Prezista^® (Tablets) Instructions for Use

ATC Code

J05AE10 (Darunavir)

Active Substance

Darunavir (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

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

Darunavir binds strongly to HIV-1 protease (K_D 4.5×10^-12M). Darunavir is resistant to mutations that cause resistance to protease inhibitors.

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

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 HIV-1 infected patients than in healthy individuals. This difference can be explained by higher concentrations of α₁-acid glycoprotein in HIV-1 infected patients. Consequently, larger amounts of darunavir bind to plasma α₁-acid glycoprotein.

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

Absorption

After oral administration, Darunavir is rapidly absorbed from the gastrointestinal tract. C_max of darunavir in plasma in the presence of a low dose of ritonavir is achieved in 2.5-4.0 hours. The absolute bioavailability of darunavir after a single oral dose of 600 mg was about 37% and increased to approximately 82% in the presence of ritonavir (100 mg twice daily). The overall pharmacokinetic effect of ritonavir was an approximately 14-fold increase in the plasma concentration of darunavir after a single oral dose of 600 mg darunavir in combination with ritonavir (100 mg twice daily). When taken on an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir was 30% lower than when taken with food. Therefore, Prezista^® tablets should be taken together with ritonavir during a meal. The type of food did not affect darunavir plasma concentrations.

Distribution

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

Metabolism

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 showed that the majority of radioactivity in plasma after a single dose of 400 mg darunavir and 100 mg ritonavir was attributable to unchanged darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; their activity against the wild-type HIV was less than 1/10 of the activity of darunavir itself.

Excretion

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 approximately 41.2% and 7.7% of the radioactivity in feces and urine, respectively.

The terminal T_1/2 of darunavir was about 15 hours when taken in combination with ritonavir. The clearance of darunavir after intravenous administration of a 150 mg dose 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

A population pharmacokinetic analysis in HIV-infected patients demonstrated no significant differences in darunavir pharmacokinetic parameters in the age group of 18-75 years. This analysis included 12 HIV-infected patients aged 65 years and older.

Population pharmacokinetic analysis revealed slightly higher (16.8%) concentrations of darunavir in HIV-infected women compared to HIV-infected men. This difference is not clinically significant.

Results from a study using ¹⁴C-darunavir in combination with ritonavir showed that approximately 7.7% of the administered darunavir dose was excreted unchanged in the urine. The pharmacokinetics of darunavir have not been studied in patients with renal impairment, but population pharmacokinetic analysis demonstrated no significant change in darunavir pharmacokinetic parameters in patients with moderate renal impairment (CrCl 30-60 ml/min, n = 20).

Darunavir is metabolized and excreted primarily by the liver. Studies in patients with hepatic impairment have not been conducted. In a study using Prezista^® in multiple doses in combination with ritonavir (600/100 mg) twice daily, it was shown that the steady-state pharmacokinetic parameters of darunavir in patients with mild (Child-Pugh class A, n=8) and moderate hepatic impairment (Child-Pugh class B, n=8) were comparable to those in healthy individuals. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied.

Indications

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

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. Prezista^® should always be prescribed in combination with low-dose ritonavir as a pharmacokinetic enhancer, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before starting therapy with the Prezista^®/ritonavir combination.

Patients should not modify or discontinue therapy without consulting their physician.

For patients previously treated with protease inhibitors, genotypic testing is recommended.

However, if genotypic testing is not possible, it is recommended that patients not previously treated with protease inhibitors take the Prezista^®/ritonavir 800 mg/100 mg once daily combination, and patients previously treated with protease inhibitors are recommended to take the Prezista^®/ritonavir 600 mg/100 mg twice daily combination.

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

In patients with mild or moderate hepatic impairment, no dose adjustment is required. There are no data on the use of the combined therapy with Prezista^®/ritonavir in severe hepatic impairment, so specific dosing recommendations cannot be made. The Prezista^®/ritonavir combination should be used with caution in patients with severe hepatic impairment.

In patients with renal impairment, no dose changes are required for the Prezista^®/ritonavir combination.

Adverse Reactions

Most side effects are moderate in severity. The most common moderate or severe (grades 2-4) side effects (≥ 5%) are diarrhea, headache, and abdominal pain. The most common severe (grades 3-4) side effects (≥1%) are changes in blood laboratory parameters. Other grade 3-4 side effects were observed in less than 1% of patients.

2.3% of patients discontinued therapy due to the occurrence of side effects.

Data on grade 2-4 side effects in adult patients not previously treated with antiretroviral therapy when using the Prezista^®/ritonavir 800/100 mg once daily combination are presented in Table 1, compared with the use of the lopinavir/ritonavir 800/200 mg once daily combination.

