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

Core: giprolose low-substituted - 2.50 mg / 5.00 mg / 10.00 mg / 13.33 mg / 20.00 mg / 26.67 mg; polysorbate 80 - 1.50 mg / 3.00 mg / 6.00 mg / 8.00 mg / 12.00 mg / 16.00 mg; crospovidone - 6,00 mg / 12,00 mg / 24,00 mg / 32,00 mg / 48,00 mg / 64,00 mg; silicon dioxide colloid - 1.50 mg / 3.00 mg / 6.00 mg / 8.00 mg / 12.00 mg / 16.00 mg; IsiTab Jaw Salt (consisting of: microcrystalline cellulose 95.0% - 98.0%, silicon colloidal dioxide 1.5% - 2.5%, carboxymethyl starch sodium 0.5% - 2.0%; sodium stearyl fumarate 0.3% - 1.0%) 69.00 mg / 138.00 mg / 276.00 mg / 368.00 mg / 552.00 mg / 736.00 mg.

Film sheath: hypromellose E5 - 2,632 mg / 5,264 mg / 10,528 mg / 14,037 mg / 21,056 mg / 28,070 mg; ferric oxide yellow oxide - 0.154 mg / 0.308 mg / 0.616 mg / 0.821 mg / 1.232 mg / 1.640 mg; macrogol 6000 - 0.5075 mg / 1.015 mg / 2.030 mg / 2.707 mg / 4.066 mg / 5.410 mg; talc - 0.0805 mg / 0.161 mg / 0.322 mg / 0.429 mg / 0.644 mg / 0.859 mg; titanium dioxide - 0.126 mg / 0.252 mg / 0.504 mg / 0.672 mg / 1.008 mg / 1.344 mg.

Description:

Tablets 75 mg, 150 mg: round, biconvex tablets, covered with a film membrane, from light yellow to dark yellow color.

Tablets 300 mg, 400 mg, 600 mg: oval, biconvex tablets, covered with a film membrane, from light yellow to dark yellow color.

Tablets 800 mg: oblong, biconvex tablets, covered with a film membrane, from light yellow to dark yellow, with a risk on one side.

On the cross-section the nucleus is white or white with a yellowish tint of color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.10 Darunavir

Pharmacodynamics:

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

Darunavir is 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 in patients infected with HIV-1 were higher than in healthy people. This difference can be explained by higher concentrations of alpha-1-acid glycoprotein in patients infected with HIV-1, and therefore large amounts of darunavir bind to the alpha-1-acid plasma glycoprotein. Darunavir is metabolized mainly by isoenzymes CYP3A. Ritonavir inhibits isoenzymes CYP3A liver and, thereby, significantly increases the concentration of darunavir in plasma.

Absorption

After oral administration darunavir quickly absorbed in the gastrointestinal tract (GIT). The maximum concentration of darunavir in plasma in the presence of a low dose of ritonavir is achieved after 2.5-4.0 hours. The absolute bioavailability of a single dose of darunavir (600 mg) when ingested is about 37% and increases to about 82% in the presence of ritonavir (100 mg two times a day). There is a 14-fold increase in the concentration of darunavir in the plasma after a single oral intake at a dose of 600 mg in combination with ritonavir (100 mg twice daily). When taking an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir is 30% lower than when taken with meals. Consequently, darunavir It 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 an alpha-1-acid glycoprotein.

Metabolism

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

Excretion

After a single dose of 400 mg ¹⁴C-darunavir and 100 mg of ritonavir were 79.5% and 13.9% of radioactivity was detected in feces and urine, respectively. The proportion of unchanged darunavir accounted for about 41.2 and 7.7% of radioactivity in feces and urine, respectively.The final half-life of darunavir was about 15 hours when taken in combination with ritonavir. The clearance of darunavir after intravenous administration of 150 mg was 32.8 l / h (without ritonavir) and 5.91 l / h in the presence of a low dose of ritonavir.

Pharmacokinetics in special clinical cases

The pharmacokinetics of darunavir in combination with ritonavir in children 6-18 years of age and weighing at least 20 kg is comparable to pharmacokinetics in adult patients receiving a dose of 600 mg / 100 mg twice a day of darunavir / ritonavir.

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).

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. 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).

Darunavir is metabolized and excreted mainly by the liver. In a study using several doses of darunavir in combination with ritonavir (600 mg / 100 mg) twice daily, it was shown that the stable pharmacokinetic parameters of darunavir in patients with mild (Class A on the Child-Pugh scale, n= 8) and the average severity of liver function disorders (class B on the Child-Pugh scale, n= 8) were comparable with those of healthy individuals.

In HIV-infected patients with mild and moderate severity of liver function disorders correction of the dose of darunavir is not required, apply darunavir in this category of patients should be cautious.

In patients with severe hepatic impairment the pharmacokinetics of darunavir have not been studied. Severe liver failure is a contraindication to the appointment of darunavir.

Indications:

Treatment of HIV infection in adults and children aged 6 years and with a body weight of 20 kg or more, previously receiving antiretroviral therapy (in combination with low-dose ritonavir and other antiretroviral drugs).

Contraindications:

- Hypersensitivity to darunavir or to any component of the drug.

