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

Core: low-substituted giprolose 2.5 mg / 5 mg / 10 mg / 13.33 mg / 20 mg; polysorbate 801,5 mg / 3 mg / 6 mg / 8 mg / 12 mg; crospovidone 6 mg / 12 mg / 24 mg / 32 mg / 48 mg; Silica colloidal dioxide 1.5 mg / 3 mg / 6 mg / 8 mg / 12 mg; PROSOLV ® EASYtab SP - 69 mg / 138 mg / 276 mg / 368 mg / 552 mg.

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

Description:

Tablets 75 mg, 150 mg: round, biconcave tablets, film-coated, from light yellow to dark yellow.

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

On a cross-section a tablet of white or white with a yellowish shade of color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.10 Darunavir

Pharmacodynamics:

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

Darunavir is resistant to mutations that cause resistance to protease inhibitors. Darunavir does not inhibit any of the 13 human cell proteases studied.

Pharmacokinetics:

The pharmacokinetic properties of darunavir, used in combination with ritonavir, were studied in healthy volunteers and in HIV-infected patients. The concentrations of darunavir in plasma were higher in patients infected with HIV-1 than in healthy people. This difference can be explained by higher concentrations of alpha-1-acid glycoprotein in patients infected with HIV-1, and therefore large amounts of darunavir bind to the alpha-1-acid plasma glycoprotein. Darunavir is metabolized mainly by enzymes CYP3A. Ritonavir inhibits enzymes CYP3A and thereby substantially 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. Therefore, Kemeruwir tablets should be taken with ritonavir while eating. 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 against wild-type HIV was less than 1/10 of that of darunavir itself.

Excretion

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

Pharmacokinetics in special clinical cases

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

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in pharmacokinetic parameters of darunavir in the age group 18-75 years (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 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 (600/100 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 administration with drugs that are metabolized predominantly by the cytochrome P450 3A4 isoenzyme, 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 antihistamine preparations (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), 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), inhibitors of HMG-Co-A-reductase (simvastatin, lovastatin), antipsychotics (pimozide, sertindole). See also "Interaction with other medicinal products".

- simultaneous administration with a combination of lopinavir / ritonavir (see also section "Interactions with other drugs");

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

- children's age till 6 years.

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;

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

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

- in patients with hemophilia.

Pregnancy and lactation:

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

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.

Action category for the fetus by FDA - AT.

Dosing and Administration:

Inside. Darunavir should always be prescribed in combination with a low dose of ritonavir as a remedy to improve its pharmacokinetic characteristics, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before initiating darunavir / ritonavir therapy. After initiating therapy with darunavir, patients should not change or discontinue therapy without consulting the attending physician.

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 ritonavir, while eating.	800 mg once a day in combination with 100 mg ritonavir, while eating.	600 mg twice a day in combination with 100 mg ritonavir, while eating

* Mutations causing resistance to darunavir: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74R, L76V, I84U and L89V

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

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

Children

Patients 6 to 18 years old who received antiretroviral therapy The recommended dose of darunavir / ritonavir for children 6 to 18 years of age and body weight of at least 20 kg depends on body weight (see table below) and should not exceed the recommended dose for adult patients 600/100 mg twice a day).Kemeruwir tablets 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

The type of food does not affect the absorption of darunavir. Ritonavir (100 mg) is used as an enhancer of the pharmacokinetics of darunavir. If a dose of darunavir and / or ritonavir is missed within 6 hours after the usual admission time, the prescribed dose of darunavir and / or ritonavir should be taken as soon as possible. In the event that after the usual time of taking the drug more than 6 hours, it is recommended to adhere to the established scheme of taking the drug. These recommendations are based on a 15-hour half-life of darunavir in the presence of ritonavir and the prescribed mode of taking the drug every 12 hours.

Patients with hepatic impairment

In patients with mild or moderate 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.

Side effects:

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

2.6% of patients discontinued therapy due to side effects. Information on the side effects of adult patients who had previously received antiretroviral therapy when using 600/100 mg of darunavir / ritonavir 2 times a day is given below.

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

From the hemopoietic system and lymphatic system:

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

From the cardiovascular system:

Infrequent: myocardial infarction, angina pectoris, lengthening of the interval QT, sinus bradycardia, tachycardia, palpitations, increased blood pressure, "hot flashes" of blood.

