Description of the active substance:
This information is a reference and it is not enough that the drug was prescribed by a doctor. .
PHARMACHOLOGIC EFFECT
Antiviral agent, HIV protease inhibitor type 1 (HIV-1). Darunavir is an inhibitor of dimerization and catalytic activity of HIV-1 protease. Selectively inhibits the cleavage of polyproteins Gag-Pol HIV in virus-infected cells, preventing the formation of full-fledged viral particles.
Darunavir is strongly linked by HIV-1 pro-therapy (K D 4.5 x 10 -12 M). 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? 1- acid glycoprotein in patients infected with HIV-1. Because of this, large amounts of darunavir are associated with? 1- acid plasma glycoprotein.
Darunavir is extensively metabolized in the liver mainly by CYP3A isoenzymes. Ritonavir inhibits CYP3A isoenzymes in the liver and, thereby, significantly increases the concentration of darunavir in plasma.
After ingestion, darunavir is rapidly absorbed from the digestive tract. C max of darunavir in plasma in the presence of a low dose of ritonavir is achieved through 2.5-4.0 hours. The absolute bioavailability of darunavir ingestion in a single dose of 600 mg was about 37% and increased to about 82% in the presence of ritonavir (100 mg 2 times / day). The general pharmacokinetic effect of ritonavir consisted in approximately 14-fold increase in the concentration of darunavir in plasma after ingestion of 600 mg of darunavir in combination with ritonavir (100 mg 2 times / day). When taking an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir was 30% lower than when taken with meals. The nature of the food did not affect the concentration of darunavir in the plasma.
The binding of darunavir to plasma proteins (predominantly with the О±1-acid glycoprotein) is about 95%.
In experiments in vitro on human liver microsomes, it has been shown that darunavir is primarily oxidative metabolism. Darunavir is extensively metabolized in the liver by the P450 enzyme system, almost exclusively by the CYP3A4 isoenzyme. A study in which healthy volunteers took 14 C-darunavir showed that most of the radioactivity in the plasma after a single dose of 400 mg of darunavir and 100 mg of ritonavir was accounted for by the unchanged darunavir. In humans, at least 3 oxidative metabolites of darunavir have been identified; whose activity against wild-type HIV was less than 1/10 of that of darunavir itself.
After one administration of 14 C-darunavir in a dose of 400 mg and ritonavir at a dose of 100 mg of about 79.5% and 13.9% of radioactivity was detected in feces and urine, respectively. The proportion of unchanged darunavir accounted for about 41.2% and 7.7% of radioactivity in feces and urine, respectively.
The final T 1/2 of darunavir was about 15 hours when taken in combination with ritonavir. The clearance of darunavir after IV injection at a dose of 150 mg was 32.8 l / hr without ritonavir and 5.91 l / h in the presence of a low dose of ritonavir.
INDICATIONS
Treatment of HIV infection in adult patients (in combination with low-dose ritonavir and other antiretroviral drugs).
DOSING MODE
Is taken internally. Dunavir is always used in combination with ritonavir in a low dose (100 mg) 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 starting therapy with the darunavir / ritonavir combination.
For patients who have not previously received protease inhibitors, the recommended dose of daunavir is 800 mg 1 time / day in combination with ritonavir at a dose of 100 mg 1 time / day.
For patients who previously received protease inhibitors, the recommended dose of darunavir is 600 mg 2 times / day in combination with ritonavir at a dose of 100 mg 2 times / day; a combination is taken during a meal.
The combination of darunavir / ritonavir should be used with caution in patients with severe impairment of liver function.
SIDE EFFECT
From the nervous system: headache.
Mental disorders: unusual dreams.
On the part of the digestive system: abdominal pain acute pancreatitis, diarrhea, dyspepsia, flatulence, nausea, vomiting, increased activity of ALT, AST, APF, acute hepatitis
Dermatological reactions: lipodystrophy (including lipohydrophy and lipoatrophy), itching, rash, Stevens-Johnson syndrome.