- Simultaneous reception with drugs that are metabolized predominantly by the cytochrome P450 3A4 isoenzyme and an increase in plasma concentration is associated with serious and / or life-threatening side effects (narrow therapeutic range). These drugs include antihistamines (astemizole, terfenadine), alfuzosin, quetiapine, sildenafil (used for the therapy of pulmonary arterial hypertension), rifampicin, sedatives / hypnotics (triazolam, midazolam for oral administration), GI motility stimulants (cisapride), colchicine (in patients with renal and / or hepatic insufficiency), preparations containing St. John's wort extract, preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergomethrin), antiarrhythmic drugs (amiodarone, beprideil, quinidine, lidocaine for systemic use, dronedaron), ranolazine, inhibitors of HMG-Co-A-reductase (simvastatin, lovastatin), antipsychotics (pimozide, sertindole). See also "Interaction with other medicinal products".

- Simultaneous reception with a combination of lopinavir / ritonavir (see also section "Interactions with other drugs").

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

- Children under 6 years of age and body weight less than 20 kg.

Carefully:

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

- Allergy to sulfonamides

- Age over 65 years

- With the simultaneous administration of drugs that are highly binding to the alpha1-acid glycoprotein.

- In patients with chronic hepatitis (including with chronic viral hepatitis B and C).

- In patients with hemophilia.

Pregnancy and lactation:

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

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

It is not known whether darunavir penetrate into breast milk in humans. Given the possibility of HIV transmission in breast milk, as well as the risk of serious side effects in infants due to exposure to darunavir, HIV-infected women receiving darunavir, should refrain from breastfeeding.

In experimental studies on animals, the toxic activity of darunavir or its negative effect on reproductive function and fertility has not been revealed. Shown, that darunavir is excreted in breast milk in lactating rats.

Dosing and Administration:

Inside.

Darunavir should always be prescribed in combination with a low dose of ritonavir as a remedy to improve its pharmacokinetic characteristics, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before initiating darunavir / ritonavir therapy.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 for use in children's practice. In adults to reach therapeutic doses of dosage data require receiving a large number of tablets, that on one hand makes them difficult to swallow, the other - may cause allergic reaction due to increased revenues auxiliary substances contained in the tablets, so they should be used only when the unavailability of other dosages .

Adult patients

Patients who have not previously received protease inhibitors:	Patients who previously received protease inhibitors:
	Not having mutations that cause resistance to darunavir *	Having at least 1 mutation that causes resistance to darunavir *
800 mg 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: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74R, L76V, I84 V and L89V

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

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

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

Children

Patients from 6 to 18 years old who received antiretroviral therapy before. The recommended dose of darunavir / ritonavir for children from 6 to 18 years of age and a body weight of at least 20 kg depends on body weight (see table below) and should not exceed the recommended dose for adult patients (600 mg / 100 mg twice daily). Darunavir should be taken with ritonavir 2 times a day during meals.

The recommended dose of ritonavir and darunavir for patients from 6 to 18 years, had been receiving antiretroviral therapy

Body weight (kg)	Dose
> 20 kg - <30 kg	375 mg of darunavir with 50 mg of ritonavir 2 times a day
≥ 30 kg - <40 kg	450 mg of darunavir with 60 mg of ritonavir 2 times a day
≥ 40 kg	600 mg of darunavir with 100 mg of ritonavir 2 times a day

Elderly patients

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

Patients with hepatic impairment

In patients with mild or moderate severity of liver function disorders, dose adjustment is not required. The use of a combination of darunavir / ritonavir in patients with severe impairment of liver function is contraindicated.

Patients with impaired renal function

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

Skipping darunavir / ritonavir combination

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

Side effects:

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

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

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

System-Organ Class / Frequency Category	Side effects
Infectious and parasitic diseases
Infrequently	Herpetic infection.
Disturbances from the hematopoiesis and lymphatic system
Infrequently	Thrombocytopenia, neutropenia, anemia, leukopenia
Rarely	Eosinophilia
Immune system disorders
Infrequently	Immunodeficiency Syndrome, (drug) hypersensitivity
Disorders from the endocrine systems
Infrequently	Hypothyroidism, increasing the concentration of thyroid-stimulating hormone in the blood
Disorders from the metabolism and nutrition
Often	Diabetes mellitus, lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridemia, hypercholesterolemia, hyperlipidemia
Infrequently	Gout, anorexia, decreased appetite, weight loss, weight gain, 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, anxiety, disorientation, sleep disorders, abnormal dreams, nightmares, decreased libido
Rarely	Confusion, mood swings, anxiety
Disturbances from the nervous system
Often	Headache, peripheral neuropathy, dizziness
Infrequently	Inhibition, paresthesia, hypoesthesia, dysgeusia, attention disorders, memory impairment, drowsiness
Rarely	Fainting, convulsions, disturbance of the rhythm of the phases of sleep, agesia
Disturbances on the part of the organ of sight
Infrequently	Hyperemia of the conjunctiva, dry eye mucosa
Rarely	Visual impairment
Hearing disorders and equilibrium
Infrequently	Vestibular Dizziness
Heart Disease
Infrequently	Tachycardia, stenocardia, lengthening interval QT on an electrocardiogram, myocardial infarction.
Rarely	Acute myocardial infarction, sinus bradycardia, palpitation.
Vascular disorders
Infrequently	Increased blood pressure, "hot flashes"
Disturbances from respiratory system, chest and mediastinum
Infrequently	Shortness of breath, cough, nosebleeds, sore throat
Rarely	Rhinorrhea
Disorders from the gastrointestinal tract
Often	Diarrhea
Often	Nausea, vomiting, abdominal pain, increased amylase activity in the blood, indigestion, bloating, flatulence
Infrequently	Pancreatitis, gastritis, gastroesophageal reflux, aphthous stomatitis, desires for vomiting, dryness of the oral mucosa, discomfort in the abdomen, constipation, increased lipase activity, eructation, impaired sensitivity in the oral cavity
Rarely	Stomatitis, vomiting with blood, cheilitis, dryness of the mucous membrane of the lips, plaque in the tongue
Disturbances from the liver and bile ducts
Often	Increased activity of alanine aminotransferase
Infrequently	Hepatitis, cytolytic hepatitis, steatosis of the liver, hepatomegaly, increased transaminase activity, increased activity of aspartate aminotransferase, 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 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. Decreased renal clearance of creatinine
Violations of the genitals and mammary gland
Infrequently	Erectile dysfunction, gynecomastia
General disorders and disorders at the site of administration
Often	Asthenia, fatigue
Infrequently	Fever, chest pain, peripheral edema, malaise, fever, irritability, pain
Rarely	Chills, bad health, skin xerosis