Table 1.

* Identified during post-marketing surveillance

Changes in laboratory parameters of grade 2-4 in patients not previously treated with antiretroviral therapy when using the Prezista^®/ritonavir 800/100 mg once daily combination are presented in Table 2.

Table 2.

Data on grade 2-4 side effects in adult patients previously treated with antiretroviral therapy when using the Prezista^®/ritonavir 600/100 mg twice daily combination are presented in Table 3, compared with the use of the lopinavir/ritonavir 400/100 mg twice daily combination.

Table 3.

* Identified during post-marketing surveillance

Changes in laboratory parameters of grade 2-4 in patients previously treated with antiretroviral therapy when using the Prezista^®/ritonavir 600/100 mg once daily combination are presented in Table 4.

Table 4.

Adverse Effects During Combined Antiretroviral Therapy

Dermatological Reactions Redistribution of body fat (lipodystrophy) may occur. This redistribution includes loss of peripheral and facial subcutaneous adipose tissue, increase in intra-abdominal and visceral fat, breast hypertrophy, and fat accumulation in the dorsocervical area (buffalo hump formation).

Metabolic Side Effects Hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia.

Musculoskeletal System Side Effects In patients receiving protease inhibitors, especially in combination with non-nucleoside reverse transcriptase inhibitors, increased CPK levels, myositis; rarely – rhabdomyolysis may occur.

Infections In HIV-infected patients with severe immunodeficiency during initial combined antiretroviral therapy, inflammatory reactions to asymptomatic or residual opportunistic infections may occur.

HIV-Infected Patients with Co-infection with Hepatitis B Virus and/or Hepatitis C Virus

In HIV-infected patients with co-infection with hepatitis B virus and/or hepatitis C virus, treatment with the Prezista^®/ritonavir combination was not associated with a higher frequency of adverse effects and changes in laboratory parameters (compared to HIV-infected patients without hepatitis B and/or C virus infection). The pharmacokinetics of darunavir and ritonavir in polyinfected patients were similar to those in patients with HIV mono-infection, except for increased liver enzyme levels.

Contraindications

• Concomitant use with drugs whose clearance is primarily determined by the CYP3A4 isoenzyme, and an increase in their plasma concentration is associated with the occurrence of serious and/or life-threatening adverse effects (narrow therapeutic index) – with astemizole, alfuzosin, sildenafil (used for the treatment of pulmonary hypertension), terfenadine, midazolam, rifampicin, triazolam, cisapride, pimozide, preparations containing St. John’s wort extract (Hypericum perforatum), preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine, and methylergometrine);
• Children and adolescents under 18 years of age (for this dosage form);
• Hypersensitivity to the components of the drug.

Use with caution in patients with impaired liver function, in case of allergy to sulfonamides.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of darunavir use during pregnancy have not been conducted.

The combination of Prezista^®/ritonavir 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 in human breast milk. Given the possibility of HIV transmission through breast milk, as well as the risk of serious adverse effects in infants associated with exposure to darunavir, HIV-infected women receiving Prezista^® should refrain from breastfeeding.

In experimental animal studies, no toxic activity of darunavir or its negative impact on reproductive function and fertility was detected. It has been shown that Darunavir is excreted in the breast milk of lactating rats.

Use in Hepatic Impairment

Currently, there are no data on the use of the Prezista^®/ritonavir combination in patients with impaired liver function, therefore specific recommendations on the dosing regimen for this category of patients have not been established. This combination should be used with caution.

Use in Renal Impairment

In patients with impaired renal function, no dose adjustment of the Prezista^®/ritonavir combination is required.

Pediatric Use

^{The drug is contraindicated in children under 18 years of age.}

Special Precautions

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

Information on the treatment of patients aged 65 years and older with the Prezista^®/ritonavir combination is very limited. Caution is required when treating patients in this age group with Prezista^®, as they more often have liver dysfunction, more often suffer from concomitant diseases, or receive concomitant therapy.

The 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 twice daily. The overall effect of ritonavir’s improvement of darunavir’s pharmacokinetic characteristics resulted in an approximately 14-fold increase in darunavir plasma concentration after taking a single dose of this drug (600 mg) in combination with 100 mg ritonavir twice daily. Therefore, Prezista^® must be taken only in combination with a low dose of ritonavir as a pharmacokinetic enhancer.

Increasing the specified dose of ritonavir does not lead to a significant increase in darunavir plasma concentration, and therefore the ritonavir dose is not recommended to be increased.

