glycoprotein).

If these drugs are combined with a darunavir / ritonavir combination, a dose reduction may be required.

The combined use of darunavir / ritonavir with pimozide or sertindole is contraindicated.

BETA-ADRENOBLATORS

Carvedilol

Metoprolol

Timolol

Not studied. It is assumed that darunavir will increase the concentration of these beta-adrenoblockers in plasma.

(inhibition of the isoenzyme CYP2D6)

With the joint use of darunavir with beta-adrenoblockers, clinical monitoring is recommended. The question of reducing the dose of beta-blocker should be addressed.

BLOCKERS OF "SLOW" CALCIUM CHANNELS

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Not studied. It can be assumed that a combination of darunavir / ritonavir can increase the concentration of slow calcium channel blockers in plasma (inhibition of CYP3A and / or CYP2D6 isoenzymes).

When these drugs are used together with the darunavir / ritonavir combination, a clinicalmonitoring of therapeutic and side effects.

Glucocorticosteroids

Fluticasone

Budesonide

In a clinical study in which ritonavir in a dose of 100 mg in capsules twice a day was used in combination with 50 μg fluticasone propionate intranasally (4 times a day) for 7 days in healthy volunteers, a significant increase in plasma concentrations of fluticasone propionate was observed, while the concentrations of endogenous cortisol decreased approximately by 86% (90% confidence interval 82-89%). With inhalation application of fluticasone, more pronounced effects can be observed. In patients receiving ritonavir and fluticasone inhalation or oral administration, systemic glucocorticosteroid effects have been reported, including Cushing's syndrome and adrenal suppression; this can also be observed with the use of other glucocorticosteroids metabolized with the participation of P4503A, for example, budesonide. Effects of high concentrations of fluticasone on the concentration of ritonavir in plasma are unknown.

The combined use of the darunavir / ritonavir combination with these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic glucocorticosteroid effects.

The question of reducing the dose of a glucocorticosteroid with a careful

monitoring of local and systemic effects, or switching to another corticosteroid that is not a substrate of the CYP3A isoenzyme (for example, beclomethasone). Moreover, in the case of cancellation of glucocorticoids, a gradual dose reduction over a longer period may be required.

Dexamethasone

(systematically)

Not studied.

Dexamethasone can reduce the concentration of darunavir in plasma.

(induction of the isoenzyme CYP3A)

Dexamethasone as a systemic drug should be used with caution in combination with a darunavir / ritonavir combination.

Prednisolone

Not studied.

Darunavir can increase the concentration of prednisone in plasma (inhibition of the isoenzyme CYP3A).

The combined use of darunavir / ritonavir with prednisone may increase the risk of systemic glucocorticosteroid effects, including Cushing's syndrome and adrenal suppression.

When using the combination darunavir / ritonavir with glucocorticosteroids, clinical monitoring is recommended.

ANTAGONISTS OF ENDOTHELIN RECEPTORS

Boszentan

Not studied.The combined use of bosentan with the darunavir / ritonavir combination may increase the concentration of bosentan in plasma.

When joint application of the darunavir / ritonavir combination is recommended, monitoring the tolerability of bosentan.

ANTIVIRAL DRUGS FOR DIRECT ACTION FOR THERAPY OF HEPATITIS C

Protease inhibitors NS3-4A

Telaprevir

750 mg every 8 hours

AUC of telaprevir ↓ 35%

C_min telaprevir ↓ 32%

FROM_max telaprevir ↓ 36%

AUC_12h darunavira ↓ 40%

C_min darunavir ↓ 42%

FROM_max darunavira ↓ 40%

The combination of darunavir / ritonavir is not recommended in combination with telaprevir.

Boceprevir

800 mg 3 times a day

AUC of bocetrevir ↓ 32%

FROM_min boceprevir ↓ 35%

FROM_max bocetrevir ↓ 25%

AUC of darunavir ↓ 44%

C_min darunavir ↓ 59%

FROM_max darunavir ↓ 36%

The combination of darunavir / ritonavir is not recommended in combination with bocetrevir.

