Darunavir, 400 mg 60 pcs

Darunavir

Indications

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

Pharmacological effect

Pharmacotherapeutic group: Antiviral [HIV] agent

Pharmacological action

Antiviral agent, HIV type 1 protease inhibitor (HIV-1). Darunavir is an inhibitor of dimerization and catalytic activity of HIV-1 protease. Selectively inhibits the cleavage of HIV Gag-Pol polyproteins in virus-infected cells, preventing the formation of full-fledged viral particles.

Darunavir binds strongly to HIV-1 protease (KD 4.5 x 10-12M). Darunavir is resistant to mutations causing protease inhibitor resistance.

Darunavir does not inhibit any of the 13 human cellular proteases tested.

Pharmacokinetics

The pharmacokinetic properties of darunavir, used in combination with ritonavir, were studied in healthy volunteers and in HIV-infected patients.

Plasma concentrations of darunavir were higher in patients infected with HIV-1 than in healthy controls. This difference may be explained by higher concentrations of α1-acid glycoprotein in patients infected with HIV-1. As a result, large amounts of darunavir bind to plasma α1-acid glycoprotein.

Darunavir is extensively metabolized in the liver mainly by CYP3A isoenzymes. Ritonavir inhibits CYP3A isoenzymes in the liver and thereby significantly increases the plasma concentration of darunavir.

After oral administration, darunavir is rapidly absorbed from the gastrointestinal tract. Cmax 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 darunavir when administered orally in a single dose of 600 mg was about 37% and increased to approximately 82% in the presence of ritonavir (100 mg 2 times / day). The overall pharmacokinetic effect of ritonavir was an approximately 14-fold increase in darunavir plasma concentrations following a single oral dose of 600 mg of darunavir in combination with ritonavir (100 mg twice daily). When administered on an empty stomach, the relative bioavailability of darunavir in the presence of low dose ritonavir was 30% lower than when administered with food. The nature of the meal did not affect the plasma concentrations of darunavir.

The binding of darunavir to plasma proteins (mainly α1-acid glycoprotein) is about 95%.

In vitro experiments on human liver microsomes showed that darunavir undergoes predominantly 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 14C-darunavir found that most of the radioactivity in plasma after a single dose of 400 mg darunavir and 100 mg ritonavir was from unchanged darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; whose activity against wild type HIV was less than 1/10 that of darunavir itself.

After a single dose of 14C-darunavir 400 mg and ritonavir 100 mg, approximately 79.5% and 13.9% of radioactivity was detected in feces and urine, respectively. 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 at a dose of 150 mg was 32.8 l/h without ritonavir and 5.91 l/h in the presence of a low dose of ritonavir.

Special instructions

Use with caution in patients with impaired liver function or allergy to sulfonamides (since darunavir contains a sulfonamide group).

Patients should be informed that current antiretroviral drugs do not cure HIV infection or prevent HIV transmission. Patients should be advised of the need to take appropriate precautions.

Information on treatment with the darunavir/ritonavir combination in patients aged 65 years and older is very limited. Caution is required when treating patients in this age group with darunavir, since they are more likely to experience 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 administration of darunavir in combination with 100 mg ritonavir twice daily. The total effect of improving the pharmacokinetic characteristics of darunavir with ritonavir was expressed in an approximately 14-fold increase in the concentration of darunavir in plasma after taking a single dose of this drug (600 mg) in combination with 100 mg of ritonavir 2 times a day. Therefore, darunavir should only be used in combination with 100 mg ritonavir to optimize pharmacokinetics.

Increasing the indicated dose of ritonavir does not lead to a significant increase in plasma concentrations of darunavir, and therefore it is not recommended to increase the dose of ritonavir.

In patients with liver disease, including chronic active hepatitis, the incidence of liver dysfunction may be increased during combination antiretroviral therapy and therefore biochemical parameters should be monitored in accordance with standard practice. If signs of deterioration in liver function are detected in such patients, treatment with the darunavir/ritonavir combination should be suspended or completely discontinued.