Prezista^® tablets contain the yellow dye “sunset yellow” (E110) and therefore may cause allergic reactions.

In 0.4% of patients taking Prezista^®, severe skin reactions were recorded, which may be accompanied by fever and/or increased liver transaminase levels. Stevens-Johnson syndrome was rarely reported (<0.1%). In the post-marketing period, toxic epidermal necrolysis was very rarely reported (<0.01%). If signs or symptoms of severe skin reactions occur (severe rash or rash accompanied by fever, general malaise, muscle or joint pain, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia), Prezista^® should be discontinued immediately.

Rash (all types) was observed in 10.3% of patients receiving Prezista^®. The rash was mostly mild or moderate and often occurred within the first 4 weeks of treatment and decreased with continued therapy. In 0.5% of cases, rash was the reason for discontinuation of the Prezista^®/ritonavir combination.

Rash was observed more frequently in patients taking raltegravir and the Prezista^®/ritonavir combination simultaneously compared to patients receiving raltegravir and the Prezista^®/ritonavir combination separately. Rash, the occurrence of which was associated with drug intake, was observed with the same frequency in all 3 groups. The rash was mild or moderate in severity and did not limit therapy. Rash was not the reason for therapy discontinuation.

Darunavir contains a sulfonamide group. In patients with allergy to sulfonamides, Prezista^® should be used with caution. In clinical studies of the Prezista^®/ritonavir combination, the degree and frequency of rash occurrence were the same in patients with and without a history of sulfonamide allergy.

Data on the use of the Prezista^®/ritonavir combination in patients with severe hepatic impairment are lacking; therefore, it is not possible to provide specific dosing recommendations. The Prezista^®/ritonavir combination should be used with caution in patients with severe hepatic impairment. Based on data showing that stable pharmacokinetic parameters for darunavir in individuals with mild to moderate hepatic impairment are comparable to those in healthy individuals, no dose adjustment is required for patients with mild to moderate hepatic impairment.

During the use of the Prezista^®/ritonavir combination, drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) is observed. Hepatitis was observed in 0.5% of patients receiving combined Prezista^®/ritonavir therapy. Patients with impaired liver function, including chronic active hepatitis B or C, have an increased risk of developing severe liver adverse effects.

Monitoring of relevant laboratory parameters should be performed before prescribing combined Prezista^®/ritonavir therapy and during treatment. Consideration should be given to monitoring increases in AST/ALT activity in patients with chronic hepatitis, cirrhosis, or in patients who had elevated transaminase activity prior to initiation of therapy and, especially, during the first few months of combined Prezista^®/ritonavir therapy. If impaired liver function or worsening of its severity is detected (including clinically significant increases in liver enzyme activity and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly), the possibility of interrupting or discontinuing therapy with the Prezista^®/ritonavir combination should be considered.

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

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. Some of these patients received factor VIII. In more than half of the described cases, treatment with protease inhibitors was continued without interruption or resumed after a temporary suspension. A causal relationship between treatment with protease inhibitors and increased bleeding in patients with hemophilia has been suggested, but the mechanism of such a relationship has not been established. Hemophilia patients receiving the Prezista^®/ritonavir combination should be informed about the possibility of increased bleeding.

Newly diagnosed cases of diabetes mellitus, hyperglycemia, or worsening of pre-existing diabetes have been described in patients receiving antiretroviral therapy, including protease inhibitors. In some of these patients, hyperglycemia was severe and in some cases accompanied by ketoacidosis. Many patients had concomitant conditions, some of which required treatment with drugs that can cause diabetes or hyperglycemia.

Combined antiretroviral therapy may cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. Currently, there are no data on the long-term consequences of this phenomenon, and its mechanism is largely unclear. A hypothesis has been put forward about a link between visceral lipomatosis and protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors. An increased risk of lipodystrophy is associated with factors such as older age, as well as long-term antiretroviral therapy and its associated metabolic disorders. During clinical examinations of HIV-infected patients receiving antiretroviral drugs, attention should be paid to physical signs of fat redistribution. It is recommended to determine fasting blood lipid and glucose levels. Lipid metabolism disorders should be treated with appropriate drugs.

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency at the start of combined antiretroviral therapy, an inflammatory response of the body to asymptomatic or residual opportunistic infections may occur, which causes serious clinical complications or worsening of symptoms. Such reactions are usually observed in the first weeks or months of combined antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. The severity of any inflammatory symptoms should be assessed and appropriate therapy administered.