From the musculoskeletal system: myalgia, in patients receiving protease inhibitors, especially in combination with non-nucleoside reverse transcriptase inhibitors, an increase in the level of CK, myositis; rarely rhabdomyolysis.
From the metabolism: anorexia, diabetes.
From the immune system: a syndrome of immune reactivation.
From the side of metabolism: increase in the content of TG, total cholesterol, LDL cholesterol, glucose, pancreatic lipase, pancreatic amylase.
Infections: In HIV-infected patients with severe immunodeficiency during the initial combination antiretroviral therapy, inflammatory responses to asymptomatic or residual opportunistic infections are possible.
Common reactions: asthenia, fatigue.
CONTRAINDICATIONS
Simultaneous administration with drugs, the clearance of which is predominantly determined by the isoenzyme CYP3A4, and the increase in plasma concentration is associated with serious and / or life-threatening side effects (narrow therapeutic range) with astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergometrine); children and adolescents under 18; increased sensitivity to darunavir.
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical studies of the safety of darunavir during pregnancy have not been conducted. The combination of darunavir / ritonavir can be given to pregnant women only when the expected benefit of therapy for the mother exceeds the potential risk to the fetus.
It is not known whether darunavir is excreted in human milk. Given the possibility of HIV transmission in breast milk, as well as the risk of serious side effects in infants related to the effects of darunavir, HIV-infected women receiving darunavir should refrain from breastfeeding.
SPECIAL INSTRUCTIONS
Use with caution in patients with impaired liver function, with allergies to sulfonamides (because darunavir contains a sulfonamide group).
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 600 mg was approximately 37% and increased to approximately 82% after taking darunavir in combination with 100 mg ritonavir 2 times / day. The overall effect of improving the pharmacokinetic characteristics of darunavir ritonavir was approximately 14-fold increase in the concentration of darunavir in plasma after taking one dose of this drug (600 mg) in combination with 100 mg of ritonavir 2 times / day. Therefore, darunavir should be used only in combination with 100 mg of ritonavir in order to optimize pharmacokinetics.
An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma, and therefore a dose of ritonavir is not recommended to be increased.
In patients with liver disease including chronic active hepatitis, the frequency of hepatic impairment may increase during combined antiretroviral therapy, and therefore it is necessary to monitor biochemical indicators in accordance with standard practice. If any signs of worsening liver function are detected in such patients, treatment with a darunavir / ritonavir combination should be suspended or reversed.
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.
DRUG INTERACTION
Darunavir and ritonavir are inhibitors of the CYP3A isoenzyme. The simultaneous use of the darunavir / ritonavir combination and drugs that are metabolized predominantly by the CYP3A isoenzyme may cause an increase in the concentrations of such drugs in the plasma, which in turn may cause a prolongation or prolongation of the therapeutic effect, as well as side effects.
Darunavir is metabolized by CYP3A isoenzymes. Simultaneous administration of drugs inducing CYP3A activity may increase the clearance of darunavir, resulting in a decrease in the concentration of darunavir in plasma. Simultaneous administration of darunavir with CYP3A inhibitors can reduce the clearance of darunavir, resulting in an increased concentration of darunavir in plasma.
The combination of darunavir / ritonavir should not be used concurrently with drugs whose clearance is largely determined by the CYP3A4 isoenzyme and whose elevated plasma concentrations can cause serious and / or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide and ergot alkaloids (eg, ergotamine, dihydroergotamine, ergometrine and methylergometrine).
Rifampicin is a strong inducer of CYP450 isoenzymes. The combination of darunavir / ritonavir should not be used concomitantly with rifampicin, since in such cases a marked decrease in the concentration of darunavir in plasma is possible. As a consequence, the therapeutic effect of darunavir may disappear.
The combination of darunavir / ritonavir should not be used concomitantly with preparations containing Hypericum perforatum extract, Hypericum perforatum. this may be accompanied by a marked decrease in the concentration of darunavir in the plasma, as a result of which the disappearance of the therapeutic effect of darunavir is possible.