On the part of the respiratory system:

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

On the part of the digestive system:

Very often: diarrhea.

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

Infrequently: pancreatitis, gastritis, gastroesophageal reflux, stomatitis, incl. aphthous, bloody vomiting, dryness of the oral mucosa, discomfort in the abdomen, constipation, increased lipase activity, belching, impaired oral sensitivity, cheilitis, dryness of the mucous membrane of the lips, plaque in the tongue.

From the hepatobiliary system:

Often: increased activity of alanine aminotransferase and aspartate aminotransferase.

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

From the nervous system:

Often: headache, peripheral neuropathy, dizziness.

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

Mental disorders:

Often: insomnia.

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

From the urinary system:

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

Rarely: decreased creatinine clearance.

From the side of the organ of vision:

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

From the organ of hearing:

Infrequently: vertigo.

From the immune system:

Infrequently: a syndrome of restoration of immunity.

From the endocrine system:

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

From the skin and soft tissues:

Often: rash (incl.macular, maculopapular, papular, erythematous and itchy), itching.

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

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

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

From the osteomuscular system and connective tissue:

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

Rarely: arthritis, joint stiffness, musculoskeletal stiffness.

On the part of the reproductive system and mammary glands:

Infrequently: erectile dysfunction, gynecomastia.

Metabolic disorders and eating disorders:

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

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

Violations of a general nature:

Often: asthenia, fatigue.

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

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

Infectious and parasitic diseases:

Infrequently: herpes simplex virus.

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

Side effects of combined antiretroviral therapy

Dermatological reactions: possibly redistribution of adipose tissue of the body (lipodystrophy). This redistribution includes the loss of peripheral and facial subcutaneous fat tissue,an increase in the number of intra-abdominal and visceral fat, mammary hypertrophy, and fat accumulation in the dorso-cervical region (formation of the fatty hump).

From the side of metabolism: hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia.

From the musculoskeletal system: in patients receiving protease inhibitors, especially in combination with non-nucleoside reverse transcriptase inhibitors, an increase in the level of creatine phosphokinase (CK), myositis; rarely rhabdomyolysis.

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

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

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

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. For removing nevsosavsheysya formulation shown gastric lavage or enema. You can apply Activated carbon. Darunavir to a large extent bound to plasma proteins, therefore it is not removed in significant quantities by dialysis.

Interaction:

Darunavir and ritonavir are inhibitors of the isoenzyme CYP3A4. Simultaneous use of a combination of darunavir / ritonavir and other drugs that are metabolized predominantly by isoenzyme CYP3A4, can cause an increase in the concentrations of such drugs in the plasma, which, in turn, may be the reason for the amplification or prolongation of their therapeutic effect, as well as the cause of side effects.

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

The combination of darunavir / ritonavir should not be used concurrently with drugs whose clearance is largely determined by the isoenzyme CYP3A4. and elevated concentrations of which in the plasma can cause serious and / or life-threatening side effects (narrow therapeutic range). These drugs include antihistamines (astemizole, terfenadine), alfuzosin, sildenafil (used for the therapy of pulmonary arterial hypertension), sedatives / hypnotics (triazolam, midazolam for oral administration), GI motility stimulants (cisapride), antipsychotics (pimozide, sertindole, quetiapine) and ergot alkaloids (for example, ergotamine, dihydroergotamine, ergometrine and methylergomethrin), antiarrhythmics (amiodarone, lidocaine (for systemic use), beprideal, quinidine).

It is not recommended to use the combination of darunavir / ritonavir concomitantly with lovastatin or simvastatin, since in the presence of the darunavir / ritonavir combination, a significant increase in the concentration of statins in the plasma is possible, which can lead to the development of myopathy, incl. rhabdomyolysis.

Rifampicin is a potent inducer of isoenzymes CYP450. The combination of darunavir / ritonavir should not be used concomitantly with rifampicin, since in such cases a significant reduction in the concentration of darunavir in plasma is possible. A consequence of this may be the loss of the therapeutic effect of darunavir.

It is not recommended to use the darunavir / ritonavir combination at the same time as the lopinavir / ritonavir combination, since there is a significant decrease in the concentration of darunavir in plasma in the presence of lopinavir / ritonavir.