Description of some side effects

Rash

In clinical studies, mainly a mild to moderate rash was observed. The rash usually appeared during the first four weeks of therapy and disappeared with continued use of the drug. When developing severe skin reactions, see the section "Special instructions". In clinical trials in patients previously treated, the rash, regardless of its cause, more often occurred with the admission of treatment regimens containing 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 concomitant infection caused by the hepatitis B virus and / or C

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

Overdose:

Data on acute overdose when taking darunavir in combination with ritonavir in humans are 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 side 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:

Darunavir, used in combination with ritonavir, is an inhibitor of isoenzymes CYP3A, CYP2D6 and P-glycoprotein. The simultaneous use of the darunavir / ritonavir combination and drugs that are metabolized predominantly by isoenzymes CYP3A, CYP2D6 and are carried by P-glycoprotein, can cause an increase in the concentrations of such drugs in the plasma, which in turn may be the cause of the amplification 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 may 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 isoenzymes CYP2C9, CYP2C19 and CYP2D6, an increase in the activity of isoenzymes CYP2C9 and CYP2C19 and inhibition of isoenzyme activity CYP2D6 in the presence of the darunavir / ritonavir combination, 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 the isoenzyme CYP2D6 (eg, flecainide, propafenone, metoprolol) may increase the concentration of these drugs in the plasma, which in turn may cause an increase or prolongation of their therapeutic effect and undesirable reactions. The combined use of darunavir and ritonavir with drugs, primarily metabolized isoenzymes CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., methadone) may lead to a reduction of systemic levels of these drugs, which in turn may be the cause of reducing or reducing their therapeutic effect.

Although the effect on isoenzyme CYP2C8 was studied only in vitro, the combined use of the darunavir / ritonavir combination with drugs that are predominantly metabolized by the CYP2C8 isoenzyme (for example, paclitaxel, rosiglitazone, repaglinide) may lead to a lower systemic level of these drugs, which in turn may be a reason for 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 increase the clearance of darunavir and ritonavir, causing a decrease in plasma concentrations of these drugs (for example, 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

Interactions between the combination of darunavir / ritonavir and antiretroviral and other drugs are given in the table below ("Undetermined" is abbreviated as "N / A"). The direction of the arrow for each pharmacokinetic 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 80-125%.