The kidneys play a minor role in the clearance of darunavir, therefore, in patients with kidney disease, the overall clearance of darunavir is practically not reduced. Darunavir and ritonavir are highly bound to plasma proteins, so hemodialysis or peritoneal dialysis does not play a significant role in removing these drugs from the body.

Active ingredient

Darunavir

Composition

Active substance: darunavir 400 mg

Excipients: microcrystalline cellulose – 389.166 mg, colloidal silicon dioxide – 16.677 mg, crospovidone – 25 mg, magnesium stearate – 2.5 mg.

Pregnancy

Adequate and strictly controlled clinical studies of the safety of darunavir during pregnancy have not been conducted. The darunavir/ritonavir combination can be prescribed to pregnant women only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

It is not known whether darunavir is excreted into breast milk in humans. Given the possibility of transmission of HIV through breast milk, and the risk of serious side effects in nursing infants associated with exposure to darunavir, HIV-infected women receiving darunavir should avoid breastfeeding.

Contraindications

Concomitant use with drugs whose clearance is predominantly determined by the CYP3A4 isoenzyme, and an increase in plasma concentrations of which is associated with the occurrence of serious and/or life-threatening side effects (narrow therapeutic range) – with astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, drugs containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergometrine); children and adolescents up to 18 years of age; hypersensitivity to darunavir.

Side Effects

From the nervous system: headache.

Mental disorders: unusual dreams.

From the digestive system: abdominal pain, acute pancreatitis, diarrhea, dyspepsia, flatulence, nausea, vomiting, increased activity of ALT, AST, alkaline phosphatase, acute hepatitis

Dermatological reactions: lipodystrophy (including lipohypertrophy 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, increased CPK levels and myositis are possible; rarely – rhabdomyolysis.

Metabolic disorders: anorexia, diabetes mellitus.

From the immune system: immune reactivation syndrome.

Metabolism: increased levels of TG, total cholesterol, LDL cholesterol, glucose, pancreatic lipase, pancreatic amylase.

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

General reactions: asthenia, fatigue.

Interaction

Darunavir and ritonavir are inhibitors of the CYP3A isoenzyme. Concomitant use of the darunavir/ritonavir combination and drugs that are predominantly metabolized by the CYP3A isoenzyme may cause an increase in plasma concentrations of such drugs, which, in turn, may cause an increase or prolongation of the therapeutic effect, as well as side effects.

Darunavir is metabolized by CYP3A isoenzymes. Concomitant use of drugs that induce CYP3A activity may increase the clearance of darunavir, resulting in a decrease in the plasma concentration of darunavir. Concomitant use of darunavir with CYP3A inhibitors may reduce the clearance of darunavir, resulting in increased plasma concentrations of darunavir.

The darunavir/ritonavir combination should not be used concomitantly with drugs whose clearance is largely determined by the CYP3A4 isoenzyme and whose elevated plasma concentrations may cause serious and/or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, and ergot alkaloids (such as ergotamine, dihydroergotamine, ergometrine, and methylergometrine).

Rifampicin is a strong inducer of CYP450 isoenzymes. The darunavir/ritonavir combination should not be used concomitantly with rifampicin, since in such cases a marked decrease in darunavir plasma concentrations may occur. As a result, the therapeutic effect of darunavir may disappear.

The darunavir/ritonavir combination cannot be used simultaneously with drugs containing St. John’s wort (Hypericum perforatum) extract, because this may be accompanied by a marked decrease in the plasma concentration of darunavir, which may result in the disappearance of the therapeutic effect of darunavir.