Overdose

Data on acute overdose with Prezista^® in combination with ritonavir in humans are limited. Healthy volunteers took single doses of up to 3200 mg of darunavir as a solution and up to 1600 mg as Prezista^® tablets in combination with ritonavir, with no adverse effects noted.

Treatment No specific antidote is known. In case of overdose, general supportive therapy with monitoring of vital physiological parameters should be carried out. Gastric lavage or cleansing enema is indicated to remove unabsorbed drug. Activated charcoal can be used. Darunavir is highly bound to plasma proteins, so it is not removed in significant quantities by dialysis.

Drug Interactions

Darunavir and ritonavir are inhibitors of the CYP3A isoenzyme. Concomitant use of the Prezista^®/ritonavir combination and drugs that are metabolized primarily by the CYP3A isoenzyme may cause an increase in the plasma concentrations of such drugs, which, in turn, may be the cause of increased or prolonged therapeutic effect, as well as adverse effects.

The Prezista^®/ritonavir combination should not be used concomitantly with drugs whose clearance is largely determined by the CYP3A4 isoenzyme and increased plasma concentrations of which may cause serious and/or life-threatening adverse effects (narrow therapeutic index). Such drugs include astemizole, alfuzosin, sildenafil (used for the treatment of pulmonary arterial hypertension), terfenadine, midazolam, triazolam, cisapride, pimozide, and ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergometrine, and methylergometrine).

Rifampicin is a strong inducer of CYP450 isoenzymes. The Prezista^®/ritonavir combination should not be used concomitantly with rifampicin, as in such cases a significant decrease in darunavir plasma concentration is possible. As a result, loss of therapeutic effect of Prezista^® is possible.

The Prezista^®/ritonavir combination should not be used concomitantly with preparations containing St. John’s wort extract (Hypericum perforatum), as this may be accompanied by a significant decrease in darunavir plasma concentration, as a result of which the therapeutic effect of Prezista^® may disappear.

Concomitant Use with Other Antiretroviral Drugs

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Didanosine. The Prezista^®/ritonavir combination (600/100 mg twice daily) can be used concomitantly with didanosine without dose adjustment. Since didanosine is recommended to be taken on an empty stomach, it can be taken 1 hour before or 2 hours after taking the Prezista^®/ritonavir combination, which is taken with food.

Tenofovir. The results of an interaction study between tenofovir (tenofovir disoproxil fumarate – 300 mg/day) and the Darunavir/ritonavir combination (300 mg/100 mg twice daily) showed that the plasma concentration of tenofovir increased by 22%. This change is not clinically significant. With concomitant use of tenofovir and darunavir, the renal excretion of both drugs did not change. Tenofovir did not have a clinically significant effect on darunavir plasma concentration. No dose adjustment is required when using the Prezista^®/ritonavir combination and tenofovir concomitantly.

Other Nucleoside Reverse Transcriptase Inhibitors (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine, and abacavir) are excreted primarily by the kidneys, so the likelihood of their interaction with the Darunavir/ritonavir combination is negligible.

Non-Nucleoside Reverse Transcriptase Inhibitors

Etravirine. In a study of the interaction between the Prezista^®/ritonavir combination (600/100 mg twice daily) and etravirine, a 37% decrease in etravirine concentration was found and no significant changes in darunavir concentration were detected. However, the Prezista^®/ritonavir combination can be prescribed concomitantly with etravirine at a dose of 200 mg twice daily without changing the dose.

Efavirenz. An interaction study was conducted between the Darunavir/ritonavir combination (300 mg/100 mg twice daily) and efavirenz (600 mg once daily). In the presence of efavirenz, a 13% decrease in darunavir plasma concentration was observed. On the other hand, the plasma concentration of efavirenz increased by 21% when used concomitantly with the Darunavir/ritonavir combination. This interaction is not clinically significant, so Prezista^®/ritonavir and efavirenz can be used concomitantly without dose adjustment of the drugs.

Nevirapine. The results of an interaction study between the Darunavir/ritonavir combination (400 mg/100 mg twice daily) and nevirapine (200 mg twice daily) showed that darunavir plasma concentrations were independent of the presence of nevirapine. However, with concomitant use with the Darunavir/ritonavir combination, nevirapine plasma concentrations increased by 27% (compared to control). This interaction is considered clinically insignificant, so the Darunavir/ritonavir combination and nevirapine can be used concomitantly without changing their doses.

Rilpivirine. The results of an interaction study between the Prezista^®/ritonavir combination (800 mg/100 mg once daily) with rilpivirine (150 mg once daily) did not show a clinically significant effect on darunavir concentration. The concentration of rilpivirine increased by 130% with concomitant use of the Prezista^®/ritonavir combination. This interaction is considered clinically insignificant, and therefore the Prezista^®/ritonavir combination and rilpivirine can be used concomitantly without changing their doses.