Symeprevir

AUC of simeprevir ↑ 159%

C_min simeprevira ↑ 358%

FROM_max simeprevira ↑ 79%

AUC of darunavir ↑ 18%

C_min darunavir ↑ 31%

FROM_max darunavira ↔

The dose of simeprevir in this interaction study was 50 mg when combined with darunavir / ritonavir and 150 mg in the monotherapy group with simeprevir.

The combination of darunavir / ritonavir is not recommended in combination with simeprevir.

VEGETABLE PREPARATIONS

Hypericum perforatum (Hypericum perforatum)

Not studied.

It is suggested that St. John's Wort will drastically reduce the concentration of darunavir and ritonavir in plasma (induction of CYP450).

The combination of darunavir / ritonavir is contraindicated in combination with preparations containing St. John's wort extract of perforated (Hypericum perforatum).

If the patient is already getting a St. John's wort, it is necessary to cancel it and, if possible, to analyze the level of the virus.

The concentration of darunavir (as well as ritonavir) may increase with the cancellation of St. John's wort.

This inducing effect may persist for at least 2 weeks after the removal of St. John's wort.

INHIBITORS OF HMG-CO-A-REDUCTASE (STATINUM)

Lovastatin

Simvastatin

Not studied. A significant increase in the concentrations of lovastatin and simvastatin in plasma is suggested when combined with darunavir and low doses of ritonavir (inhibition of the CYP3A isoenzyme).

An increase in the concentration of lovastatin or simvastatin in plasma can cause myopathy, including rhabdomyolysis. Thus, the combined use of darunavir / ritonavir with lovastatin or simvastatin is contraindicated.

Atorvastatin

10 mg once a day

AUC atorvastatin ↑ 3-4 times

C_min atorvastatin ↑ at ≈ 5.5-10 times

FROM_max atorvastatin ↑ ≈ 2 times^#darunavir

In the case of using atorvastatin with the darunavir / ritonavir combination, the recommended initial dose of atorvastatin is 10 mg once a day. A gradual increase in the dose of atorvastatin may be possible in accordance with the clinical response.

Pravastatin

40 mg once

AUC pravastatin ↑ 81% *

C_min pravastatin N / O

FROM_max pravastatin ↑ 63%

* a limited subpopulation of patients showed an increase to 5 times

If joint use of pravastatin with the darunavir / ritonavir combination is required, it is recommended to start with the minimum possible dose of pravastatin with titration to the desired clinical effect with safety monitoring.

Rosuvastatin

10 mg once a day

AUC of rosuvastatin ↑ 48% *

FROM_max rosuvastatin ↑ 144% *

* Based on published data

If joint application of rosuvastatin with the darunavir / ritonavir combination is required, it is recommended to start with the lowest possible dose of rosuvastatin with titration to the desired clinical effect with safety monitoring.

H₂-gistaminovyh receptors blockers

Ranitidine

150 mg twice daily

^#AUC of darunavir ↔

^#C_min darunavira ↑ ↔

^#FROM_max darunavir ↑ ↔

The combination of darunavir / ritonavir can be used in combination with H₂- histamine receptors with blockers without dose correction.

Immunosuppressants

Cyclosporin

Sirolimus

Tacrolimus

Everolimus

Not studied.

The concentration of these immunosuppressants will increase when combined with a combination of darunavir / ritonavir (inhibition of the isoenzyme CYP3A).

In case of joint use, therapeutic monitoring of the concentration of immunosuppressants is recommended.

The combined use of everolimus with a combination of darunavir / ritonavir is not recommended.

INHALATION BETA-ADRENOMMETICS

Salmeterol

Not studied.

The combined use of salmeterol and darunavir with low doses of ritonavir can lead to an increase in salmeterol concentrations in the plasma.

The combined use of salmeterol with a combination of darunavir / ritonavir is not recommended. The use of this combination may increase the risk of cardiovascular adverse events associated with salmeterol, including prolongation of the QT interval, severe heartbeat and sinus tachycardia.