Overall, the effect of optimizing the pharmacokinetics of darunavir with ritonavir was that darunavir plasma concentrations increased approximately 14-fold after taking one dose of darunavir (600 mg) and 100 mg ritonavir 2 times a 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 an interaction study between the darunavir/ritonavir combination (300 mg/100 mg twice daily) and the lopinavir/ritonavir combination (400 mg/100 mg twice daily) showed that in the presence of the lopinavir/ritonavir combination (with or without the use of an additional dose of ritonavir 100 mg), plasma concentrations of darunavir increased by 53%. In the presence of darunavir alone, the plasma concentration of lopinavir decreased by 19%, and in the presence of the darunavir/ritonavir combination it increased by 37%. It is not recommended to use the lopinavir/ritonavir combination concomitantly with darunavir, regardless of taking a small additional dose of ritonavir.

An interaction study of darunavir (400 mg 2 times/day), saquinavir (1000 mg 2 times/day) and ritonavir (100 mg 2 times/day) showed that plasma concentrations of darunavir increased by 26% in the presence of saquinavir and ritonavir; on the other hand, the darunavir/ritonavir combination had no effect on saquinavir plasma concentrations. It is not recommended to use saquinavir concomitantly with darunavir, regardless of the use of a small additional dose of ritonavir.

A study of the interaction between the combination of darunavir/ritonavir (400 mg/100 mg 2 times/day) and atazanavir (300 mg 1 time/day) showed no significant change in the concentrations of darunavir and atazanavir in plasma when used simultaneously. Atazanavir can be used concomitantly with the darunavir/ritonavir combination.

In an interaction study between darunavir/ritonavir (400 mg/100 mg twice daily) and indinavir (800 mg twice daily), plasma darunavir concentrations 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 used in combination with darunavir/ritonavir, the dose of indinavir in patients who do not tolerate it may be reduced from 800 mg twice daily to 600 mg twice daily.

The interaction between the darunavir/ritonavir combination and protease inhibitors other than lopinavir, saquinavir, atazanavir and indinavir has not been studied to date, and therefore protease inhibitors not listed here are not recommended for concomitant use with the darunavir/ritonavir combination.

When using the darunavir/ritonavir combination simultaneously, maraviroc should be prescribed at a dose of 150 mg 2 times a day. In an interaction study between darunavir/ritonavir (600 mg/100 mg twice daily) and maraviroc (150 mg twice daily), maraviroc concentrations increased to 305%. There was no effect of maraviroc on darunavir/ritonavir concentrations.

The combination of darunavir/ritonavir may increase plasma concentrations of bepridil, lidocaine (when administered systemically), quinidine and amiodarone, flecainide and propafenone. Therefore, when using the combination of darunavir/ritonavir and the listed antiarrhythmics, caution is required and, if possible, monitoring of their concentrations in blood plasma.

All studies of the interaction of the combination of darunavir/ritonavir (600/100 mg 2 times / day) and digoxin in a single dose (400 μg) showed an increase in the final plasma concentration of digoxin by 77%. It is recommended to initially prescribe the minimum dose of digoxin and determine its serum concentration to obtain the desired clinical effect when administered simultaneously with this combination.

The combination of darunavir/ritonavir may affect plasma concentrations of warfarin. If warfarin is used concomitantly with this combination, INR monitoring is recommended.

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

A study of the interaction between the combination of darunavir/ritonavir (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 increases by 45%. No dose change is required for the darunavir/ritonavir combination. If simultaneous use of the combination of darunavir/ritonavir and carbamazepine is necessary, patients’ condition should be monitored due to the possibility of developing side effects of carbamazepine. Plasma concentrations of carbamazepine should be monitored and the dose adjusted according to clinical manifestations. Thus, carbamazepine doses can be reduced by 25-50% when co-administered with the darunavir/ritonavir combination.

With simultaneous use of the combination of darunavir/ritonavir with trazodone and desipramine, an increase in the concentration of trazodone and desipramine in plasma is possible. This may cause side effects such as nausea, dizziness, hypotension, and fainting. If it is necessary to use these drugs together with the darunavir/ritonavir combination, caution is required and the use of trazodone and desipramine in lower doses should be considered, especially in the case of long-term therapy.