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 2 times / day. Therefore, darunavir should be used in combination with 100 mg of ritonavir in order to improve the pharmacokinetic characteristics of darunavir.
The results of the study of the interaction between the darunavir / ritonavir combination (300 mg / 100 mg 2 times / day) and the combination of lopinavir / ritonavir (400 mg / 100 mg 2 times / day) showed that in the presence of lopinavir / ritonavir combination (with or without use an additional dose of ritonavir 100 mg), the concentration of darunavir in plasma increased by 53%. In the presence of a single darunavir, the concentration of lopinavir in plasma decreased by 19%, and in the presence of a combination of darunavir / ritonavir increased by 37%. It is not recommended to use the combination of lopinavir / ritonavir simultaneously with darunavir, regardless of taking a small additional dose of ritonavir.
The study of the interaction of darunavir (400 mg 2 times / day), saquinavir (1000 mg 2 times / day) and ritonavir (100 mg 2 times / day) showed that the concentration of darunavir in plasma increased by 26% in the presence of saquinavir and ritonavir; on the other hand, the combination of darunavir / ritonavir did not affect the concentration of saquinavir in plasma. It is not recommended to use saquinavir at the same time as darunavir, regardless of the use of a small additional dose of ritonavir.
When investigating the interaction between the darunavir / ritonavir combination (400 mg / 100 mg 2 times / day) and atazanavir (300 mg 1 time / day), there was no significant change in the concentrations of darunavir and atazanavir in plasma when they were used simultaneously. Atazanavir can be used concurrently with a combination of darunavir / ritonavir.
In a study of the interaction between darunavir / ritonavir (400 mg / 100 mg 2 times / day) and indinavir (800 mg 2 times / day), 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 2 times / day to 600 mg 2 times / day.
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, protease inhibitors not listed here should not be used concomitantly with the darunavir / ritonavir combination.
If the combination of darunavir / ritonavir maraviroc is used concomitantly, a dose of 150 mg should be given 2 times / day. In a study of the interaction between the darunavir / ritonavir combination (600 mg / 100 mg 2 times / day) and maraviroc (150 mg 2 times / day), the concentration of maraviroc increased to 305%. The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.
The combination of darunavir / ritonavir can increase plasma concentrations of bepristil, lidocaine (with systemic administration), quinidine and amiodarone, flecainide and propafenone. Therefore, with the simultaneous use of the darunavir / ritonavir combination and listed antiarrhythmics, care should be taken and, if possible, monitoring of their concentrations in the blood plasma.
In all studies of the interaction of the darunavir / ritonavir combination (600/100 mg 2 times / day) and digoxin in a single dose (400 Ојg), an increase in the final concentration of digoxin in plasma by 77% was shown. It is recommended that a minimum dose of digoxin be initially administered and its serum concentration determined in order to obtain the desired clinical effect with simultaneous administration with this combination.
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 INR.
Phenobarbital, phenytoin and carbamazepine are inducers of CYP450 isoenzymes. The combination of darunavir / ritonavir is not recommended in combination with these drugs, as it 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 (600/100 mg 2 times / day) and carbamazepine (200 mg 2 times / day) showed that the concentration of darunavir in this case does not change, while the concentration of ritonavir decreases by 49%. The concentration of carbamazepine is increased by 45%. Changes in the dose of the darunavir / ritonavir combination are not required. If simultaneous use of the darunavir / ritonavir and carbamazepine combination is necessary, the 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.
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. If the use of these drugs and the combination of darunavir / ritonavir is necessary, caution should be considered, and the use of trazodone and desipramine in smaller doses should be considered, especially in the case of prolonged therapy.
With the simultaneous use of a combination of darunavir / ritonavir with parenterally administered midazolam may increase the concentration of midazolam in the plasma. When combined, careful clinical monitoring should be undertaken and immediate action should be taken in the event of respiratory depression 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.