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

A drug used in conjunction with the darunavir / ritonavir combination	Interaction Mean geometric variation (%)	Recommendations for joint use
Antiretroviral drugs used to treat HIV infection
Integrase inhibitors
Dolutegravir	AUC dolutegravir ↓ 32% FROM_24h dolutegravir ↓ 38% FROM_m_Oh 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.
Elvitegravir	AUC elvitegrewra ↔ C_min elvitegrewra ↔ FROM_mOh elvitegrewra ↔ AUC darunavira ↔ C_min darunavir ↓ 17% FROM_mOh darunavira ↔	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. Pharmacokinetics and dosage recommendations for other darunavir doses or for the combination of 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.	At present, it is suggested 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	AUC didanosine ↓ 9 % C_min Didanosine H / O FROM_m_Oh didanosine ↓16% AUC darunavira ↔ C_min darunavira ↔ FROM_m_Oh darunavir ↔	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 while eating.
Tenofovir disoproxil fumarate 300 mg once daily	AUC tenofovir ↑ 22% C_min tenofovir ↑ 37% FROM_mOh tenofovir ↑ 24% # AUC of darunavir ↑ 21% #C_min darunavir ↑ 24% # FROM_mOh ↑ darunavir ↑ 16% (↑ concentrations of tenofovir due to influence on mediated MDR-1 transport in the renal tubules)	With simultaneous use of the darunavir / ritonavir and tenofovir combination, 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, lamivudine, stavudine, emtricitabine), which are excreted mainly by the kidneys, and abacavir, in the metabolism of which is not involved CYP 450, no interaction between these drugs and the combination of darunavir / ritonavir is expected.	The combination of darunavir / ritonavir can be used concomitantly with these NRTIs without dose adjustment.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz 600 mg once daily	AUC efavirenz ↑ 21% C_min efavirenz ↑ 17% FROM_mOh efavirenz ↑ 15% # AUC of darunavir ↓ 13% # C_min darunavir ↓ 31% # FROM_mOh darunavir ↓ 15% (↑ efavirenz concentration due to inhibition CYP3A) (↓ concentrations of darunavir due to induction CYP3A)	When the darunavir / ritonavir combination with efavirenz is used concomitantly, clinical monitoring of central nervous system toxicity associated with increased efavirenz concentration may be required. The use of efavirenz in combination with the darunavir / ritonavir combination at a dose of 800/100 mg once a day can result in a suboptimal value of C_min darunavir. If a combination of darunavir / ritonavir is required in combination with efavirenz, 600/100 mg should be used 2 times a day.
Etravirine 100 mg twice daily	AEC etravirine ↓ 37% C_min etravirine ↓ 49% FROM_mOh etravirine ↓ 32% AUC of darunavir ↑ 15% C_min darunavira ↔ FROM_mOh 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_mOh nevirapine ↑ 18% ^#Darunavir: Concentrations corresponded to historical data (↑ concentrations of nevirapine due to inhibition CYP3A)	The combination of darunavir / ritonavir with nevirapine can be used without dose adjustment.
Rilpivirine 150 mg once daily	AUC of rilpivirin ↑ 130% C_min rilpivirine ↑ 178% FROM_mOh rilpivirin ↑ 79% AUC of darunavir ↔ C_min darunavir ↓ 11% FROM_mOh darunavira ↔	The combination of darunavir / ritonavir with rilpivirin can be used without dose adjustment.
HIV protease inhibitors without additionalmLow-dose ritonavir *
Atazanavir 300 mg once daily	AUC atazanavir C_min atazanavir ↑ 52% FROM_mOh atazanavir ↑ 11% ^#AUC of darunavir ↔ ^#C_min darunavira ↔ ^#FROM_mOh darunavira ↔ Atazanavir: a comparison of atazanavir / ritonavir 300/100 mg once a day and atazanavir 300 mg once daily 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 a day.	The combination of darunavir / ritonavir with atazanavir can be used without dose adjustment.
Indinavir 800 mg twice daily	AUC indinavir ↑ 23% C_min indinavir ↑ 125% # FROM_mOh indinavir ↔ # AUC of darunavir ↑ 24% # C_min darunavir ↑ 44% # FROM_mOh darunavir ↑ 11% # Indinavir: a comparison of indinavir / ritonavir 800/100 mg 2 times a day with indinavir / darunavir / ritonavir 800/400/100 mg 2 times a day. Darunavir: A comparison of darunavir / ritonavir 400/100 mg 2 times a day with darunavir / ritonavir 400/100 mg in combination with indinavir 800 mg 2 times a day.	When prescribed in combination with the darunavir / ritonavir combination, it may be necessary to adjust the dose of indinavir from 800 mg twice a day to 600 mg twice a day in case of intolerance.
Saquinavir 1000 mg twice daily	#AUC of darunavir ↓ 26% # C_min darunavir ↓ 42% # FROM_mOh darunavir ↓ 17% AUC of saquinavir ↓ 6% C_min saquinavir ↓ 18% FROM_mOh saquinavir ↓ 6% Saquinavir: Comparison of saquinavir / ritonavir 1000/100 mg twice daily and saquinavir / darunavir / ritonavir 1000/400/100 mg twice daily. Darunavir: A comparison of darunavir / ritonavir 400/100 mg twice daily 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 lopinavir ↑ 9% FROM_min lopinavir ↑ 23% FROM_mOh lopinavir ↓ 2% AUC darunavir ↓ 38% † FROM_min darunavir ↓51%† FROM_mOhdarunavir ↓ 21%†	Due to a decrease in concentration (AUC) darunavir by 40% suitable doses of this combination are not 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 lopinavir ↔ FROM_min lopinavir ↑ 13% FROM_mOh lopinavir ↑ 11% AUC darunavir ↓ 41% FROM_min darunavira ↓ 55% FROM_mOh darunavir ↓ 21% † based on non-normalized doses
Receptor antagonists CCR5
Maraviroc 150 mg twice daily	AUC maraviroc ↑ 305% FROM_min maraviroc N / O FROM_mOh 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 isoenzyme participates CYP3A, therefore, the metabolism of alfentanil can be inhibited by darunavir, used in conjunction with low doses of ritonavir.	When combined with a darunavir / ritonavir combination, a reduction in the dose of alfentanil may be required, as well as monitoring the risks of prolonged or delayed respiratory depression.
Antianginal / antiarrhythmic drugs
Disopyramide Flecainide Mexiletin Propafenone	Not studied. It is assumed that darunavir increases the concentration of these antiarrhythmic drugs in the blood plasma (by inhibiting the isoenzyme CYP3A).	Precautions are necessary, in addition, monitoring of the therapeutic concentration (if possible) of these antiarrhythmic drugs when combined with the darunavir / ritonavir combination is recommended.