Concomitant use of the darunavir/ritonavir combination with parenterally administered midazolam may lead to an increase in plasma midazolam concentrations. If coadministration is necessary, use close clinical monitoring and prompt action should be taken if respiratory depression or prolonged sedation occurs. A dose reduction of midazolam should be considered, especially in the case of long-term therapy.

The use of darunavir/ritonavir combination with oral midazolam is contraindicated.

When antipsychotics are co-administered with the darunavir/ritonavir combination, their plasma concentrations may increase. Therefore, when used simultaneously, the doses of antipsychotic drugs (neuroleptics) should be reduced.

Plasma concentrations of calcium channel blockers (e.g. felodipine, nifedipine, nicardipine) may be increased when co-administered with darunavir/ritonavir. In such situations, it is necessary to closely monitor the condition of patients.

An interaction study between the combination of darunavir/ritonavir (400 mg/100 mg 2 times a day) and clarithromycin (500 mg 2 times a day) showed that the plasma concentration of clarithromycin 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, when released into the bloodstream, induces the CYP3A4 isoenzyme in the liver and, therefore, reduces plasma concentrations of darunavir. This may lead to a decrease in the therapeutic effect of darunavir. Caution is recommended during concomitant use of dexamethasone and darunavir.

With simultaneous use of inhaled fluticasone propionate and the combination of darunavir/ritonavir, it is possible to increase the concentration of fluticasone propionate in the blood plasma. Similar interactions may occur with other corticosteroids metabolized by CYP3A4, such as budesonide. It is advisable to use alternative drugs to fluticasone propionate that are not CYP3A4 substrates (for example, beclomethasone).

The CYP3A4 isoenzyme plays a major role in the metabolism of statins such as simvastatin, rosuvastatin and lovastatin, so their plasma concentrations may increase significantly when used simultaneously with the darunavir/ritonavir combination. It is not recommended to use the darunavir/ritonavir combination concomitantly with lovastatin, rosuvastatin or simvastatin due to an increased risk of myopathy, including rhabdomyolysis.

An interaction study between atorvastatin (10 mg 1 time / day) and the combination of darunavir / ritonavir (300 mg / 100 mg 2 times / day) showed that in this situation the plasma concentration of atorvastatin was only 15% lower than with atorvastatin monotherapy (40 mg 1 time / day). If simultaneous use of atorvastatin and the darunavir/ritonavir combination is necessary, it is recommended to start with a 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 twice daily) increased plasma pravastatin concentrations after a single dose of this drug (40 mg) by approximately 80%, but only in some patients. If it is necessary to co-prescribe pravastatin and the darunavir/ritonavir combination, it is recommended to start taking pravastatin with the lowest possible doses and increase the dose until a clinical effect appears, monitoring the manifestation of side effects of the drug.

The use of omeprazole (20 mg 1 time / day) or ranitidine (150 mg 2 times / day) simultaneously with the combination of darunavir / ritonavir (400 mg / 100 mg 2 times / day) did not affect the concentration of darunavir in plasma. Given this, the combination of darunavir/ritonavir can be used concomitantly with histamine H2 receptor antagonists and proton pump inhibitors without changing the dose of either drug.

Plasma concentrations 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 plasma concentrations of the immunosuppressant.

Ketoconazole, itraconazole and voriconazole are strong inhibitors of the CYP3A4 isoenzyme, as well as its substrates. Systemic use of ketoconazole, itraconazole and voriconazole concomitantly with the darunavir/ritonavir combination may result in increased darunavir plasma concentrations. On the other hand, this combination may increase plasma concentrations of ketoconazole or itraconazole. This was confirmed by an interaction study between ketoconazole (200 mg twice daily) and the darunavir/ritonavir combination (400 mg/100 mg twice daily), in which the concentrations of ketoconazole and darunavir increased by 212% and 42%, respectively. If it is necessary to use the combination of darunavir/ritonavir simultaneously with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg. Voriconazole plasma concentrations may be decreased when coadministered with darunavir/ritonavir. Voriconazole should not be used concomitantly with darunavir/ritonavir; concomitant use is only possible if the potential benefit of voriconazole outweighs the potential risk.