With the combined use of neuroleptics with a combination of darunavir / ritonavir, their concentrations in the plasma may increase. Therefore, while the application should be reduced doses of antipsychotics (neuroleptics).
The plasma concentrations of calcium channel blockers (e.g. felodipine, nifedipine, nicardipine) may increase when the simultaneous use of a combination of darunavir / ritonavir. In such situations, you need to closely monitor the patient's condition.
Investigation of the interaction between a combination of darunavir / ritonavir (400 mg / 100 mg, 2 times / day) and clarithromycin (500 mg, 2 times / day) showed that the plasma concentration of clarithromycin was increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function is recommended to reduce the dose of clarithromycin.
Dexamethasone at entry into the bloodstream induces CYP3A4 isoenzyme in the liver and thus reduces the plasma concentration of darunavir. This can lead to a decrease in therapeutic effect of darunavir. We recommend caution, while the use of darunavir and dexamethasone.
With simultaneous use of inhaled fluticasone propionate, and combinations of darunavir / ritonavir may increase the concentration of fluticasone propionate in plasma. A similar interaction may occur when using other corticosteroids metabolized isoenzyme CYP3A4, such as budesonide. It is advisable to use preparations of fluticasone propionate alternative non-substrate CYP3A4 (e.g., beclomethasone).
The metabolism of statins, such as simvastatin, lovastatin and rosuvastatin, plays an important role isoenzyme CYP3A4, therefore the plasma concentrations can increase substantially simultaneously with the application of a combination of darunavir / ritonavir. It is not recommended to use a combination of darunavir / ritonavir concomitantly with lovastatin, rosuvastatin or simvastatin because of the increased risk of myopathy, including rhabdomyolysis.
Investigation of the interaction between atorvastatin (10 mg 1 time / day) and a combination of darunavir / ritonavir (300 mg / 100 mg, 2 times / day) showed that in this situation, the concentration of atorvastatin in plasma was only 15% lower than with monotherapy with atorvastatin ( 40 mg 1 time / day). If necessary, the simultaneous application of a combination of atorvastatin and darunavir / ritonavir recommended starting dose of atorvastatin 10 mg 1 time / 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, 2 times / day) increased the concentration of pravastatin in plasma after a single dose of the drug (40 mg) at approximately 80%, but in some patients. If necessary, concomitant administration of pravastatin and combinations of darunavir / ritonavir is recommended to start receiving pravastatin with the lowest possible dose and increase the dose until a clinical effect, controlling the side effects of the drug.
Omeprazole (20 mg 1 time / day) or ranitidine (150 mg, 2 times / day) together with a combination darunanir / ritonavir (400 mg / 100 mg, 2 times / day) had no effect on plasma concentrations of darunavir. Given this, the combination of darunavir / ritonavir can be used in conjunction with antagonists of the histamine H2receptor antagonists and proton pump inhibitors without changing any of the doses of these drugs.
Concentrations in plasma cyclosporine, tacrolimus and sirolimus may increase in the case of use of these drugs simultaneously with a combination of darunavir / ritonavir. In these situations, it is recommended to monitor the concentration of an immunosuppressant in the plasma.
Ketoconazole, itraconazole and voriconazole are potent inhibitors of isoenzyme CYP3A4, as well as its substrates. Systemic administration of ketoconazole, itraconazole and voriconazole simultaneously with a combination of darunavir / ritonavir can lead to increased plasma concentrations of darunavir. On the other hand, this combination may increase the plasma concentrations of ketoconazole or itraconazole. This was confirmed by the study of the interaction between ketoconazole (200 mg, 2 times / day) and a combination of darunavir / ritonavir (400 mg / 100 mg, 2 times / day), wherein the concentration of ketoconazole and darunavir increased by 212% and 42% respectively. If necessary, use a combination of darunavir / ritonavir simultaneously with ketoconazole or itraconazole last daily dose should not exceed 200 mg.The concentrations of voriconazole in plasma may be reduced when combined with darunovirom / ritonavir. Voriconazole should not be used concurrently with darunovirom / ritonavir, simultaneous use is possible only if the potential benefits from the use of voriconazole outweighs the potential risk.