Amiodarone Bepridil Dronedaron Lidocaine (for systemic use) Quinidine Ranolazine		Contraindicated simultaneous use of the combination of darunavir / ritonavir with amiodarone, bepridilom, dronedarone, lidocaine (with systemic administration), quinidine, ranolazinom.
Digoxin 0.4 mg once	AUC digoxin ↑ 61% FROM_min digoxin H / O FROM_mOh 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, the minimum possible dose of digoxin is initially recommended. Next, a careful titration of the dose of digoxin should be performed in order to achieve the desired clinical effect against the background of assessing the overall clinical state of the patient.
Antibiotics
Clarithromycin	AUC of clarithromycin ↑ 57% FROM_min clarithromycin ↑ 174% FROM_mOh clarithromycin ↑ 26% ^#AUC of darunavir ↓ 13% ^#C_min darunavira ↑ 1% ^#FROM_m_Oh darunavir ↓ 17% Concentrations of 14-OH-clarithromycin were not detected when combined with a darunavir / ritonavir combination. (↑ concentration 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 ethoxylate Rivaroxaban	Not studied. Simultaneous administration of the darunavir / ritonavir combination may increase anticoagulant concentrations (inhibition of the isoenzyme CYP3A and / or P-glycoprotein).	The combined use of the darunavir / ritonavir combination with these anticoagulants is not recommended.
Warfarin	Not studied. With simultaneous use with a combination of darunavir / ritonavir, a change in the concentration of warfarin in the plasma is possible.	If both warfarin and the darunavir / ritonavir combination are used concomitantly, it is recommended that the international standardized ratio (INR) be monitored.
Anticonvulsants
Phenobarbital Phenytoin	Not studied. It is assumed that phenobarbital and phenytoin can lead to a decrease in the concentration of darunavir (due to the induction of isoenzymes CYP450).	The use of a combination of darunavir / ritonavir concomitantly with these drugs is contraindicated.
Carbamazepine 200 mg twice daily	AUC carbamazepine ↑ 45% C_min carbamazepine ↑ 54% FROM_mOh carbamazepine ↑ 43% AUC darunavira ↔ C_min darunavir ↓ 15% FROM_mOh darunavira ↔	Dose changes for the darunavir / ritonavir combination are not required. If simultaneous prescribing of darunavir / ritonavir and carbamazepine is required, monitoring of potential carbamazepine-associated adverse events is required. 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 with simultaneous use with a combination of darunavir / ritonavir, a dose reduction of carbamazepine by 25% to 50% may be required.
Antidepressants
Paroxetine 20 mg once a day	AUC paroxetine ↓ 39% C_min paroxetine ↓ 37% FROM_mOhparoxetine ↓ 36% ^#AUC darunavira ↔ ^#C_min darunavir ↔ ^#FROM_mOh, darunavir ↔	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 daily	AUC sertraline ↓ 49% C_min sertraline ↓ 49% FROM_mOh, sertraline ↓ 44% ^#AUC darunavira ↔ ^#C_min darunavir ↓ 6% ^#FROM_mOh darunavira ↔
Amitriptyline Desipramine Imipramine Nortriptyline Trazodone	The combined use of the darunavir / ritonavir combination with these antidepressants can increase the concentration of antidepressants, (inhibition CYP2D6 and / or CYP3A).	In the case of combined use of these antidepressants with the combination of darunavir / ritonavir, clinical monitoring is recommended, in addition, dosage adjustment of antidepressants may be required.
Antifungal drugs
Voriconazole	Not studied. Ritonavir can reduce the concentration of voriconazole in plasma (induction of enzymes CYP450 under the action of ritonavir)	Voriconazole should not be used in combination with a darunavir / ritonavir combination, when on the basis of an assessment of the relationship between risk and benefit, the use of voriconazole is necessary.
Ketoconazole	AUC ketoconazole ↑ 212% C_min ketoconazole ↑ 868% FROM_m_Oh ketoconazole ↑ 111% ^#AUC darunavir ↑ 42% ^#C_min darunavir ↑ 73% ^#FROM_m_Oh darunavir ↑ 21% (inhibition of isoenzyme 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 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 under the influence of darunavir with low doses of ritonavir (inhibition of the isoenzyme CYP3A)	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 application of clotrimazole and darunavir in combination 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.
Anti-gouty drugs
Colchicine	The combined use of colchicine and darunavir with low doses of ritonavir can increase the concentration of colchicine.	If therapy with a combination of darunavir / ritonavir is required, patients with normal liver 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-malarial drugs
Artemether / Lumefantrine 80/480 mg, 6 doses after 0, 8, 24, 36, 48 and 60 hours	AUC artemeter ↓ 16% C_min artemether ↔ FROM_mOh artemeter ↓ 18% AUC dihydroartemisine ↓ 18% C_min dihydroartemizine ↔ FROM_m_Oh dihydroartemisine ↓ 18% AUC lumefantrine ↑ 175% C_min lumefantrine ↑ 126% FROM_m_Oh lumefantrine ↑ 65% AUC darunavira ↔ 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-TB drugs
Rifampicin Rifapentin	Not studied. Rifapentin and rifampicin are powerful inductors of isoenzyme CYP3A, they caused a marked decrease in the concentrations of other protease inhibitors, which can lead to virological inefficiency and development of resistance (induction of enzymes CYP450). 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 frequency of reactionsfrom the side of the liver.	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 in 2 days	AUC rifabutin ↑ 55% C_min rifabutin N / O FROM_m_Oh rifabutin ↔ AUC darunavir ↑ 53% C_min darunavir ↑ 68% FROM_max darunavir ↑ 39% the sum of the active derivatives of rifabutin (initial preparation + 25-O-deacetyl metabolite) In a study of the interaction, comparable daily systemic levels of rifabutin were observed when administered at a dose of 300 mg once a day as monotherapy and 150 mg every other day, combined with a darunavir / ritonavir combination (600/100 mg twice daily) with approximately a tenfold increase in the daily level active metabolite (25-O-deacetyl rifabutin). Besides, AUC the sum of the active derivatives of rifabutin (starting drug + 25-0-deacetyl metabolite) increased by a factor of 1.6, while the value of C_mOh remained comparable. Currently, there is no data compared with the standard dose of 150 mg once a day. (Rifabutin is an inducer and isoenzyme substrate CYP3A.) In a combination of darunavir / ritonavir with rifabutin (150 mg every other day), the systemic concentration of darunavir was increased.	Patients receiving combination 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, a dose reduction of 75% also refers to patients receiving rifabutin in a dose different from 300 mg / day.