NARCOTIC ANALGETICS / OPIODE DEPENDENCE THERAPY

Methadone

Individual doses in the range from 55 to 150 mg once a day

AUC R (-) methadone ↓ 16%

C_min R (-) methadone ↓ 15%

FROM_max R (-) methadone ↓ 24%

At the beginning of a joint application with a combination of darunavir / ritonavir, a dose adjustment of methadone is not required. However, in the case of combined use over a longer period of time, an increase in the dose of methadone may be required due to the induction of its metabolism by ritonavir. Therefore, clinical monitoring is recommended, as some patients may need a correction of maintenance therapy.

Buprenorphine / naloxone

8/2 mg - 16/4 mg once a day

AUC buprenorphine ↓ 11%

FROM_min buprenorphine ↔

FROM_max buprenorphine ↓ 8%

AUC of norbuprenorphine ↑ 46%

C_min norbuprenorphine ↑ 71%

FROM_max norbuprenorphine ↑ 36%

AUC of naloxone ↔

C_min naloxone N / O

FROM_max naloxone ↔

The clinical significance of the increase in the parameters of the pharmacokinetics of norbuprenorphine has not been established. When combined with darunavir / ritonavir combination, dosage adjustment of buprenorphine may not be necessary, nevertheless careful clinical monitoring is recommended for symptoms of opiate toxicity.

ESTROGEN CONTAINING ORAL CONTACT-REPEATED PREPARATIONS

Ethinylestradiol Norethindrone

35 μg / 1 mg once daily

AUC of ethinylestradiol ↓ 44%

C_min ethinyl estradiol ↓ 62%

FROM_max ethinyl estradiol ↓ 32%

AUC of norethindrone ↓ 14%

C_min norethindrone ↓ 30%

FROM_max norethindrone ↔

If estrogen-containing contraceptives are used in combination with a darunavir / ritonavir combination, the use of alternative or additional contraceptives is recommended. Patients receiving estrogens as hormone replacement therapy should be monitored for symptoms of estrogen deficiency.

INHIBITORS OF PHOSPHODYESTERASE OF 5-GO TYPE (PDE-5)

For the treatment of erectile dysfunction

Avanafil

Sildenafil

Tadalafil

Vardenafil

In the study of interaction^#comparable systemic concentrations of sildenafil were observed after a single dose of sildenafil 100 mg in monotherapy and in a dose of 25 mg in combination with a darunavir / ritonavir combination.

The use of avanafil in combination with the darunavir / ritonavir combination is not recommended. Other PDE-5 inhibitors for the treatment of erectile dysfunction in combination with the darunavir / ritonavir combination should be used with caution.If concomitant use of the combination of darunavir / ritonavir with sildenafil, vardenafil or tadalafil is recommended, sildenafil should be taken in a single dose not exceeding 25 mg in 48 hours, vardenafil in a single dose not exceeding 2.5 mg in 72 hours or tadalafil in a single dose not exceeding 10 mg for 72 hours.

For the treatment of pulmonary arterial hypertension

Sildenafil

Tadalafil

Not studied.

Joint use of sildenafil or tadalafil as drugs for the treatment of pulmonary arterial hypertension and darunavir with low doses of ritonavir can lead to an increase in the concentration of sildenafil or tadalafil in plasma.

A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension when used in combination with the darunavir / ritonavir combination has not been established.

Potentially, it is possible to increase the incidence of sildenafil-related adverse events (including visual disorders, hypotension, prolonged erections and syncope). Thus, the concomitant use of the darunavir / ritonavir combination with sildenafil for the treatment of pulmonary arterial hypertension is contraindicated.The joint use of tadalafil for the treatment of pulmonary arterial hypertension with a combination of darunavir / ritonavir is not recommended.

PROTON PUMP INHIBITORS

Omeprazole

20 mg once a day

^#AUC of darunavir ↔

^#C_min darunavira ↔

^#FROM_max darunavira ↔

The combination of darunavir / ritonavir can be used in combination with proton pump inhibitors without dose adjustment.

SEDATIVE / SNORTHAGE PREPARATIONS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Triazolam

Zolpidem

Midazolam

Not studied.

Sedatives / hypnotics are heavily metabolized by the CYP3A isoenzyme.