With simultaneous use of the darunavir/ritonavir combination with beta-blockers, an increase in the concentration of beta-blockers is possible. When these drugs are used concomitantly with the darunavir/ritonavir combination, caution and close clinical monitoring should be used, and a dose reduction of beta-blockers may also be required.

In a study of the effect of the combination of darunavir/ritonavir (600/100 mg 2 times/day) on stable methadone maintenance therapy, a 16% decrease in the plasma concentration of R-methadone was shown. Based on pharmacokinetic and clinical results, no dose adjustment of methadone is required during initiation of darunavir/ritonavir combination therapy. However, clinical monitoring is recommended because In some patients, maintenance therapy requires adjustment.

The results of a study of the interaction of the darunavir/ritonavir combination with buprenorphine/naloxone showed no effect of the darunavir/ritonavir combination on the concentration of buprenorphine when used together. The concentration of the active metabolite of buprenorphine, norbuprenorphine, increased by 46%. No buprenorphine dose adjustment was required. Close clinical monitoring is recommended when darunavir/ritonavir and buprenorphine are co-administered.

The results of an interaction study between the combination of darunavir/ritonavir (600/100 mg 2 times/day) and ethinyl estradiol and norethisterone indicate that plasma Css of ethinyl estradiol 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.

One study examined the concentrations of sildenafil after taking a single dose of 100 mg, as well as after taking 25 mg of sildenafil simultaneously with the combination of darunavir/ritonavir (400 mg/100 mg 2 times a day). Sildenafil concentrations were similar in both situations. Caution is required when using PDE5 inhibitors and the combination of darunavir/ritonavir simultaneously. If it is necessary to use a combination of darunavir/ritonavir simultaneously with sildenafil, vardenafil or tadalafil, a single dose of sildenafil should not exceed 25 mg over 48 hours, a single dose of vardenafil should not exceed 2.5 mg over 72 hours, and a single dose of tadalafil should not exceed 10 mg over 72 hours.

Rifabutin is an inducer and substrate of CYP450 isoenzymes. When studying the interaction of the combination darunavir/ritonavir (600/100 mg 2 times/day) and rifabutin (150 mg every other day), an increase in darunavir concentration by 57% was observed. Based on the safety profile of the darunavir/ritonavir combination, increased concentrations of darunavir in the presence of rifabutin do not require dose adjustment for the darunavir/ritonavir combination. An interaction study showed comparable concentrations when using rifabutin at a dose of 300 mg 1 time / day and 150 mg every other day in combination with the darunavir / ritonavir combination (600/100 mg 2 times / day), as well as an increase in the concentration of the active metabolite 25-O-desacetylrifabutin. When using this combination, a reduction in the dose of rifabutin by 75% from the usual dose of 300 mg / day is required and increased monitoring of the side effects of rifabutin.

An interaction study between paroxetine (20 mg 1 time/day) or sertraline (50 mg 1 time/day) and the darunavir/ritonavir combination (400 mg/100 mg 2 times/day) showed that darunavir plasma concentrations were not affected by the presence of sertraline 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 simultaneous use with the darunavir/ritonavir combination is necessary, it is necessary to carefully select the dose of selective serotonin reuptake inhibitors, based on a clinical assessment of the antidepressant effect. In addition, in patients receiving a stable dose of sertraline or paroxetine who are initiated on the darunavir/ritonavir combination, the severity of the main antidepressant effect should be closely monitored.

Manufacturer

Makis-Pharma, Russia