Antineoplastic agents
Dasatinib Nilotinib Vinblastine Vincristine	Not studied. It is suggested that the combination of darunavir / ritonavir will increase the concentration of these antitumor drugs in plasma (by inhibiting the isoenzyme CYP3A).	When these drugs are combined with the darunavir / ritonavir combination, it is possible to increase their concentration, thus increasing the undesirable phenomena 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.
Antiplatelet drugs
Tikagrelor	Not studied. Co-administration with a combination of darunavir / ritonavir can lead to a significant increase in ticagrelor concentration.	The simultaneous use of a combination of darunavir / ritonavir with ticagrelor is contraindicated.
Antipsychotic drugs / antipsychotics
Quetiapine	Due to inhibition of the isoenzyme CYP3A darunavir is expected to increase the concentration of antipsychotic drugs / 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.When combined with the darunavir / ritonavir combination, an increase in the concentration of these antipsychotics in plasma (due to 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.
Pimozide Sertindole		The simultaneous use of the darunavir / ritonavir combination with pimozide or sertindole is contraindicated.
Beta-blockers
Carvedilol Metoprolol Timolol	Not studied. An increase in the concentration of these beta-adrenoblockers in plasma is contemplated with simultaneous use with darunavir (due to inhibition of the isoenzyme CYP2D6).	With the joint application of darunavir beta-adrenoblockers, clinical monitoring is recommended. The question of reducing the dose of beta-blocker should be addressed.
Blocks of "slow" calcium channels
Amlodipine Diltiazem Felodipine Nifedipine Nicardipine Verapamil	Not studied. It can be assumed that the combination of darunavir / ritonavir can increase the concentration of blockers of "slow" calcium channels in the plasma (by inhibiting isoenzymes CYP3A and / or CYP2D6).	When these drugs are combined with the darunavir / ritonavir combination, clinical monitoring of therapeutic and side effects is recommended.
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 inhaled or oral systemic glucocorticosteroid effects, including Cushing's syndrome and adrenal suppression; this can also be observed when using other glucocorticosteroids metabolized with the participation of the isoenzyme CYP3A, 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 glucocorticosteroids is not recommended unless the potential benefit of the treatment outweighs the risk of systemic glucocorticosteroid effects. It is necessary to solve the problem of reducing the dose of a glucocorticosteroid with careful monitoring of local and systemic effects, or about switching to another corticosteroid that is not a substrate of the isoenzyme CYP3A (eg, beclomethasone). Moreover, in the case of cancellation of glucocorticosteroids, it may be necessary to gradually reduce the dose over a longer period.
Dexamethasone (systemically)	Not studied. Dexamethasone may reduce the concentration of darunavir in plasma (induction of isoenzyme CYP3A).	Dexamethasone as a systemic drug should be used with caution in combination with a combination of darunavir / ritonavir
Prednisone	Not studied. Darunavir can increase the concentration of prednisone in plasma (by inhibiting 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 a combination of darunavir / ritonavir is combined 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 is recommended.
Antivirus Direct action drugs for hepatitis C therapy
Protease Inhibitors NS3-4A
Telaprevir 750 mg every 8 hours	AUC telaprevir ↓ 35% C_min telaprevir ↓ 32% FROM_mOh telaprevir ↓ 36% AUC12 darunavir ↓ 40% C_min darunavir ↓ 42% FROM_mOh darunavir ↓ 40%	The combination of darunavir / ritonavir is not recommended in combination with telaprevir.
Boceprivir 800 mg 3 times daily	AUC bocetrevir ↓ 32% C_min boceprevir ↓ 35% FROM_mOh boceprevir ↓ 25% AUC darunavira ↓ 44% C_min darunavir ↓ 59% FROM_mOh darunavir ↓ 36%	The combination of darunavir / ritonavir is not recommended in combination with bocetrevir.
Symeprevir	AUC simeprevira ↑ 159% C_min simeprevira ↑ 358% FROM_mOh simeprevira ↑ 79% AUC of darunavir ↑ 18% C_min darunavir ↑ 31% FROM_mOh darunavira ↔ The dose of simeprevir in this interaction study was 50 mg in a co-presence with darunavir / ritonavir and 150 mg in the monotherapy group with simeprevir.	The combination of darunavir / ritonavir is not recommended in combination with simeprevir.
Herbal preparations
St. John's wort perforated (Hyperium perforatum)	Not studied. It is suggested that St. John's wort will reduce the concentration of darunavir and ritonavir in plasma (induction CYP450).	The combination of darunavir / ritonavir is contraindicated in combination with preparations containing Hyperium perforatum extract of St. John's wort. If the patient is already getting a St. John's wort, it is necessary to mark it and, if possible, 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-CoA reductase
Lovastatin Simvastatin	Not studied. A significant increase in the concentration of lovastatin and simvastatin in plasma is suggested when combined with darunavir and low doses of ritonavir (inhibition of the isoenzyme CYP3A).	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 daily	AUC atorvastatin ↑ 3-4 times C_min atorvastatin ↑ at ≈ 5.5-10 times FROM_mOh atorvastatin ↑ ≈ 2 times	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%^π C_min pravastatin N / O FROM_mOh pravastatin ↑ 63% ^π in a limited subpopulation of patients, an increase of up to 5	If a combined use of pravastatin with a darunavir / ritonavir, 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 rosuvastatin ↑ 48%^π FROM_maxrosuvastatin ↑ 144%^π ^π on the basis of 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.