The combination of darunavir / ritonavir should not be used concomitantly with preparations containing St. John's wort extract (perforated (Hypericum perforatum), t. this may be accompanied by a significant decrease in the concentration of darunavir in the plasma, so that the therapeutic effect of the drug darunavir may disappear. The simultaneous use of a combination of darunavir / ritonavir and drugs that are metabolized predominantly by isoenzyme CYP2D6 (e.g., flecainide, propafenone, metoprolol), can lead to an increase in the plasma concentrations of these drugs (due to inhibition of activity CYP2D6 ritonavir), which, in turn, may be the reason for the enhancement or prolongation of their therapeutic effect, as well as the cause of side effects

Recommendations for concurrent use with other antiretroviral drugs

Nucleoside / nucleotide reverse transcriptase inhibitors

Didanosine

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

Tenofovir

The results of the study of the interaction between tenofovir (tenofovir disoproxil fumarate 300 mg / day) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that the concentration of tenofovir in plasma increased by 22%. This change is not clinically significant. With the simultaneous use of tenofovir and darunavir, the renal excretion of both drugs did not change.

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

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

Non-nucleoside reverse transcriptase inhibitors

Etravirine

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

Efavirenz

A study was made of the interaction between the darunavir / ritonavir combination (300 mg / 100 mg twice daily) and efavirenz (600 mg once daily).

In the presence of efavirenz, the concentration of darunavir in plasma was decreased by 13%. On the other hand, the concentration of efavirenz in the blood plasma increased by 21% with its simultaneous use with a combination of darunavir / ritonavir. This interaction is not clinically relevant, so the combination of darunavir / ritonavir and efavirenz can be used simultaneously without correction of the doses of the drugs.

Nevirapine

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

Rilpivirine

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

Protease Inhibitors

Ritonavir

In general, the effect of optimizing the pharmacokinetics of darunavir ritonavir was manifested in the fact that the concentrations of darunavir in plasma increased approximately 14-fold after taking one dose of darunavir (600 mg) and 100 mg of ritonavir twice a day. Consequently, the Kemeruwir preparation should be used in combination with a low dose of ritonavir as an enhancer of the pharmacokinetics of darunavir.

The combination of lopinavir / ritonavir

The results of the study of the interaction between the darunavir / ritonavir combination (1200 mg / 100 mg twice daily) or 1200 mg of darunavir without ritonavir and the combination of lopinavir / ritonavir (400 mg / 100 mg twice daily or 533 / 133.3 mg twice a day day)that in the presence of a combination of lopinavir / ritonavir there is a decrease in the area under the pharmacokinetic curve "concentration-time" (AUC) of darunavir by 40%. It is not recommended to use a combination of lopinavir / ritonavir at the same time as the darunavir / ritonavir combination.

Saquinavir

The study of the interaction of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily) showed that in the presence of saquinavir and ritonavir, there was a decrease AUC, the minimum and maximum concentrations of darunavir by 26%, 42% and 17%, respectively. On the other hand, the combination of darunavir / ritonavir had no significant effect on saquinavir concentrations in plasma. It is not recommended to apply saquinavir simultaneously with darunavir, regardless of the use of a small additional dose of ritonavir.

Atazanavir

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

Indinavir

In a study of the interaction between darunavir / ritonavir (400 mg / 100 mg twice daily) and indinavir (800 mg twice daily), the concentration of darunavir in plasma increased by 24% in the presence of indinavir and ritonavir. In the presence of the darunavir / ritonavir combination, plasma concentrations of indinavir increased by 23%. When administered in combination with a darunavir / ritonavir combination, the dose of indinavir in patients who do not tolerate it can be reduced from 800 mg twice daily to 600 mg twice daily.

Other protease inhibitors

Until now, the interaction between the darunavir / ritonavir combination and protease inhibitors in addition to lopinavir, saquinavir, atazanavir and indinavir has not been studied, and therefore it is not recommended to apply the above-mentioned protease inhibitors simultaneously with the darunavir / ritonavir combination.