Joint use with a combination of darunavir / ritonavir can cause a significant increase in the concentration of these drugs.

Based on data on other inhibitors of the isoenzyme CYP3A is assumed. that when joint use of midazolam orally with the drug darunavir with low doses of ritonavir, there will be a significant increase in midazolam concentrations in plasma.

When joint application of midazolam parenterally with the drug darunavir with low doses of ritonavir, a significant increase in the concentration of this benzodiazepine is possible.

Data on the joint use of midazolam parenterally with other protease inhibitors indicate the possibility of an increase in the level of midazolam in plasma by 3-4 times.

When the drug is used together darunavir with these sedative / hypnotics and drugs, clinical monitoring is recommended, in addition, the question of reducing the dose of these drugs should be addressed.

The use of a combination of darunavir / ritonavir with triazolam is contraindicated.

Application of the drug darunavir with low doses of ritonavir and midazolam orally is contraindicated (see section "Contraindications"); while with the drug darunavir with low doses of ritonavir and midazolam, parenteral care must be taken.

If midazolam parenteral will be used in combination with the drug darunavir with low doses of ritonavir, treatment should be initiated in an intensive care unit (ICU) or under similar conditions in which thorough clinical monitoring and appropriate therapy can be provided in the event of respiratory center depression and / or prolonged sedation.

It is necessary to solve the problem of correcting the dose of midazolam, especially if it is used more than once.

** The effectiveness and safety of the use of darunavir with ritonavir 100 mg and any other HIV inhibitors (eg, (phospho) amprenavir, nelfinavir and tipranavir) in HIV-infected patients has not been established. According to the current guidelines for the treatment of HIV-infected patients, treatment regimens including 2 protease inhibitors are generally not recommended.

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. Against the background of drug therapy, it is necessary to regularly assess the virologic response. In the absence or loss of a virologic response, a study should be conducted for the presence of resistance.

Patients previously treated - once a day

The combination of darunavir / ritonavir should not be used at a frequency of 1 time per day in patients,previously received protease inhibitors and having at least one mutation that caused resistance to darunavir (V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74R. L76V, I84V and L89V) or with a plasma level of HIV-1 RNA ≥ 100,000 copies / ml and the amount Cd4+ cells <100 x 10⁶/ l. The use of the darunavir / ritonavir combination with an optimized baseline therapy (CBT), including 2 or more NRTIs, has not been studied in these patients. Data on the use in patients with HIV-1 other groups, except for group B, are limited.

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 because they are more likely to have liver dysfunction and they are more likely to suffer from concomitant diseases or take combination therapy.

Absolute bioavailability after a single dose of 600 mg of darunavir was approximately 37% and increased to approximately 82% after taking darunavir in combination with 100 mg of ritonavir twice a day. The overall effect of improving the pharmacokinetics of darunavir with ritonavirexpressed approximately in a 14-fold increase in the concentration of darunavir in plasma after taking one dose of this drug (600 mg) in combination with 100 mg of ritonavir twice a day. 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 to 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 hepatic transaminase activity. The Stevens-Johnson syndrome was rarely recorded (<0.1%). In the post-marketing 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 (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.), darunavir should be taken immediately stop.

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 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 appointment of darunavir to patients with an allergy to sulfonamides should be done with caution. In clinical studies of the darunavir / ritonavir combination, the extent and incidence of rash were similar in patients, regardless of the history of allergy to sulfonamides.

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 use of darunavir in patients with mild to moderate degree of impaired liver function (Child-Pugh class A and B) are comparable with those of healthy individuals, dose adjustment for patients with mild to moderate liver function disorder class A and B by Child-Pugh) is not required. The combination of darunavir / ritonavir in patients with severe hepatic impairment (Child-Pugh class C) is contraindicated.

Hepatotoxicity

When using the darunavir / ritonavir combination, it is possible to develop hepatitis caused by the use of medications (eg, acute hepatitis, cytological hepatitis). Hepatitis was observed in 0,5% patients receiving combination therapy with darunavir / ritonavir. 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 therapy and during treatment. Consideration should be given to monitoring the increase in ACT / ALT activity in patients with chronic hepatitis, cirrhosis, or in patients who have experienced increased transaminase activity prior to initiation of therapy, and especially during the first few months of combination therapy with the darunavir / ritonavir combination.