Lovastatin Simvastatin	Not studied. A significant increase in the concentration of lovastatin and simvastatin in plasma is suggested when combined with darunavir and low doses of ritonavir (inhibition of the isoenzyme CYP3A).	An increase in the concentration of lovastatin or simvastatin in plasma can cause myopathy, including rhabdomyolysis. Thus, the combined use of the darunavir / ritonavir combination with lovastatin or simvastatin it is contraindicated.
H₂-gistaminovyh receptors blockers
Ranitidine 150 mg twice daily	^#AUC darunavira ↔ ^#C_min darunavira ↔ ^#FROM_mOh darunavira ↔	The combination of darunavir / ritonavir can be used in combination with H₂- histamine receptors with blockers without dose correction.
Immunosuppressive drugs
Cyclosporin Sirolimus Tacrolimus	Not studied. It is possible to increase the concentration of these immunosuppressants when combined with the darunavir / ritonavir combination (due to inhibition of the isoenzyme CYP3A).	In case of joint use, therapeutic monitoring of the concentration of immunosuppressants is recommended.
Everolimus		The combined use of everolimus with the combination of darunavir / ritonavir is not recommended.
Inhaled beta-adrenomimetics
Salmeterol	Not studied. The combined use of salmeterol and darunavir with low doses of ritonavir can lead to an increase in the concentration of salmeterol in plasma.	The joint use of salmeterol with a combination of darunavir / ritonavir is not recommended. With simultaneous application, an increased risk of cardiovascular adverse events associated with salmeterol, including prolongation of the QT interval, severe heartbeat and sinus tachycardia.
Narcotic analgesics / opioid dependence therapy
Methadone individual doses in the range of 55 to 150 mg once daily	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, dose adjustment with 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 daily	AUC buprenorphine ↓ 11% C_min buprenorphine ↔ FROM_mOh buprenorphine ↓ 8% AUC norbuprenorphine ↑ 46% C_min norbuprenorphine ↑ 71% FROM_mOh norbuprenorphine ↑ 36% AUC naloxone ↔ C_min naloxone N / O FROM_mOh naloxone ↔	The clinical significance of the increase in the parameters of the pharmacokinetics of norbuprenorphine has not been established. When combined with a darunavir / ritonavir combination, buprenorphine dosage adjustment may not be necessary, careful clinical monitoring is recommended for symptoms of opiate toxicity.
Estrogen-containing oral contraceptive drugs
Ethinylestradiol Norethindrone 35 μg / 1 mg once daily	AUC ethinyl estradiol ↓ 44% C_min ethinyl estradiol ↓ 62% FROM_mOh ethinyl estradiol ↓ 32% AUC norethindrone ↓ 14% C_min norethindrone ↓ 30% FROM_mOh norethindrone ↔	If estrogen-containing contraceptives are used in combination with a darunavir / ritonavir combination, alternative contraceptive methods are recommended.It is necessary to monitor patients receiving estrogens as hormone replacement therapy for symptoms of estrogen deficiency.
Inhibitors of phosphodiesterase type 5 (PDE-5)
For treatment Erectile Dysfunction Avanafil Sildenafil Tadalafil Vardenafil	In the study of interaction, * comparable systemic sildenafil concentrations were observed after a single dose of 100 mg of sildenafil in the form of monotherapy and at a dose of 25 mg in combination with darunavir / ritonavir.	It is not recommended simultaneous administration of avanafil and darunavir / ritonavir. Other PDE-5 inhibitors for the treatment of erectile dysfunction in combination with the darunavir / ritonavir combination should be used with caution. If the concomitant use of the combination of darunavir / ritonavir with sildenafil, vardenafil or tadalafil is indicated, sildenafil is recommended in a single dose of not more than 25 mg for 48 hours, vardenafil in a single dose not exceeding 2.5 mg in 72 hours or tadalafil in a single dose not higher 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, concomitant use of the combination of darunavir / ritonavir and sildenafil for the treatment of pulmonary arterial hypertension is contraindicated. The combined use of tadalafil to treat pulmonary arterial hypertension with a combination of darunavir / ritonavir is not recommended.
Proton Pump Inhibitors
Omeprazole 20 mg once daily	^#AUC ↔ ^#C_min darunavira ↔ ^#FROM_mOhdarunavira ↔	The combination of darunavir / ritonavir can be used in combination with proton pump inhibitors without dose adjustment.
Sedatives / hypnotics
Buspirone Clorazepate Diazepam Estazolam Flurazepam Triazolam Zolpidem	Not studied. Sedation / hypnotics are metabolized to a large extent by isoenzyme CYP3A. Joint use with a combination of darunavir / ritonavir can cause a significant increase in the concentration of these drugs.	When the darunavir / ritonavir combination is used together with these sedatives / hypnotics, 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.
Midazolam	Based on data on other isoenzyme inhibitors CYP3A It is assumed that when joint use of midazolam orally with darunavir in combination with low doses of ritonavir, there will be a significant increase in midazolam concentrations in plasma. When joint use of midazolam parenterally with darunavir in combination with low doses of ritonavir, a significant increase in the concentration of midazolam 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 in3-4 times.	The use of darunavir with low doses of ritonavir and midazolam is contraindicated orally. In applying darunavir with low doses of ritonavir and midazolam parenterally necessary caution. If midazolam parenterally will be used in combination with darunavir in combination with low doses of ritonavir, treatment should begin under conditions of the intensive care unit (ICU) or similar conditions in which careful clinical monitoring and appropriate therapy in the case of depression of the respiratory center and / or long may be provided sedation. It is necessary to solve the problem of correcting the dose of midazolam, especially if it is used more than once.