Receptor antagonists CCR5

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

Integrase inhibitors

When used concomitantly with a combination of darunavir / ritonavir decreases AUC raltegravir, there are no clinically significant deviations in the pharmacokinetic parameters of darunavir / ritonavir. Correction of the dose is not required.

Recommendations for simultaneous use with preparations of other classes

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

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

Digoxin

In all studies of the interaction of the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and digoxin in a single dose (400 μg), an increase in the final plasma digoxin concentration by 77% was demonstrated.It is recommended that a minimum dose of digoxin be initially prescribed and its serum concentration determined in order to obtain the desired clinical effect when given concomitantly with the darunavir / ritonavir combination.

Anticoagulants

The combination of darunavir / ritonavir can affect the concentrations of warfarin in the plasma. With the simultaneous use of warfarin and this combination, it is recommended to monitor the international normalized relationship (INR).

Anticonvulsant drugs (phenobarbital, phenytoin and carbamazepine)

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

The study of the interaction between the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the concentration of darunavir does not change in this case, while the concentration of ritonavir decreases by 49%.The concentration of carbamazepine is increased by 45%. Dose changes for the darunavir / ritonavir combination are not required. If it is necessary to simultaneously prescribe a combination of darunavir / ritonavir and carbamazepine, patients should be monitored for possible side effects of carbamazepine. It is necessary to monitor the concentration of carbamazepine in the blood plasma and adjust its dose in accordance with clinical manifestations. Thus, doses of carbamazepine can be reduced by 25-50% when given concomitantly with the darunavir / ritonavir combination.

Antidepressants (trazodone, desipramine)

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

Benzodiazepines (midazolam parenterally)

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

Antipsychotics

Risperidone, thioridazine

When these neuroleptics are combined with the darunavir / ritonavir combination, their concentrations in the plasma may increase. Therefore, with simultaneous use should reduce the dose of antipsychotic drugs (neuroleptics).

Pimozide

Darunavir / ritonavir can increase the exposure of pimozide and lengthen the interval QT. Pimozide is contraindicated in patients taking the darunavir / ritonavir combination,in connection with the high risk of development of life-threatening disturbances of the heart rhythm (see the section "Contraindications"),

Sertindole

With the simultaneous use of darunavir / ritonavir and sertindole, an increase in the serotindol concentration in the plasma is possible. therefore sertindole It is not recommended to apply simultaneously with a combination of darunavir / ritonavir because of the potential danger of lengthening the interval QT and the development of violations of the heart rate (see the section "Contraindications"),

Quetiapine

When used simultaneously with darunavir / ritonavir, an increase in the concentration of quetiapine in the plasma (due to inhibition CYP3A). Because of the possible increased toxic effects of quetiapine and the risk of coma, concurrent administration of quetiapine and a combination of darunavir / ritonavir is contraindicated.

Anti-malarial drugs

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

Colchicine

With the simultaneous use of colchicine with a combination of darunavir / ritonavir, colchicine concentration in the blood plasma can increase. The following scheme for changing the dose of colchicine is recommended. For therapy of gout exacerbations in patients receiving the darunavir / ritonavir combination, the recommended dose of colchicine is 0.6 mg, followed by 0.3 mg after 1 hour. The course of treatment should be repeated no earlier than 3 days later. To prevent gout exacerbations in patients receiving the darunavir / ritonavir combination, the recommended dose of colchicine is 0.3 mg every other day or every other day. For the treatment of familial Mediterranean fever in patients receiving the darunavir / ritonavir combination, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg twice daily).Patients with reduced renal or hepatic function should not be prescribed colchicine simultaneously with a combination of darunavir / ritonavir.

Blockers of slow calcium channels

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

Clarithromycin

The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and clarithromycin (500 mg twice daily) showed that the concentration of clarithromycin in the plasma increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function, it is recommended to reduce the dose of clarithromycin.

Dexamethasone

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

Boszentan

With the simultaneous use of bosentan and the combination of darunavir / ritonavir, the concentration of bosentan in the blood plasma can increase. Patients receiving a darunavir / ritonavir combination for at least 10 days are recommended an initial dose of 62.5 mg bosentan every day or every other day, depending on individual tolerability. For patients receiving bosentan and initiating therapy with a combination of darunavir / ritonavir, it is recommended to cancel bosentan at least 36 hours before the start of therapy with darunavir / ritonavir. At least 10 days after initiation of therapy with darunavir / ritonavir should continue taking bosentan at a dosage of 62.5 mg every other day or every other day, depending on individual tolerability.