In case 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 be considered 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 treated with protease inhibitors. Some of these patients received a coagulation factor VIII. In more than half of the cases described, treatment with protease inhibitors continued without interruption or was resumed after a temporary suspension. It was suggested a causal relationship between the treatment of protease inhibitors and increased bleeding in patients with hemophilia, but the mechanism of such a connection is not established. Patients with hemophilia receiving the 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 course of an already existing diabetes mellitus. In some of these patients, hyperglycemia was severe and in some cases was accompanied by ketoacidosis.Many patients had concomitant diseases, some of which required treatment with drugs that promote the development of diabetes or hyperglycemia.

Redistribution of fat and metabolic disorders

Combined antiretroviral therapy can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. At present, there are no data on the long-term consequences of this phenomenon, and its mechanism is largely unclear. A hypothesis has been made about the relationship between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy is associated with factors such as old age, as well as with long-term therapy with antiretroviral drugs and the associated metabolic disorders. In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to physical signs of fat redistribution.

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

Osteonecrosis

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

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, 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. Examples include cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumonia caused by Pneumocystis carinii. It is necessary to determine the severity of any symptoms of inflammation and to conduct appropriate therapy. Autoimmune diseases (such as Graves' disease) were also noted in the event of immune reactivation. However, the time to onset of the disease may vary, and such diseases may begin months after initiation of therapy.

Interaction with other medicinal products

Darunavir and ritonavir are inhibitors of isoenzymes CYP3A and CYP2D6, as well as inhibitors of P-glycoprotein. The simultaneous use of a combination of darunavir / ritonavir and other drugs that are metabolized predominantly by isoenzymes CYP3A, CYP2D6 and transferred by P-glycoprotein may lead to an increase in the concentration of such drugs in the plasma, so that their therapeutic and side effects may be intensified or prolonged.

Darunavir is metabolized by an enzyme CYP3A. Simultaneous reception of drugs that induce activity CYP3A, can increase the clearance of darunavir, resulting in a decrease in the concentration of darunavir in plasma. Simultaneous reception of darunavir with inhibitors CYP3A can reduce the clearance of darunavir, as a result of which the concentration of darunavir in plasma will increase. Simultaneous use of a combination of darunavir / ritonavir with a combination of lopinavir / ritonavir, rifampicin and herbal preparations containing St. John's wort extract perforated (Hypericum perforatum), it is contraindicated. The use of efavirenz together with a combination of darunavir / ritonavir 800/100 mg once a day can lead to an insufficient value C_min darunavir. If efavirenz should be used in conjunction with the combination of darunavir / ritonavir, then it is advisable to use a combination of darunavir / ritonavir 600/100 mg twice a day. In patients receiving colchicine and strong inhibitors of isoenzyme CYP3A and P-glycoprotein, life-threatening and deadly drug interactions were noted.

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

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

Form release / dosage:

Tablets, film-coated, 75 mg, 150 mg, 300 mg, 400 mg, 600 mg.

Packaging:

For 10 tablets (for dosages of 75 mg, 150 mg, 300 mg, 400 mg and 600 mg) or 15 tablets (for a dosage of 600 mg) in a loop cell pack of aluminum foil and PVC film.

75 mg: For 48 contour mesh packages together with instructions for use in a pack of cardboard.

150 mg: For 24 contour mesh packages together with instructions for use in a pack of cardboard.

300 mg: For 12 contour packagings together with instructions for use in a pack of cardboard.

400 mg: 6 contour packs with instructions for use in a pack of cardboard.

600 mg: 6 contour packs (10 tablets) or 4 contour packs (15 tablets each) together with instructions for use in a pack of cardboard.

Storage conditions:

Store in the original packaging in a dark place at a temperature not higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003745

Date of registration:20.07.2016

Expiration Date:20.07.2021

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

PHARMSTANDART-TOMSKHIMFARM, OJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp18.03.2017

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