* Efficacy and safety of darunavir with ritonavir 100 mg, and any other HIV inhibitors (e.g., (phos) amprenavir, nelfinavir and tipranavir) in HIV-infected patients is not installed. According to current treatment recommendations, therapy that includes 2 protease inhibitors is 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.Patients should explain the need for appropriate precautions. Information on the combination of darunavir / ritonavir in patients 65 years of age or older is very limited. Care must be taken when treating darunavir patients of this age group, because they are more likely to have liver dysfunction, they are more likely to suffer from concomitant diseases, or receive concomitant therapy.

Absolute bioavailability after a single dose of darunavir at a dose of 600 mg is approximately 37% and increases to about 82% after taking darunavir in combination with 100 mg of ritonavir twice a day. There is a 14-fold increase in the concentration of darunavir in the plasma after taking a single dose of 600 mg in combination with ritonavir 100 mg 2 times a day. In this way, darunavir should be taken only in combination with a low dose of ritonavir (100 mg) as a pharmacokinetic enhancer. An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma, so a dose of ritonavir should not be increased.

Severe skin reactions

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

In the postmarketing period, toxic epidermal necrolysis and acute generalized exentematous pustulosis were recorded very rarely (<0.01%). If there are signs or symptoms of severe skin reactions (rash or rash accompanied by fever, general malaise, pain in the muscles or joints, blisters, oral cavity, conjunctivitis, hepatitis and / or eosinophilia), darunavir should be discontinued immediately. A rash (of all types) was observed in 10.3% of patients receiving darunavir. The rash was mostly mild or moderate and was often observed during the first four weeks of treatment and decreased with continued therapy. In 0.5% of cases, the rash was the cause of withdrawal of the darunavir / ritonavir combination.

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

Darunavir contains a sulfonamide group. In patients with allergies to sulfonamides darunavir should be used with caution. In clinical studies of the darunavir / ritonavir combination, the extent and incidence of rash were similar in patients with and without an allergy to sulfonamides in the anamnesis.

Patients with impaired hepatic function

Since stable pharmacokinetic parameters in the use of darunavir in persons with mild and moderate severity of liver function disorders are comparable to those of healthy individuals, dose adjustment for patients with mild and moderate severity of liver dysfunction is not required. Severe liver failure is a contraindication to the appointment of darunavir.

Hepatotoxicity

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

It is necessary to monitor appropriate laboratory parameters before prescribing darunavir / ritonavir combination and during treatment. Consider monitoring the increase in activity ACT and ALT in patients with chronic hepatitis, liver cirrhosis, or in patients who experienced increased transaminase activity prior to initiation of therapy, and especially during the first few months of combination therapy with darunavir / ritonavir. If symptoms of liver function disorders or their progression are detected (including a clinically significant increase in hepatic enzyme activity and / or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, tenderness in palpation of the liver,hepatomegaly) should consider discontinuing or canceling therapy with a combination of darunavir / ritonavir.

Patients with impaired renal function

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

Patients with hemophilia

There are reports of increased bleeding, including spontaneous cutaneous hematomas and hemarthrosis, in patients with haemophilia type A and B treated with protease inhibitors. Some of these patients received coagulation factor VIII. In more than half of the cases described, treatment with protease inhibitors continued without interruption or resumed after suspension for some time. It has been suggested that there is a causal relationship between the treatment of protease inhibitors and increased bleeding in patients with hemophilia, but the mechanism for such a link has not been established.Patients with hemophilia receiving the darunavir / ritonavir combination should be informed of the possibility of increased bleeding.

Hyperglycaemia

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

Lipodystrophy

Combined antiretroviral therapy can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. The increased risk of lipodystrophy is associated with factors such as old age, as well as with long-term therapy with antiretroviral drugs and the associated metabolic disorders. In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to physical signs of fat redistribution.It is recommended to determine the content of lipids and fasting blood glucose. Disorders of lipid metabolism should be treated with appropriate drugs.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, an inflammatory response of the body to asymptomatic or residual opportunistic infections may occur at the onset of combined antiretroviral therapy, which causes serious clinical complications or worsening of symptoms. Typically, such reactions are observed in the first weeks or months of combined antiretroviral therapy. Possible development of cytomegalovirus retinitis, generalized and / or local mycobacterial 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, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

Osteonecrosis

There have been cases of osteonecrosis, especially in patients with common risk factors, late HIV infection or long-term combined antiretroviral therapy. Patients should be advised to consult a doctor if joint pain occurs, joint stiffness, or difficulty in moving.

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 and / or CYP2D6 or are transported by P-glycoprotein, can lead to an increase in the concentration of such drugs in the plasma, so that their therapeutic and side effects may be intensified or prolonged.

Darunavir is metabolized by isoenzymes CYP3A. Simultaneous reception of drugs that induce isozyme activity CYP3A, can increase the clearance of darunavir. leading to a decrease in the concentration of darunavir in plasma. Simultaneous administration of darunavir with isozyme inhibitors CYP3A can reduce the clearance of darunavir, as a result of which the concentration of darunavir in plasma will increase.

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

Studies on the effects of darunavir / ritonavir combination on the ability to drive and move vehicles have not been conducted. However, when considering the patient's ability to drive and move vehicles, the clinical condition of the patient, as well as the side effects of darunavir, should be taken into account.

Form release / dosage:

Film-coated tablets, 75 mg, 150 mg, 300 mg, 400 mg, 600 mg and 800 mg.

Packaging:

Primary packaging of medicinal product

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

For 30, 60, 100, 120, 240, 360, 480 tablets in a polymer jar with a cover pulled with the control of the first opening. Free space is filled with cotton wool. On cans are labeled with paper label or from polymer materials, self-adhesive.

Secondary packaging of medicinal product

By 3, 6 or 10 contour mesh packages together with the instruction for use are placed in a pack of cardboard for consumer containers.

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

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-003813

Date of registration:31.08.2016 / 07.03.2017

Expiration Date:31.08.2021

The owner of the registration certificate:Profarm, LLCProfarm, LLC Russia

Manufacturer: & nbsp

Pharmasintez-Tyumen, Open Company Russia

Information update date: & nbsp18.03.2017

Illustrated instructions

Instructions

Darunavir (Darunavir)