Protease Inhibitors

Ritonavir. Overall, the effect of ritonavir’s optimization of darunavir’s pharmacokinetics resulted in darunavir plasma concentrations increasing approximately 14-fold after taking a single dose of darunavir (600 mg) and 100 mg ritonavir twice daily. Therefore, Prezista^® must be used in combination with 100 mg ritonavir to improve the pharmacokinetic characteristics of darunavir.

Lopinavir/ritonavir combination. The results of an interaction study between the Darunavir/ritonavir combination (1200 mg/100 mg twice daily) or 1200 mg darunavir without ritonavir and the lopinavir/ritonavir combination (400 mg/100 mg twice daily or 533/133.3 mg twice daily) showed that in the presence of the lopinavir/ritonavir combination, darunavir plasma concentration decreased by 40%. It is not recommended to use the lopinavir/ritonavir combination concomitantly with the Prezista^®/ritonavir combination.

Saquinavir. A drug interaction study of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily), and ritonavir (100 mg twice daily) showed that the plasma concentration of darunavir increased by 26% in the presence of saquinavir and ritonavir; on the other hand, the Darunavir/ritonavir combination did not affect the plasma concentration of saquinavir. Concomitant use of saquinavir with Prezista^® is not recommended, regardless of the use of a low additional dose of ritonavir.

Atazanavir. A drug interaction study between the Darunavir/ritonavir combination (400 mg/100 mg twice daily) and atazanavir (300 mg once daily) showed no significant change in the plasma concentrations of darunavir and atazanavir when used concomitantly. Atazanavir can be used concomitantly with the Darunavir/ritonavir combination.

Indinavir. In a drug interaction study between the Darunavir/ritonavir combination (400 mg/100 mg twice daily) and indinavir (800 mg twice daily), the plasma concentration of darunavir increased by 24% in the presence of indinavir and ritonavir. In the presence of the Darunavir/ritonavir combination, the plasma concentration of indinavir increased by 23%. When used in combination with Prezista^®/ritonavir, the dose of indinavir in patients who poorly tolerate it can be reduced from 800 mg twice daily to 600 mg twice daily.

Other Protease Inhibitors

To date, the interaction between the Prezista^®/ritonavir combination and protease inhibitors other than lopinavir, saquinavir, atazanavir, and indinavir has not been studied, and therefore, protease inhibitors not listed here are not recommended for concomitant use with the Darunavir/ritonavir combination.

CCR5 Receptor Antagonists

When the Prezista^®/ritonavir combination is used concomitantly, maraviroc should be administered at a dose of 150 mg twice daily. In a drug interaction study between the Darunavir/ritonavir combination (600 mg/100 mg twice daily) and maraviroc (150 mg twice daily), the maraviroc concentration increased by 305%. No effect of maraviroc on the darunavir/ritonavir concentration was noted.

Concomitant Use with Other Drugs

Antiarrhythmic Agents (bepridil, systemic lidocaine, quinidine, amiodarone, flecainide, propafenone)

The Prezista^®/ritonavir combination may increase the plasma concentrations of bepridil, lidocaine, quinidine, amiodarone, flecainide, and propafenone. Therefore, caution is required when using the Prezista^®/ritonavir combination concomitantly with the listed antiarrhythmics, and, if possible, monitoring of their plasma concentrations is recommended.

Digoxin

In all drug interaction studies of the Prezista^®/ritonavir combination (600/100 mg twice daily) and a single dose of digoxin (400 mcg), an increase in the terminal plasma concentration of digoxin by 77% was shown. It is recommended to initially prescribe the minimum dose of digoxin and determine its serum concentration to achieve the desired clinical effect when co-administered with the Prezista^®/ritonavir combination.

Anticoagulants

The Prezista^®/ritonavir combination may affect the plasma concentrations of warfarin. When warfarin and this combination are used concomitantly, monitoring of INR is recommended.

Anticonvulsants (phenobarbital, phenytoin, and carbamazepine)

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

A drug interaction study between the Prezista^®/ritonavir combination (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the concentration of darunavir did not change in this case, while the concentration of ritonavir decreased by 49%. The concentration of carbamazepine increased by 45%. No dose adjustment for Prezista^®/ritonavir is required. If concomitant administration of Prezista^®/ritonavir and carbamazepine is necessary, patients should be monitored for the possibility of developing carbamazepine side effects. The plasma concentration of carbamazepine should be monitored and its dose adjusted according to clinical manifestations. Thus, carbamazepine doses may be reduced by 25-50% when co-administered with the Prezista^®/ritonavir combination.