Fluticasone propionate, budesonide

With the simultaneous use of inhalation fluticasone propionate and the combination of darunavir / ritonavir, an increase in the concentration of fluticasone propionate in the blood plasma is possible. A similar interaction can be observed with the use of other corticosteroids metabolized by the isoenzyme CYP3A4, for example budesonide.It is advisable to use drugs alternative to fluticasone propionate, which are not a substrate of isoenzyme CYP3A4 (e.g., beclomethasone).

Antiviral drugs of direct action

Inhibitors NS 3-4 A hepatitis C proteases

Boceprevir

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

Telaprevir

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

Preparations from the group of statins

In the metabolism of statins, such as simvastatin, rosuvastatin and lovastatin, an important role is played by the isoenzyme CYP3A4, therefore their concentrations in plasma can increase significantly when applied simultaneously with the darunavir / ritonavir combination.Stalines at elevated concentrations are capable of causing myopathy, including rhabdomyolysis.

It is not recommended to use the combination of darunavir / ritonavir concomitantly with lovastatin or simvastatin.

The study of the interaction between atorvastatin (10 mg once a day) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that in this situation the concentration of atorvastatin in plasma was only 15% lower than with monotherapy with atorvastatin ( 40 mg once a day). If it is necessary to simultaneously use atorvastatin and a combination of darunavir / ritonavir, it is recommended to start with a dose of atorvastatin 10 mg once a day. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy.

The combination of darunavir / ritonavir (600 mg / 100 mg twice daily) increased the concentration of pravastatin in plasma after taking one dose of this drug (40 mg) by about 80%, but only in a part of the patients. If it is necessary to co-administer pravastatin and a combination of darunavir / ritonavir, it is recommended to start taking pravastatin from the lowest possible doses and increase the dose until the clinical effect appears, controlling the manifestation of the side effects of the drug.The study of the interaction between rosuvastatin (10 mg) and the combination of darunavir / ritonavir (600 mg / 100 mg) revealed an increase in the concentration of rosuvastatin. If a rosuvastatin and a combination of darunavir / ritonavir are required, rosuvastatin should be taken with the lowest dose. Then the dose of rosuvastatin can be gradually increased until the appearance of a clinical effect, constantly monitoring the safety of therapy.

Antagonists of histamine H₂-receptor and proton pump inhibitors

The use of omeprazole (20 mg once daily) or ranitidinia (150 mg twice daily) along with the combination of darunavir / ritonavir (400 mg / 100 mg twice daily) did not affect the concentration of darunavir in plasma. Given this, a combination of darunavir / ritonavir can be used concomitantly with histamine antagonists H₂- receptors and proton pump inhibitors without changing the dose of any of these drugs.

Inhalation beta-adrenomimetics (salmeterol)

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

Immunosuppressants (ciclosporin, tacrolimus, sirolimus)

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

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

Ketoconazole, itraconazole and voriconazole

Ketoconazole, itraconazole and voriconazole are strong inhibitors of the isoenzyme CYP3A4, as well as its substrates. Systemic use of ketoconazole, itraconazole, and voriconazole concomitantly with the combination of darunavir / ritonavir can lead to an increase in darunavir plasma concentrations. On the other hand, this combination can increase plasma concentrations of ketoconazole or itraconazole. This was confirmed by a study of the interaction between ketoconazole (200 mg twice daily) and a combination of darunavir / ritonavir (400 mg / 100 mg twice daily) in which concentrations of ketoconazole and darunavir increased 212% and 42%, respectively.

If a darunavir / ritonavir combination is required simultaneously with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg.Concentrations of voriconazole in plasma may decrease when combined with darunavir / ritonavir. Voriconazole should not be used concomitantly with darunavir / ritonavir, concurrent use is only possible if the potential benefits of using voriconazole exceed the potential risk.