With the simultaneous application of a combination darunavir / ritonavir with beta-blockers may increase the concentration of beta-blockers. With the simultaneous use of these drugs and combinations darunavir / ritonavir should be careful to carry out careful clinical monitoring may also be necessary to decrease the dose of beta-blockers.
In the combination study the influence darunavir / ritonavir (600/100 mg of 2 times / day) on stable methadone maintenance therapy, has been shown to decrease by 16% R-methadone concentration in plasma. Based on the pharmacokinetic and clinical results, methadone dose correction during initiation of therapy combination darunavir / ritonavir is required. However, the recommended clinical monitoring, since in some patients, maintenance therapy requires correction.
Results of the study of interaction combination darunavir / ritonavir with buprenorphine / naloxone combination shows no effect darunavir / ritonavir at concentration of buprenorphine in their joint application. The concentration of the active metabolite of buprenorphine - norbuprenorfina increased by 46%. Dose adjustment of buprenorphine was required. When co-administered combination of darunavir / ritonavir and buprenorphine recommended careful clinical monitoring.
The study results on the interaction between a combination of darunavir / ritonavir (600/100 mg of 2 times / day) and ethinyl estradiol and norethisterone indicate that the C ssplasma ethinyl estradiol and norethisterone, respectively reduced by 44% and 14%. When applying the combination of darunavir / ritonavir is recommended to use alternative methods of hormonal contraception.
One study investigated the concentration of sildenafil after receiving a single dose of 100 mg, and upon receiving 25 mg sildenafil simultaneously with a combination of darunavir / ritonavir (400 mg / 100 mg, 2 times / day). Concentration of sildenafil were similar in both situations. caution is required while the use of PDE5 inhibitors and combinations darunavir / ritonavir. If necessary, use a combination of darunavir / ritonavir simultaneously with sildenafil, vardenafil or tadalafil single dose of sildenafil should not exceed 25 mg for 48 hours, a single dose of Vardenafil should not be more than 2.5 mg for 72 h, and a single dose of tadalafil should not exceed 10 mg for 72 hours.
Rifabutin is an inducer and substrate isoenzymes CYP450. When studying the interaction combination darunavir / ritonavir (600/100 mg of 2 times / day) and rifabutin (150 mg every other day) was observed increase darunavir concentration of 57%. Based on the safety profile of the combination of darunavir / ritonavir, darunavir concentration increase in the presence of rifabutin does not require correction for a combination of doses darunavir / ritonavir. Study of the interaction showed comparable concentration when using a dose of rifabutin of 300 mg 1 time / day and 150 mg a day in combination with a combination of darunavir / ritonavir (600/100 mg of 2 times / day) and increasing concentrations of the active metabolite 25-O-dezatsetilrifabutina . In applying such a combination of rifabutin required dose reduction by 75% of the usual dose of 300 mg / day and increased control of side effects of rifabutin.
Investigation of the interaction between paroxetine (20 mg 1 time / day) or sertraline (50 mg 1 time / day) and a combination of darunavir / ritonavir (400 mg / 100 mg, 2 times / day) showed that darunavir concentrations were independent of sertraline presence in plasma or paroxetine. On the other hand, in the presence of a combination of darunavir / ritonavir plasma concentration of sertraline and paroxetine decreased by 49% and 39% respectively. If necessary, the simultaneous application of a combination of darunavir / ritonavir, dose must be carefully selected selective serotonin reuptake inhibitor, based on the clinical assessment of antidepressant action. In addition, patients receiving a stable dose of sertraline or paroxetine who start to treat the combination of darunavir / ritonavir,you must carefully control the intensity of the main effect of the antidepressant.