Antidepressants (trazodone, desipramine)

When the Prezista^®/ritonavir combination is used concomitantly with trazodone and desipramine, an increase in the plasma concentrations of trazodone and desipramine is possible. This may cause side effects such as nausea, dizziness, arterial hypotension, and fainting. If concomitant use of these drugs and the Prezista^®/ritonavir combination is necessary, caution is required, and consideration should be given to using trazodone and desipramine at lower doses.

Benzodiazepines (parenteral midazolam)

Concomitant use of the Prezista^®/ritonavir combination with parenterally administered midazolam may lead to an increase in the plasma concentration of midazolam. With concomitant use, careful clinical monitoring should be conducted and urgent measures taken in case of respiratory depression or prolonged sedative effect. Consideration should be given to reducing the dose of midazolam, especially in the case of long-term therapy.

Use of the Prezista^®/ritonavir combination with oral midazolam is contraindicated.

Antipsychotic Drugs (risperidone, thioridazine)

When antipsychotics are used concomitantly with the Prezista^®/ritonavir combination, their plasma concentrations may increase. Therefore, when used concomitantly, the doses of antipsychotic drugs should be reduced.

Antimalarial Drugs

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

Colchicine

When colchicine is used concomitantly with the Prezista^®/ritonavir combination, an increase in the plasma concentration of colchicine is possible. The following colchicine dose modification scheme is recommended. For the treatment of gout flares in patients receiving the Prezista^®/ritonavir combination, the recommended dose of colchicine is 0.6 mg, followed by 0.3 mg after 1 hour. The treatment course should be repeated no sooner than 3 days later. For prophylaxis of flares in patients receiving the Prezista^®/ritonavir combination, the recommended dose of colchicine is 0.3 mg every day or every other day. For the treatment of familial Mediterranean fever in patients receiving the Prezista^®/ritonavir combination, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg twice daily).

Patients with impaired renal or hepatic function should not be prescribed colchicine when used concomitantly with the Prezista^®/ritonavir combination.

Calcium Channel Blockers

The plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when used concomitantly with the Prezista^®/ritonavir combination. In such situations, it is necessary to carefully monitor the patient’s condition.

Clarithromycin

A drug interaction study between the Darunavir/ritonavir combination (400 mg/100 mg twice daily) and clarithromycin (500 mg twice daily) showed that the plasma concentration of clarithromycin increased by 57%, while the concentration of darunavir remained unchanged. In patients with renal impairment, a dose reduction of clarithromycin is recommended.

Dexamethasone

Dexamethasone, upon entering the bloodstream, induces the CYP3A4 isoenzyme in the liver and, consequently, reduces the plasma concentrations of darunavir. This may lead to a decrease in the therapeutic effect of darunavir. Caution is recommended when using dexamethasone and darunavir concomitantly.

Bosentan

When bosentan and the Prezista^®/ritonavir combination are used concomitantly, the plasma concentration of bosentan may increase. For patients receiving the Prezista^®/ritonavir combination for at least 10 days, the initial dose of bosentan is recommended to be 62.5 mg daily or every other day depending on individual tolerance. For patients receiving bosentan, when the Prezista^®/ritonavir combination is prescribed, it is recommended to discontinue bosentan at least 36 hours before starting therapy with the Prezista^®/ritonavir combination. At least 10 days after starting therapy with the Prezista^®/ritonavir combination, bosentan should be resumed at a dose of 62.5 mg daily or every other day depending on individual tolerance.

Fluticasone Propionate, Budesonide

Concomitant use of inhaled fluticasone propionate and the Prezista^®/ritonavir combination may lead to an increase in the plasma concentration of fluticasone propionate. A similar interaction may be observed with the use of other corticosteroids metabolized by the CYP3A4 isoenzyme, such as budesonide. It is advisable to use drugs alternative to fluticasone propionate that are not a substrate of CYP3A4 (e.g., beclomethasone).

Direct-Acting Antiviral Drugs. Hepatitis C NS3-4A Protease Inhibitors

Boceprevir. In a drug interaction study between the Prezista^®/ritonavir combination (600/100 mg twice daily) and boceprevir (800 mg three times a day), the exposure to darunavir decreased by 44%, and the exposure to boceprevir decreased by 32%. Thus, it is not recommended to use the Prezista^®/ritonavir combination together with boceprevir.