Clotrimazole

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

Beta-blockers (metoprolol, timolol)

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

Methadone

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

Buprenorphine / naloxone

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

Estrogen-containing oral contraceptives

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

Inhibitors of phosphodiesterase type 5 (PDE-5)

When treating erectile dysfunction

One study examined sildenafil concentrations after taking one dose of this drug (100 mg), and after taking 25 mg of sildenafil concomitantly with the darunavir / ritonavir combination (400 mg / 100 mg twice daily). The concentrations of sildenafil were similar in both situations. Caution is required when concurrent use of PDE-5 inhibitors for the treatment of erectile dysfunction and the combination of darunavir / ritonavir. If a darunavir / ritonavir combination is required, together with sildenafil, vardenafil or tadalafil, a single dose of sildenafil should not exceed 25 mg within 48 hours, a single dose of vardenafil should not exceed 2.5 mg within 72 hours, and a single dose of tadalafil should not exceed 10 mg for 72 hours.

In the treatment of pulmonary arterial hypertension

A safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension has not been established. There is an increased risk of side effects of sildenafil (including visual impairment, arterial hypotension, prolonged erection and fainting). Thus, simultaneous use of the combination of darunavir / ritonavir and sildenafil in the treatment of pulmonary arterial hypertension is contraindicated. For the treatment of pulmonary arterial hypertension, tadalafil, when used concomitantly with the darunavir / ritonavir combination, requires correction of doses of tadalafil. For patients receiving a darunavir / ritonavir combination for at least one week, the initial dose of tadalafil should be 20 mg once daily, with a possible increase to 40 mg once daily based on individual tolerability. For patients receiving tadalafil and initiating therapy with a combination of darunavir / ritonavir, it is recommended to cancel tadalafil at least 24 hours before the start of therapy with a combination of darunavir / ritonavir. It should avoid simultaneous use of tadalafil within the first weektreatment with a combination of darunavir / ritonavir. 1 week after starting therapy with darunavir / ritonavir Tadalafil administration should be resumed at a dosage of 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerability.

Rifabutin

Rifabutin is an inducer and substrate of isoenzymes CYP450. In studies of the interaction of the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and rifabutin (150 mg every other day), the concentration of darunavir increased by 57%. Based on the safety profile of the darunavir / ritonavir combination, an increase in the concentration of darunavir in the presence of rifabutin does not require a dose adjustment for the darunavir / ritonavir combination. The study of the interaction showed comparable concentrations with rifabutin 300 mg once daily and 150 mg every other day with a combination of darunavir / ritonavir (600 mg / 100 mg twice daily) and an increase in the concentration of the active metabolite 25-0- deacetyltrifabutin. When this combination is prescribed, a reduction in the dose of rifabutin by 75% of the usual dose of 300 mg per day and an increased control of the side effects of rifabutin are required.

Selective serotonin reuptake inhibitors

Investigation of the interaction between paroxetine (20 1 mg once a day) or sertraline (50 1 mg once a day) and a combination of darunavir / ritonavir (400 mg / 100 mg twice a day) showed that darunavir plasma concentration was independent of sertraline presence or paroxetine. On the other hand, in the presence of the darunavir / ritonavir combination, plasma concentrations of sertraline and paroxetine decreased by 49% and 39%, respectively. If necessary, the simultaneous application of a combination of darunavir / ritonavir should be carefully titrate doses of selective serotonin reuptake inhibitors in the clinical evaluation of antidepressant effect. In addition, patients receiving a stable dose of sertraline or paroxetine, who are being treated with the darunavir / ritonavir combination, should carefully monitor the severity of the underlying effect of the antidepressant.

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 plasma after taking a single dose of 600 mg in combination with ritonavir (100 mg twice daily). In this way, darunavir should be taken only in combination with a low dose of ritonavir (100 mg) as a pharmacokinetic enhancer. An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma, so a dose of ritonavir should not be increased.

Severe skin reactions

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

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

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

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

Patients with 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), consider the possibility interruption or withdrawal of 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, the onset of combined antiretroviral therapy may result in an inflammatory response to asymptomatic orresidual opportunistic infections, which causes severe 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.

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:

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

For 6 or 10 contour packagings together with the instructions 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 not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:4 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002448

Date of registration:28.05.2014

Expiration Date:28.05.2019

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC

Information update date: & nbsp28.12.2017

Illustrated instructions

Instructions

Kemeruwir® (KEMERUVIR®)