Telaprevir. In drug interaction studies between the Prezista^®/ritonavir combination (600 mg/100 mg twice daily) and telaprevir (750 mg every 8 hours), the exposure to darunavir was reduced by 40%, and the exposure to telaprevir was reduced by 35%. Concomitant administration of the Prezista^®/ritonavir combination with telaprevir is not recommended.

Drugs from the Statin Group

The CYP3A4 isoenzyme plays a major role in the metabolism of statins such as simvastatin, rosuvastatin, and lovastatin; therefore, their plasma concentrations may significantly increase when used concomitantly with the Prezista^®/ritonavir combination. Statins at elevated concentrations can cause myopathy, including rhabdomyolysis. Therefore, it is not recommended to use the Prezista^®/ritonavir combination concomitantly with lovastatin, rosuvastatin, or simvastatin.

A drug interaction study between atorvastatin (10 mg once daily) and the Darunavir/ritonavir combination (300 mg/100 mg twice daily) showed that in this situation, the plasma concentration of atorvastatin was only 15% lower than with atorvastatin monotherapy (40 mg once daily). If concomitant use of atorvastatin and the Darunavir/ritonavir combination is necessary, it is recommended to start with an atorvastatin dose of 10 mg once daily. The atorvastatin dose can then be gradually increased, guided by the clinical effect of therapy.

The Darunavir/ritonavir combination (600 mg/100 mg twice daily) increased the plasma concentration of pravastatin after a single dose of this drug (40 mg) by approximately 80%, but only in some patients. If concomitant administration of pravastatin and the Prezista^®/ritonavir combination is necessary, it is recommended to start pravastatin at the minimum possible doses and increase the doses until a clinical effect appears, monitoring for the manifestation of the drug’s side effects.

A drug interaction study between the Prezista^®/ritonavir combination (600 mg/100 mg) with rosuvastatin (10 mg) revealed an increase in the concentration of rosuvastatin. If concomitant use of rosuvastatin and the Prezista^®/ritonavir combination is necessary, it is recommended to start with the lowest dose of rosuvastatin, gradually increasing the dose to achieve a clinical effect, constantly monitoring the safety of therapy.

Histamine H₂-Receptor Blockers and Proton Pump Inhibitors

Use of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) concomitantly with the Darunavir/ritonavir combination (400 mg/100 mg twice daily) did not affect the plasma concentration of darunavir. Given this, the Prezista^®/ritonavir combination can be used concomitantly with histamine H₂-receptor blockers and proton pump inhibitors without changing the dose of any of the specified drugs.

Inhaled Beta-Adrenergic Agonists (salmeterol)

Concomitant use of salmeterol and the Prezista^®/ritonavir combination is not recommended, as it may increase the risk of salmeterol side effects from the cardiovascular system, including QT interval prolongation, palpitations, and sinus tachycardia.

Immunosuppressants (cyclosporine, tacrolimus, sirolimus)

The plasma concentrations of cyclosporine, tacrolimus, and sirolimus may increase if these drugs are used concomitantly with the Prezista^®/ritonavir combination. In these situations, it is recommended to monitor the plasma concentration of the immunosuppressant.

Ketoconazole, Itraconazole, and Voriconazole

Ketoconazole, itraconazole, and voriconazole are strong inhibitors of the CYP3A4 isoenzyme and are also its substrates. Systemic use of ketoconazole, itraconazole, and voriconazole concomitantly with the Prezista^®/ritonavir combination may lead to an increase in the plasma concentrations of darunavir. On the other hand, this combination may increase the plasma concentrations of ketoconazole or itraconazole. This was confirmed by a drug 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 concomitant use of the Darunavir/ritonavir combination with ketoconazole or itraconazole is necessary, the daily dose of the latter should not exceed 200 mg. Plasma concentrations of voriconazole may decrease when co-administered with darunavir/ritonavir. Voriconazole should not be used concomitantly with darunavir/ritonavir; concomitant use is possible only if the potential benefit from voriconazole use outweighs the potential risk.

Beta-Blockers (metoprolol, timolol)

When the Prezista^®/ritonavir combination is used concomitantly with beta-blockers, an increase in the concentration of beta-blockers is possible. When using the specified drugs and the Prezista^®/ritonavir combination concomitantly, caution should be exercised and careful clinical monitoring should be conducted; a reduction in the dose of beta-blockers may also be required.

Methadone

In a study of the effect of the Prezista^®/ritonavir combination (600/100 mg twice daily) on stable maintenance therapy with methadone, a 16% decrease in the plasma concentration of R-methadone was shown. Based on pharmacokinetic and clinical results, no methadone dose adjustment is required during the initiation of Prezista^®/ritonavir therapy. However, clinical monitoring is recommended, as maintenance therapy may require adjustment in some patients.

Buprenorphine/naloxone

The results of a drug interaction study of the Prezista^®/ritonavir combination with buprenorphine/naloxone demonstrated no effect of the Prezista^®/ritonavir combination on the concentration of buprenorphine when used concomitantly. The concentration of the active metabolite of buprenorphine – norbuprenorphine increased by 46%. No dose adjustment of buprenorphine was required. When the Prezista^®/ritonavir combination and buprenorphine are co-administered, careful clinical monitoring is recommended.

Estrogen-Containing Oral Contraceptives

The results of a drug interaction study between the Prezista^®/ritonavir combination (600/100 mg twice daily) and ethinyl estradiol and norethisterone indicate that the C_ss of ethinyl estradiol and norethisterone in plasma decreases by 44% and 14%, respectively. When using the Prezista^®/ritonavir combination, alternative non-hormonal methods of contraception are recommended.

PDE5 Inhibitors

For the treatment of erectile dysfunction. In one study, the concentrations of sildenafil after a single dose of this drug (100 mg), as well as after taking 25 mg of sildenafil concomitantly with the Darunavir/ritonavir combination (400 mg/100 mg twice daily), were studied. The concentrations of sildenafil were similar in both situations. Caution is required when using PDE5 inhibitors for the treatment of erectile dysfunction and the Prezista^®/ritonavir combination concomitantly. If it is necessary to use Prezista^® and ritonavir concomitantly with sildenafil, vardenafil, or tadalafil, the single dose of sildenafil should not exceed 25 mg within 48 hours, the single dose of vardenafil should not exceed 2.5 mg within 72 hours, and the single dose of tadalafil should not exceed 10 mg within 72 hours.

For the treatment of pulmonary arterial hypertension. A safe and effective dose of sildenafil for the treatment of pulmonary arterial hypertension has not been established. There is an increased risk of developing sildenafil side effects (including visual impairment, arterial hypotension, prolonged erection, and fainting). Thus, concomitant use of the Prezista^®/ritonavir combination and sildenafil for the treatment of pulmonary arterial hypertension is contraindicated. For the treatment of pulmonary arterial hypertension with tadalafil when used concomitantly with the Prezista^®/ritonavir combination, dose adjustments of tadalafil are required. For patients receiving the Prezista^®/ritonavir combination for at least 1 week, the initial dose of tadalafil should be 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerance. For patients receiving tadalafil and starting therapy with the Prezista^®/ritonavir combination, tadalafil should be discontinued at least 24 hours before starting therapy with the Prezista^®/ritonavir combination, and concomitant use of tadalafil should be avoided during the initiation of therapy with the Prezista^®/ritonavir combination. One week after starting therapy with the Prezista^®/ritonavir combination, tadalafil should be resumed at a dose of 20 mg once daily with a possible increase to 40 mg once daily based on individual tolerance.

Rifabutin

Rifabutin is an inducer and substrate of CYP450 isoenzymes. In a study of the interaction between the Prezista^®/ritonavir combination (600/100 mg twice daily) and rifabutin (150 mg every other day), an increase in the concentration of darunavir by 57% was observed. Based on the safety profile of the Prezista^®/ritonavir combination, the increase in darunavir concentration in the presence of rifabutin does not require a dose adjustment for the Prezista^®/ritonavir combination. The interaction study showed comparable concentrations when using rifabutin at a dose of 300 mg once daily and 150 mg every other day in combination with the Prezista^®/ritonavir combination (600/100 mg twice daily), as well as an increase in the concentration of the active metabolite 25-O-desacetylrifabutin. When prescribing such a combination, a reduction in the rifabutin dose by 75% of the usual dose of 300 mg/day is required, along with increased monitoring for rifabutin side effects.

Selective Serotonin Reuptake Inhibitors

A study of the interaction between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and the Prezista^®/ritonavir combination (400 mg/100 mg twice daily) showed that the plasma concentration of darunavir was not affected by the presence of sertraline or paroxetine.

On the other hand, in the presence of the Prezista^®/ritonavir combination, the plasma concentrations of sertraline and paroxetine decreased by 49% and 39%, respectively.

If concomitant use with the Prezista^®/ritonavir combination is necessary, the doses of selective serotonin reuptake inhibitors should be carefully adjusted based on clinical assessment of the antidepressant effect.

Furthermore, in patients receiving a stable dose of sertraline or paroxetine who are starting treatment with the Prezista^®/ritonavir combination, the degree of the primary antidepressant effect should be carefully monitored.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.